Pediatric Rehabilitation Principles and Practice 4th Edition

["282 Pediatric Rehabilitation with falls. Patients compensate for this by decreasing the forefoot as they reach the transitional phase of stance-phase knee flexion, and they posture the ankle ambulation before wheelchair reliance (see Fig. 12.7). increasingly over time into plantar flexion. This pro- Finally, weakness of the hip abductors produces a ten- duces a knee extension moment at foot contact and dency toward lateral pelvic tilt and pelvic drop of the plantarflexion of the ankle during mid- to late-stance swing phase side. Patients with proximal weakness phase of gait, which helps position the weight line\/ compensate for this by bending or lurching the trunk center of gravity anterior to the knee joint (thus pro- laterally over the stance-phase hip joint (Fig. 12.8). ducing a stabilizing knee extension moment). Patients This produces the so-called \u201cgluteus medius lurch\u201d or with DMD will progressively demonstrate toe walking Trendelenburg\u2019s gait pattern. with initial floor contact, with the foot contact increas- ingly moving forward onto the midfoot and finally Patients with distal weakness affecting the ankle dorsiflexors and ankle everters and less severe proximal AB CD Figure 12.5 (A\u2013F) Gower\u2019s sign in a seven-year-old boy with Duchenne muscular dystrophy due to hip extension weakness.","Chapter 12 Neuromuscular Diseases 283 E F Figure 12.5 Continued weakness (eg, CMT, Emery-Dreifuss muscular dystro- However, in congenital muscular dystrophy, the CK phy, myotonic muscular dystrophy, FSHD, and other value may be extremely variable, ranging from nor- conditions) often exhibit a foot slap at floor contact mal values to a fairly marked elevation. There is no with a steppage gait pattern to facilitate swing-phase close association between disease severity and CK val- clearance of the plantar-flexed ankle. Alternatively, ues. In all dystrophic myopathies, the CK values tend these patients may clear the plantar-flexed ankle using to decrease over time, with increasing severity of the some degree of circumduction at the hip or vaulting disease owing to progressive loss of muscle fiber and on the stance-phase side. Milder distal lower extrem- irreversible cell death. Thus, a 3-year-old with DMD ity weakness may become clinically evident by testing may have a CK value of 25,000, while a 10-year-old heel walking and toe walking. with DMD may show a CK value of 2,000. Other con- ditions with significant elevations in CK may include Serum Laboratory Studies polymyositis, dermatomyositis, acute rhabdomyolysis, and malignant hyperthermia. In many of the congeni- Those neuromuscular diseases with inherent sar- tal structural myopathies, such as central core disease, colemmal muscle membrane injury often show sig- nemaline rod myopathy, and fiber-type disproportion nificant elevations in transaminases, aldolase, and syndrome, a serum CK is likely to be normal or only creatine kinase (CK). The CK enzyme catalyzes the mildly elevated. release of high-energy phosphates from creatine phosphate. It occurs mainly in muscle and leaks into CK levels have ranged from normal to elevated two the serum in large amounts in any disorder involv- to four times in SMA I and II. SMA III patients have ing muscle fiber injury. The MM fraction is specific also been found to have normal to slightly elevated CK to skeletal muscle. The CK value may be significantly values, with elevations generally to two to five times elevated in early stages of DMD and BMD, with val- normal. A serum CK level greater than 10 times the ues up to 50\u2013100 times normal. A normal CK value upper limit of normal generally is exclusionary criteria may help exclude DMD and BMD. Overlap in CK val- for SMA and, in this setting, workup for other disor- ues occurs between DMD and BMD. Other forms of ders such as inflammatory or dystrophic myopathies muscular dystrophy, such as Emery-Dreifuss muscular should be pursued. In a child with muscle weakness, a dystrophy (EMD), LGMD, FSHD, and congenital mus- normal CK does not exclude a myopathy or other NMD cular dystrophy, may show moderate elevations in CK. conditions; however, a severely elevated CK is sugges- tive of but not diagnostic of a dystrophic myopathy or inflammatory myopathy.","284 Pediatric Rehabilitation Figure 12.6 \u201cMyopathic\u201d stance in an eight-year-old male Figure 12.7 Toe walking with initial \ufb02oor contact in the with Duchenne muscular dystrophy. Notice the lumbar transitional phase of ambulation in Duchenne muscular lordosis to compensate for hip extensor weakness and dystrophy is, in part, a compensatory mechanism to primarily forefoot contact to compensate for knee extensor maintain knee stability. weakness. encephalomyopathy should be evaluated with cerebro- Lactate and pyruvate levels are useful in the eval- spinal fluid (CSF) lactate and pyruvate levels, because uation of possible metabolic myopathy. The presence these values are less subject to flux than are either of a lactic acidosis may be seen in such mitochondrial venous or arterial values. The ischemic forearm test, encephalomyopathies as Kearns-Sayre syndrome, myo- initially utilized by McArdle, and the nonischemic clonic epilepsy and ragged-red fibers (MERRF) and forearm exercise test are widely used means of assess- mitochondrial encephalomyopathy with lactic acidosis ing muscle and aerobic metabolism in older, more and strokelike episodes (MELAS). Whenever clinical cooperative patients (1,2). evidence suggests a disorder of oxidative metabolism, blood lactate and pyruvate levels should be obtained. Electrodiagnostic Studies Arterial lactate values are a more reliable guide. Stable or reduced levels of lactate and pyruvate, with con- Nerve conduction and electromyography are an exten- comitany increases in ammonia with ischemic or sion of the clinician\u2019s physical examination and a use- nonischemic forearm exercise testing, suggests a mito- ful tool for the localization of lesions within the lower chondrial dysfunction. In a setting of lactic acidemia, motor neuron. In addition, electromyogramy (EMG) and the lactate\/pyruvate ratio may aid in the differential nerve conduction studies help guide further studies, diagnosis. Children with suspected mitochondrial such as muscle biopsy, by providing information about the most appropriate muscle site for biopsy. With spinal","Chapter 12 Neuromuscular Diseases 285 A thorough discussion of the role of electrodiag- nosis and neuromuscular disease is provided in the chapter on pediatric electrodiagnosis. Molecular Genetic Studies The application of molecular genetic techniques has resulted in enormous gains in our understand- ing of the molecular and pathophysiologic basis of many neuromuscular diseases. In addition, molecu- lar genetic studies now aid in the diagnostic evalua- tion of the dystrophin-deficient muscular dystrophies (DMD, BMD), myotonic muscular dystrophy, predom- inantly proximal autosomal-recessive spinal muscular atrophy, Charcot-Marie-Tooth neuropathy (hereditary motor and sensory neuropathy), and a host of other neuromuscular disease conditions. The clinical appli- cation of molecular genetic studies is described in the following sections on specific neuromuscular disease conditions. Figure 12.8 Trendelenburg or \u201cgluteus medius\u201d gait Muscle Biopsy Evaluation pattern in a male with Duchenne muscular dystrophy. Note the lateral lean over the stance side due to hip abductor Muscle Biopsy Technique weakness; ankle dorsi\ufb02exion weakness necessitates swing phase in circumduction for clearance. The two techniques for obtaining a muscle biopsy specimen include the traditional open biopsy and the muscular atrophy, an electrodiagnostic evaluation can needle biopsy (3,4). Either technique can be performed allow the clinician to defer muscle biopsy and proceed under local anesthesia; however, most clinicians in the with molecular genetic studies of the survival motor United States use general anesthesia for open biopsies neuron gene. Electrodiagnostic studies in patients with and local anesthesia for needle biopsies. There may be CMT help to categorize the neuropathy as either pri- some disruption in the architecture of the tissue with marily demyelinating or axonal, and such information needle biopsy technique, which can affect the evalua- may help focus subsequent molecular genetic analyses tion of histologic examination and electron microscopy. for a more cost-effective approach. In patients with sus- Immunocytochemistry analyses, such as Western blot, pected CMT and positive family histories with geneti- and metabolic studies do not require strict mainte- cally confirmed diagnoses, the diagnosis of CMT may nance of the muscle cellular architecture. be confirmed in the clinic by a simple, reliable, and relatively inexpensive nerve conduction study. Muscle Biopsy Site Selection Selection of the muscle is based on distribution of muscle weakness found clinically in addition to elec- trodiagnostic findings, if obtained. In a dystrophic myopathy, the muscle biopsy should be clinically affected, but not so severely affected that it is largely replaced by fat and connective tissue with minimal residual muscle fiber present for evaluation. The inser- tional activity on EMG or muscle imaging studies can be helpful in this respect. Sufficient normative infor- mation about proportional fiber type and fiber diam- eter should be available with age-appropriate norms. A diagnosis of congenital myopathy with fiber-type disproportion cannot be made without careful con- sideration of the normal fiber-type predominance in a given muscle. For example, the vastus lateralis is two-thirds type II fibers (with equal proportions of","286 Pediatric Rehabilitation type IIa and type IIb fibers) and one-third type I fibers. oxidase C, succinic dehydrogenase (mitochondrial The anterior tibialis, on the other hand, contains a enzymes), and specific immunostains for dystrophin predominance of type I fibers, and the anconeus is and sarcolemmal membrane associated proteins. mostly type I fibers. In addition, some muscles, such as the quadriceps and biceps, have longitudinally A variety of histochemical stains, including NADH running fibers that facilitate orientation of the speci- stains and ATPase stains, at different pH values can be men for preparation of cross-sectional slices. The gas- used to differentiate fiber types (types I, IIa, IIb, IIc). trocnemius and middle deltoid muscles, on the other Based on the histochemical analyses, information hand, may be difficult to orient because fibers run is obtained about pattern of fiber types (eg, normal in different planes. The posterior deltoid is preferred predominance, fiber type predominance, selective over the middle deltoid. Muscles that have undergone fiber type involvement, or reinnervation evidenced by recent needle electromyographic evaluation should be fiber type grouping), analysis of muscle fiber diam- avoided as muscle biopsy sites because of the possibil- eters (eg, fiber hypertrophy or atrophy, increased var- ity of cellular changes in the muscle fiber secondary iability in fiber diameter, or denervation atrophy with to the needle study. narrow range of diameters among atrophic and nona- trophic fibers), or alterations in the muscle fiber (eg, For routine diagnostic studies, the vastus lat- central nuclei, necrosis, splitting or branching, regen- eralis muscle in the lower extremity and the triceps, eration or the presence of a variety of other accumu- biceps, or posterior deltoid in the upper extremity are lations and fiber alterations, both specific to certain often preferred. When proximal muscles are severely conditions and nonspecific). affected or only distal muscles are involved, the exten- sor carpi radialis or anterior tibialis muscles are often Congenital myopathies are a group of structural biopsied. myopathies whose diagnosis is based on classic histo- logic characteristics seen on muscle biopsy (eg, centro- Histology\/Histochemistry nuclear or myotubular, central core, nemaline rod, and fiber type disproportion myopathies). The histopathologic study is likely to provide informa- tion on whether the basic disease process is primarily a Immunoblotting and Immunostaining myopathy or a neurogenic process. In some instances, the diagnosis of specific disorders (such as dystrophic Imunoblotting of a muscle sample provides informa- myopathy or inflammatory myopathy) is delineated. tion about amounts of specific muscle protein, such as When analyzing paraffin sections, basic pathologic dystrophin or other structural proteins important in reactions of muscle may include fiber necrosis, cen- maintaining structural integrity of the muscle mem- tral nuclei indicative of regeneration, abnormalities of brane. Immunoblotting can be performed with as lit- muscle fiber diameter (atrophy, hypertrophy, abnor- tle as 10 mg of frozen tissue. Quantitative dystrophin mal variation, and fiber size), fiber splitting, vacuo- analysis using Western blot technique can differentiate lar change, inflammatory infiltrates, and proliferation DMD from BMD and thus help determine the progno- of connective tissue\/fibrosis. A dystrophic myopathy sis in a young symptomatic patient\u2014information not frequently is characterized by the presence of normal precisely determined by standard molecular genetic fibers, hypertrophied fibers, degenerating fibers, atro- analysis of the dystrophin gene. Dystrophin quantity phic fibers, regenerating fibers, and connective tissue 0% to 5% is consistent with DMD, 5% to 20% dystro- and fatty infiltration. Neurogenic changes may be char- phin is seen in some with less severe \u201coutlier\u201d DMD acterized by small or large groups of atrophic fibers, or severe BMD, and either 20% to 80% dystrophin or with or without target fibers, and frequently by hyper- normal quantity and reduced or increased molecular- trophy of the nonatrophic fibers. Pyknotic nuclear weight dystrophin is consistent with BMD. A normal clumps, target fibers, and darkly staining angulated dystrophin level in a patient with histologic evidence fibers are consistent with a neurogenic process. Red- of a dystrophic myopathy is suggestive of LGMD. rimmed vacuoles suggest inclusion-body myositis. Immunofluorescent staining of muscle biopsy sections Ragged red fibers are consistent with a mitochondrial for dystrophin helps identify symptomatic female DMD myopathy. Perifascicular atrophy is consistent with carriers and some female BMD carriers. dermatomyositis. The progressive loss of muscle fibers evident in Frozen sections can be assessed with standard H & muscular dystrophy is now thought to be caused by E NADH, ATPase, and trichrome stains. Other stains primary muscle sarcolemmal membrane abnormalities include include PAS (for glycogen), Oil Red-O (for due to inherited structural abnormalities (abnormal lipid), congo red (for amyloid), acetylcholinesterase (for molecular weight, deficiency, or absence) of dystro- motor end plates), myophosphorylase (for McArdle\u2019s), phin or dystrophin-associated transmembrane gly- acid phosphatase (for type II glycogenosis), cytochrome coproteins. Membrane instability leads to membrane injury from mechanical stresses, transient breaches","Chapter 12 Neuromuscular Diseases 287 of the membrane, and membrane leakage. Ultimately, is limited to those disorders giving rise to demyelinat- after multiple cycles of degeneration and regeneration, ing or axonal changes in sensory fibers. Occasionally, irreversible muscle cell death occurs. The muscle fiber a small portion of the motor nerve can be obtained is then replaced by connective tissue and fat, and this simultaneously with an anconeus motor point biopsy, fibrotic replacement of the muscle may be exceedingly where the motor branch is excised along with the aggressive. This has given rise to the concept of dis- entire muscle from origin to insertion. eases of the dystrophin-glycoprotein complex. Primary genetic abnormalities lead to abnormalities of intra- SPECIFIC NEUROMUSCULAR cellular dystrophin, transmembrane sarcoglycans, or DISEASE CONDITIONS transmembrane dystroglycans. An abnormality in the muscle protein merosin, located in the extracellular Dystrophic Myopathies matrix, gives rise to one of the forms of congenital muscular dystrophy. Immunoblotting and\/or immuno- Muscular dystrophies are debilitating myopathic disor- fluorescent staining of the proteins of the dystrophin- ders that present with muscle wasting and diffuse mus- glycoprotein complex allows many LGMD patients to cle weakness. They are caused by genetic mutations, be subtyped. which produce muscle fiber necrosis and regeneration, ultimately resulting in muscle fiber loss. Traditionally, Electron Microscopy patients with the muscular dystrophies were grouped together because they had similar pathologies, and Electron microscopy (EM) is used to evaluate ultra- they were subdivided into categories based upon their structural changes of muscle fiber organelles\/internal modes of inheritance, ages of onset, and distributions components, as well as changes in the muscle fiber. of affected muscles. Most types of muscular dystrophy At times, this may provide additional complimentary are not purely muscle disorders, but multisystem dis- information to the histologic and histochemical assess- orders with disease manifestations in a variety of body ment of muscle fibers that may be diagnostically rel- systems, which may include the musculoskeletal, car- evant. For example, ultrastructural alterations of the diovascular, pulmonary, and gastrointestinal systems, mitochondria may provide important information and as well as endocrine system, skin, eyes, brain, and direct additional metabolic studies in the workup of other organ systems. Muscular dystrophies are caused mitochondrial myopathy. In a congenital structural by mutations of the genes encoding for proteins impor- myasthenic syndrome, ultrastructural alterations at tant for the stability of the sarcolemmal membrane and the neuromuscular junction may be present by EM, the maintenance of muscle fiber intracellular homeo- either presynaptically or postsynaptically. stasis. They are genetically, biochemically, and clini- cally diverse diseases. Metabolic Studies Dystrophinopathies Depending on clinical suspicion and histologic and ultrastructural changes on muscle biopsy, additional Duchenne Muscular Dystrophy metabolic studies may be obtained to evaluate for the presence of metabolic myopathies, including glycog- Duchenne muscular dystrophy (DMD) is an X-linked enoses, lipid disorders, or mitochondrial myopathies. disorder caused by an abnormality at the Xp21 gene loci. The DMD\/BMD gene occupies 2.5 million base Nerve Biopsy Evaluation pairs of DNA on the X chromosome and is about 10 times larger than the next largest gene identified to Nerve biopsies are occasionally useful in the charac- date. The gene coding sequence contains 79 exons. terization of more severe hereditary motor sensory The primary protein product, dystrophin, is localized neuropathies, congenital hypomyelinating neuropathy, to the intracellular side of the plasma membrane of all and neuroaxonal dystrophy. In addition, perineural myogenic cells, certain types of neurons, and in small immune complex deposition seen in some autoim- amounts of other cell types (5). Dystrophin deficiency mune neuropathies and changes consistent with vas- at the plasma membrane of muscle fibers disrupts the culitis also may be useful diagnostically. Otherwise, membrane cytoskeleton and leads to the secondary nerve biopsies rarely add specific information to the loss of other components of the muscle cytoskeleton. diagnostic evaluation of the NMD patient beyond that The primary consequence of the cytoskeleton abnor- information obtained from nerve conduction studies malities is membrane instability, leading to membrane and EMG. injury from mechanical stresses, transient breaches of the membrane, and membrane leakage. Chronic Generally, the sural nerve is utilized. Since this is a pure sensory nerve, the usefulness of this specimen","288 Pediatric Rehabilitation dystrophic myopathy is characterized by aggressive a severely truncated protein that would be unstable fibrotic replacement of the muscle and eventual fail- (6). Characteristics of DMD and BMD are shown in ure of regeneration with muscle fiber death and fiber Table 12.1. loss. Generally, loss of the reading frame causes com- plete absence of dystrophin and a Duchenne pheno- Diagnostic Evaluation. Serum creatine kinase is a use- type. For cases with a deletion mutation, the \u201creading ful screening test. Gene abnormalities may be iden- frame\u201d hypothesis predicts that BMD patients with in- tified by full gene sequencing of a blood specimen in frame deletions produce a semifunctional, internally 99% of all patients with a dystrophinopathy. Full gene deleted dystrophin protein, whereas DMD patients sequencing in addition to evaluation for large deletions with frameshift or \u201cout of frame\u201d deletions produce to identify point mutations, deletions, duplications, 12.1 Characteristics of Dystrophinopathies DUCHENNE MUSCULAR DYSTROPHY BECKER MUSCULAR DYSTROPHY U.S. Prevalence (est.) 15,000 2,200 Incidence rate 1\/3,500 male births unknown Inheritance X-linked X-linked Gene location Xp21 (reading frame shifted) Xp21 (reading frame maintained) Protein Dystrophin Dystrophin Onset 2 to 6 years 4\u201312 years (severe BMD) Late teenage to adulthood (mild BMD) Severity and course Relentlessly progressive Slowly progressive Reduced motor function by 2\u20133 yrs Severity and onset correlate with muscle Ambulation status Steady decline in strength dystrophin levels Weakness Life span <35 years Loss of ambulation: >16 years Cardiac Loss of ambulation: 7 to 13 yrs (no corticosteroids) Respiratory Loss of ambulation 9 to 15 years (corticosteroids) Proximal > distal Muscle size Symmetric Musculoskeletal Proximal > distal Legs and arms CNS Symmetric Cardiomyopathy (may occur before weakness); Muscle pathology Legs and arms third to fourth decade frequent Respiratory involvement in subset of patients Dilated cardiomyopathy first to second decade Ventilatory dependency in severe patients Onset of signs second decade Calf hypertrophy Contractures: ankles and others in adulthood Profoundly reduced vital capacity in second decade Ventilatory dependency in second decade Some patients have reduced cognitive ability Variable fiber size Calf hypertrophy Endomysial connective tissue and fatty infiltration Fiber degeneration Contractures: ankles, hips, and knees Fiber regeneration Scoliosis: onset after loss of ambulation Dystrophin: reduced (usually 10%\u201360% of normal) Reduced cognitive ability oReduced verbal ability CK: 5,000 to 20,000 Lower levels with increasing age Endomysial fibrosis and fatty infiltration Variable fiber size and myopathic grouping Fiber degeneration\/regeneration Dystrophin: absent Sarcoglycans: secondary reduction Blood chemistry and CK: Very high (10,000\u201350,000) hematology High AST and ALT (normal GGT) High aldolase","Chapter 12 Neuromuscular Diseases 289 inversions, etc. rather than simple deletion screening patients arms abducted to 90 degrees and externally with polymerase chain reaction (PCR) is now standard rotated, the hypertrophy of the posterior deltoid and of care in all patients at risk of a dystrophinopathy. infraspinatus frequently leaves a depression between This is both for diagnostic purposes and to identify these two muscles referred to as the \u201cposterior axil- candidates for future molecular-based therapies such lary depression sign\u201d in DMD (Fig. 12.9). The tongue as exon skipping with oligonucleotides, nonsense- is also frequently enlarged. There is also commonly mediated suppression therapy for the 10% to 15% of an associated wide arch to the mandible and maxilla patients with DMD and BMD with stop codon muta- with separation of the teeth, presumably secondary to tions, and specific gene therapy strategies that will the macroglossia. require knowledge of specific gene sequence altera- tions. In patients with no family history and molecu- Pattern and Progression of Weakness. Earliest weakness lar genetics that do not clearly differentiate a DMD and is seen in the neck flexors during preschool years (Fig. BMD phenotype, a muscle biopsy with immunostain- 12.10). Weakness is generalized, but predominantly ing and quantitative dystrophin analysis with Western proximal early in the disease course. Pelvic girdle blot is critical to allow patients to be eligible for future weakness predates shoulder girdle weakness by sev- clinical trials with rigid inclusionary criteria. eral years. Ankle dorsiflexors are weaker than ankle plantar flexors; ankle everters are weaker than ankle Epidemiology. The incidence of Duchenne muscular inverters; knee extensors are weaker than knee flex- dystrophy, based on a number of population studies as ors; hip extensors are weaker than hip flexors; and hip well as neonatal screening, has been estimated to be abductors are weaker than hip adductors (9). around 1:3,500 male births (7). As many as one-third of isolated cases may be due to new mutations, which The weakness progresses steadily, but the rate may is considerably higher than observed in other X-linked be variable during the disease course. Quantitative conditions. This high mutation rate may relate to the strength testing shows greater than 40% to 50% loss large size of the gene. of strength by 6 years of age (9). With manual mus- cle testing, DMD subjects exhibit loss of strength in a Onset and Early Signs. While the history of hypoto- fairly linear fashion from ages 5 to 13, and measure- nia and delayed motor milestones are often reported ments obtained several years apart will show fairly in retrospect, the parents are often unaware of any steady disease progression. A variable course may be abnormality until the child starts walking. Variability noted when analyzing individuals over a shorter time has been reported in the age of onset (8,9). In 74% to course (9). Quantitative strength measures have been 80% of instances, the onset has been noted before the shown to be more sensitive for demonstrating strength age of 4 years (8\u201310). The vast majority of cases are loss than manual muscle testing when strength is identified by 5 to 6 years of age. The most frequent pre- grades 4\u20135 (9). senting symptoms have been abnormal gait, frequent falls, and difficulty climbing steps. Parents frequently Loss of Ambulation. Average age to wheelchair in a note the toe walking, which is a compensatory adapta- DMD population not treated with corticosteroids has tion to knee extensor weakness, and a lordotic posture to the lumbar spine, which is a compensatory change Figure 12.9 Posterior axillary depression sign in due to hip extensor weakness (Fig. 12.7). Duchenne muscular dystrophy. Note the prominent deltoid superolaterally and infraspinatus inferomedially. Occasionally, Duchenne muscular dystrophy is identified presymptomatically in situations where a CK value is obtained with a markedly elevated value, malignant hyperthermia occurs during general anes- thesia for an unrelated surgical indication, or a diagno- sis is pursued in a male with an affected older sibling. Difficulty negotiating steps is an early feature, as is a tendency to fall due to the child tripping or stum- bling on a plantar-flexed ankle or the knee buckling or giving way due to knee extensor weakness. There is progressive difficulty getting up from the floor with presence of a Gower\u2019s sign (see Fig. 12.5). Pain in the muscles, especially the calves, is a common symptom. Enlargement of muscles, partic- ularly the calves (see Fig. 12.1), is commonly noted. The deltoid may also be hypertrophied. With the","290 Pediatric Rehabilitation Figure 12.10 Weakness of neck \ufb02exors in an eight-year-old dystrophy older than age 13 (9,14,15). The most com- child with Duchenne muscular dystrophy makes it dif\ufb01cult mon contractures include ankle plantar flexion, knee for him to bring his chin to the chest when supine and to flexion, hip flexion, iliotibial band, elbow flexion, and hold his head up when placed at the end of the examination wrist flexion contractures (9). Significant contractures table. have been shown to be rare in DMD before age 9 for all joints. There is no association between muscle imbal- been age 10, with a range of 7\u201313 years. Treatment with ance around a specific joint (defined as grade 1 or prednisone or deflazacort helps maintain strength and greater difference in flexor and extensor strength) and prolongs ambulation by two years (11,12). There does the frequency or severity of contractures involving the not appear to be an advantage of deflazacort over daily hip, knee, ankle, wrist, and elbow in DMD (9). Flexion prednisone. The optimal dose of prednisone is 0.75 mg\/ contractures have been shown to be rare in those with kg\/day up to a maximum of 40 mg\/day (11,12,13). The \u2265grade 3 extensor strength about a joint, an expected optimal dose of deflazacort appears to be 0.90 mg\/kg\/ finding because of the definition of a grade 3 muscle day. With both corticosteroid regimens, patients need on manual muscle testing (MMT). For those DMD sub- to be monitored for cataracts, hypertension, weight jects with less than antigravity strength about a joint, gain, osteoporosis, growth retardation, diabetes, and there is low correlation between the MMT strength behavioral side effects. of these specific muscle groups and the severity of joint contracture (9). The presence of lower extremity Timed motor performance is useful for the pre- contractures in DMD has been shown to be strongly diction of time when ambulation will be lost without related to onset of wheelchair reliance (9). Lower provision of long-leg braces. One large natural history extremity contractures were rare while DMD sub- study showed that all DMD subjects who took nine jects were still upright, but developed soon after they seconds or longer to ambulate 30 feet lost ambula- developed a sitting position in a wheelchair for most tion within two years. All DMD subjects who took 12 of the day. The occurrence of elbow flexion contrac- seconds or longer to ambulate 30 feet lost ambulation tures also appears to be directly related to prolonged within one year (9). Ambulation past the age of 14 in a static positioning of the limb, and these contractures noncorticosteroid-treated patient should raise the sus- develop soon after wheelchair reliance. The relation- picion of a milder form of muscular dystrophy such as ship between wheelchair reliance and hip and knee BMD or limb girdle muscular dystrophy. Ambulation flexion contractures has been noted (9). Mild contrac- beyond 16 years has been previously used as an exclu- tures of the iliotibial bands, hip flexor muscles, and sionary criteria for Duchenne muscular dystrophy in heel cords occurs in most DMD patients by 6 years of studies of BMD. Immobilization for any reason can age (16). Limitations of knee, elbow, and wrist exten- lead to a marked and often precipitous decline in mus- sion occurs about two years later (9,16); however, these cle power, rapid development of contractures, and loss early observed contractures were relatively mild. Given of ambulatory ability. A fall with resultant fracture the tremendous replacement of muscle by fibrotic tis- leading to immobilization and loss of ambulatory abil- sue in DMD subjects, it is not surprising that a muscle ity is not an uncommon occurrence. of less than antigravity extension strength, statically positioned in flexion, would develop a flexion con- Contractures. Significant joint contractures have been tracture (subsequent to wheelchair reliance). The lack found in nearly all children with Duchenne muscular of lower extremity weight bearing likely contributes to the rapid acceleration in the severity of these con- tractures after transition to wheelchair. Ankle plantar flexion contractures are not likely a significant cause of wheelchair reliance, as few subjects exhibit plantar flexion contractures of \u226515 degrees before their transi- tion to a wheelchair (9). Natural history data suggests that weakness is the major cause of loss of ambulation in DMD, not contracture formation. Spine Deformity. Reported ultimate prevalence of scoli- osis in DMD subjects not treated with corticosteroids varies from 33% to 100% (17). This marked variability is primarily because of retrospective selection for sco- liosis, the inclusion or exclusion of functional curves, and dissimilar age groups. The prevalence of scoli- osis is strongly related to age. Fifty percent of DMD","Chapter 12 Neuromuscular Diseases 291 patients acquire scoliosis between ages 12 and 15, cor- severe DMD cases reached plateaus in FVC of greater responding to the adolescent growth spurt. Ten percent than 1,700 mL. Similarly, McDonald and colleagues of older DMD subjects with no treatment of scoliosis (9) found that those patients with higher peak FVC show no clinical spinal deformity. This is consistent (>2,500 mL) had a milder disease progression, losing with Oda\u2019s report (18) that 15% of older DMD patients 4% predicted FVC per year. Those with peak predicted show mild nonprogressive curves (usually 10 degrees FVC less than 1,700 mL lost 9.6% predicted FVC per to 30 degrees). The rate of progression of the primary year. Thus, the peak obtained absolute values of forced or single untreated lateral curve has been reported to vital capacity usually occurring in the early part of range from 11 degrees to 42 degrees per year, depend- the second decade is an important prognostic indica- ing on the age span studied. Johnson and Yarnell (19) tor for severity of spinal deformity, as well as ultimate reported an association between side of curvature, con- severity of restrictive pulmonary compromise due to vexity, and hand dominance, an association recently muscular weakness. Prednisone and deflazacort both confirmed (20). Oda and colleagues (18) reported that appear to reduce the loss of pulmonary function over the likelihood of severe progressive spinal deformity time during the second decade in DMD (22,23,24,26). could be predicted by type of curve and early pulmo- nary function measurements. Those with spines lack- Maximal static airway pressures (both maximal ing significant kyphosis or hyperlordosis and a peak inspiratory pressure and maximal expiratory pressure) obtained absolute forced vital capacity (FVC) greater are the earliest indicators of restrictive pulmonary com- than 2,000 mL tended not to show severe progressive promise in DMD with impaired values noted between scoliosis. 5 and 10 years of age. Vital capacity typically increases concomitant with growth between 5 and 10 years of No cause-and-effect relationship has been estab- age, with percent predicted FVC remaining relatively lished between onset of wheelchair reliance and stable and close to 100% predicted. DMD patients typ- occurrence of scoliosis (9,21). Wheelchair reliance ically show a linear decline in percent predicted FVC and scoliosis has been found to be an age-related phe- between 10 and 20 years of age. An FVC falling below nomenon. The causal relationship between loss of 35% is associated with increased perioperative morbid- ambulatory status and scoliosis is doubtful, given the ity in DMD (27) and optimally, surgery should ideally substantial time interval between the two variables in be performed with % predicted FVC greater than 40%. most subjects (scoliosis usually develops after three Recent evidence suggests that spinal arthrodesis may to four years in a wheelchair). Both wheelchair reli- be safely performed in a population of DMD with % ance and spinal deformity may be significantly related predicted vital capacity less than 30% (28). to other factors (eg, age, adolescent growth spurt, increase in weakness of trunk musculature, and other Ultimately, respiratory failure in DMD is insidi- unidentified factors) and thus represent coincidental ous in its onset and results from a number of factors, signs of disease progression. including respiratory muscle weakness and fatigue, alteration in respiratory system mechanics, and impair- In retrospective series, treatment of DMD with ment of the central control of respiration. Noninvasive deflazacort and prednisone have been shown to reduce forms of both positive and negative pressure ventila- the occurrence of significant scoliosis (22,23,24). It tory support are increasingly being offered to DMD remains to be seen whether the apparent arrest in the patients nocturnally and continuously with acceptable development of scoliosis with corticosteroids will con- quality of life. Airway clearance strategies, such as the tinue past the age of skeletal maturity. cough assist\/inexsufflator, TheraVest, or intrapulmo- nary percussion ventilation (IPV) are also important Pulmonary Function. In DMD, absolute forced vital pulmonary management strategies (29). capacity volumes increase during the first decade and plateau during the early part of the second decade (9). Cardiomyopathy. The dystrophin protein is present in A linear decline in percent predicted FVC is apparent both the myocardium and the cardiac Purkinje fibers. between 10 and 20 years of age in DMD (9). Rideau Abnormalities of the heart may be detected by clini- and colleagues (25) reported forced vital capacity to cal examination, electrocardiogram (ECG), echocardi- be predictive of the risk of rapid scoliosis progression. ography, and Holter monitoring. Cardiac examination In the most severe DMD cases, maximal forced vital is notable for the point of maximal impulse palpable capacity reached a plateau of less than 1,200 mL. This at the left sternal border due to the marked reduc- was associated with loss of ability to walk before age tion in anteroposterior chest dimension common in 10 and severe progressive scoliosis. Moderately severe DMD. A loud pulmonic component of the second heart DMD cases with respiratory compromise reached sound suggests pulmonary hypertension in patients maximum forced vital capacities between 1,200 mL with restrictive pulmonary compromise. Nearly all and 1,700 mL. Spinal deformity was present consis- patients over the age of 13 demonstrate abnormalities tently in these cases, but varied in severity. The least of the ECG (9). Q-waves in the lateral leads are the first","292 Pediatric Rehabilitation abnormalities to appear, followed by elevated ST seg- angiotensin-converting enzyme inhibitors (ACE inhib- ments and poor R-wave progression, increased R\/S itors) such as perindopril or enalapril delayed the onset ratio, and finally resting tachycardia and conduction and progression of prominent left ventricle dysfunc- defects. ECG abnormalities have been demonstrated to tion in children with DMD (36). In another series, 43% be predictive for death from the cardiomyopathy with with impaired left ventricular (LV) systolic dysfunction the major determinants including R-wave in lead V1 responded to enalapril with the normalization of func- less than 0.6 mV; R-wave in lead V5 less than 1.1 mV; tion (37). Alternatively, angiotensin II type 1 receptor R-wave in lead V6 less than 1.0 mV; abnormal T-waves in blockers (ARBs) such as losartan may be considered leads II, III, AVF, V5, and V6; cardiac conduction distur- for afterload reduction in DMD. Animal studies show bances; premature ventricular contraction; and sinus that the angiotensin II type 1 receptor blocker losartan tachycardia (30). Sinus tachycardia may be due to low attenuates TGF-beta\u2013induced failure of muscle regen- stroke volume from the progressive cardiomyopathy, or eration in dystrophinopathy, presenting an additional in some cases, may be sudden in onset and labile, sug- potential for therapeutic benefit vis-a-vis skeletal mus- gesting autonomic disturbance or direct involvement of cle in DMD (38). the sinus node by the dystrophic process (31). Cognition and Behavioral Phenotype. There is a dystro- Autopsy studies and thallium 201 single-photon phin isoform present in the brain. Previous studies emission computed tomography (SPECT) imaging have on intellectual function on children with DMD have demonstrated left ventricular lateral and posterior wall generally revealed decreased IQ scores when these defects that may explain the lateral Q-waves and the children are compared with both control and norma- increased R\/S ratio in V1 seen on ECG. Localized pos- tive groups (9). A mean score for the DMD population terior wall fibrosis was found to be peculiar to DMD of 1.0 to 1.5 standard deviation (SD) below population and was not found in other types of muscular dystro- norms has been reported. There has generally been phy (32). Pulmonary hypertension leading to right ven- a considerable consistency in the degree of impair- tricular enlargement also is known to affect prominent ment across measures reflecting a rather mild global R-waves in V1 and has been demonstrated in patients deficit. Some studies (39) have demonstrated relative with DMD (33). deficits in verbal IQ. In a longitudinal assessment of cognitive function, McDonald and colleagues (9) Ventricular ectopy and sudden death are known found IQ measure in DMD to be stable over time. complications of the cardiomyopathy in DMD, and On neuropsychological testing, a large proportion this association likely explains observed cases of sud- of DMD subjects fell within the \u201cmildly impaired\u201d den death. Severe ventricular ectopy in DMD has been or \u201cimpaired\u201d range according to normative data associated with left ventricular dysfunction and sud- (9). Again, no particular areas of strength or weak- den death. Yanagisawa and colleagues (34) reported ness were identified. These findings likely reflect a an age-related increase in the prevalence of cardiac mild global deficit rather than focal nervous system arrhythmias detected by ambulatory 24-hour electro- impairment (9). Hinton found that DMD is associ- cardiographic recordings. They also noted an asso- ated with poor attention to complex verbal informa- ciation between ventricular arrhythmias and sudden tion (more so than verbal or memory measures), and death in DMD. Clinically evident cardiomyopathy they exhibit decreased verbal span capacity, but not is usually first noted after age 10 and is apparent in impaired recall (40,41). An increased incidence of nearly all patients over age 18 (35). Development of autism spectrum disorder has been found in DMD cardiomyopathy is a predictor of poor prognosis. (42). In one large series of DMD subjects, 11.7% were Echocardiography has been used extensively to fol- reported to have a comorbid diagnosis of attention- low the development of cardiomyopathy and predict deficit hyperactivity disorder (ADHD), 3.1% had prognosis in patients with DMD. The onset of systolic autism spectrum disorder, and 4.8% had obsessive- dysfunction noted by echocardiography is associated compulsive disorder (43). In addition, impaired facial with a poor short-term prognosis (35). The myocardial affect recognition has found to be a part of the phe- impairment remains clinically silent until late in the notype associated with DMD (44). course of the disease, possibly caused by the absence of exertional dyspnea, secondary to lack of physical Anthropometric Changes. Substantial anthropometric activity. Death has been attributed to congestive heart alterations have been described in DMD. Short stat- failure in as many as 40% to 50% of patients with ure and slow linear growth with onset shortly after DMD by some investigators (35). Regular cardiac eval- birth has been reported (45). Accurate measurement uations with an ECG, echocardiography, and Holter of linear height is extremely difficult in this popula- monitor should be employed in teenagers with preclin- tion. Arm span measurements may be an alternative ical cardiomyopathy. measure of linear growth; however, this measurement Recent studies suggest that early presymptom- atic treatment to achieve afterload reduction with","Chapter 12 Neuromuscular Diseases 293 might also be difficult, as elbow flexion contractures Epidemiology. Becker muscular dystrophy has a lower of greater than 30 degrees are frequently present in incidence than DMD, with prevalence rates for BMD patients older than age 13. Forearm segment has been ranging from 12\u201327 per million and a recent estimated proposed as an alternative linear measurement in overall prevalence of 24 per million (7,53). DMD patients with proximal upper extremity contrac- tures, and radius length may be followed for those Molecular Genetics and Diagnostic Evaluation. Full gene with wrist and finger contractures. Obesity is a sub- sequencing of the dystrophin gene, which demon- stantial problem in DMD, subsequent to the loss of strates large deletions, duplications, and point muta- independent ambulation (9,46). Weight control during tions, identifies 99% of patients with dystrophinopathy early adolescence has its primary rationale in ease and is now the standard of care. This is essential for of care, in particular, ease of transfers during later identification of patients with stop codons and specific adolescence. gene alterations that will be targeted for molecular- based therapies. Not all DMD and BMD patients have Immediately following spine fusion, there has been deletion mutations: Many have point mutations that a documented tendency for DMD patients to lose sig- cannot be detected by screening deletion testing. Thus, nificant weight. Those who lost weight were unable to full sequence analysis is necessary. About 55% of DMD self-feed. The weight loss after surgery was associated patients and 70% of BMD patients show large dele- with loss of self-feeding (47). There was no association tion mutations of the gene. A positive DNA test result with weight loss and loss of biceps strength. A correc- (presence of a point mutation, duplication, or dele- tion of the kyphosis may actually make self-feeding tion) is diagnostic of a dystrophinopathy (Duchenne problematic in DMD. A feeding evaluation and incor- or Becker dystrophy)\u2014there are no false-positives if poration of kyphosis into the spinal instrumentation the test is done appropriately. While genetic testing is construct may help preserve self-feeding and prevent improving with regard to the differentiation of DMD weight loss subsequent to spine fusion. and BMD, there remains some overlap and variability. Differential diagnosis between DMD and BMD is best Longitudinal weight measurements in DMD con- done by a consideration of clinical findings, family firm significant rates of weight loss in subjects ages history of clinical phenotype, and muscle biopsy with 17\u201321 (9,48). This is likely caused by relative nutritional quantitative dystrophin analysis. If the patient is still compromise during the later stages when boys with ambulating at 16\u201320 years of age and has a deletion DMD have higher protein and energy intake require- mutation, the correct diagnosis is BMD. Mutations at ments because of hypercatabolic protein metabolism. the Xp21 locus, which maintain the translational read- Protein and calorie requirements may often be 160% ing frame (in-frame mutations), result in an abnormal of that predicted for able-bodied populations during but partially functional dystrophin protein, whereas the later stages of DMD (49,50). Restrictive lung dis- in Duchenne muscular dystrophy, the mutations shift ease becomes more problematic during this time, and the reading frame (out-of-frame mutations) so that vir- this may also influence caloric intake and require- tually no dystrophin is produced. The reading frame ments. Self-feeding often becomes impossible during interpretation is most accurate for deletions in the cen- this period because of significant biceps weakness. ter of the gene (exons 40\u201360) and is least accurate for In addition, boys with DMD may develop signs and deletions in the beginning of the gene (exons 1\u201320). symptoms of upper gastrointestinal dysfunction (51). Absent dystrophin or levels less than 5% of nor- Becker Muscular Dystrophy mal generally are considered diagnostic of Duchenne muscular dystrophy; however, 5% of such patients Existence of a form of muscular dystrophy with a simi- have BMD phenotypes. In BMD, dystrophin typically lar pattern of muscle weakness seen in Duchenne mus- has abnormally small molecular weight (<427 kDa). cular dystrophy, X-linked inheritance, but with later A minority of patients have dystrophin of larger-than- onset and a much slower rate of progression, was first normal molecular weight (>427 kDa) or normal molec- described by Becker and Kiener in 1955 (52). The disor- ular weight. Most BMD patients with larger or smaller der has the same gene location as the DMD gene (Xp21) molecular-weight dystrophin also have decreased and is thus allelic. On immunostaining of muscle biopsy quantities of the protein. All BMD patients with nor- specimens, the presence of patchy abundance of dystro- mal molecular-weight dystrophin have decreased phin suggests a Becker muscular dystrophy phenotype. quantities, usually less than 30% normal. Smaller-size On Western blot for quantitative dystrophin analysis, dystrophin typically is caused by deletion mutations, either 20% to 80% dystrophin levels or normal quan- and larger-size dystrophin by duplication mutations. tity and reduced or increased molecular-weight dystro- A further refinement is the use of antibodies specific phin is consistent with BMD. Studies show that 5% to to the carboxy-terminal (C-terminal) region of dystro- 20% dystrophin quantity is consistent with an outlier phin. Using such antibodies, immunohistochemistry or intermediate phenotype (5).","294 Pediatric Rehabilitation reveals that the C-terminal region is almost always DMD cases usually stop ambulating by 13 years unless absent in DMD but invariably present in BMD. Thus, treated with corticosteroids. Outlier DMD or interme- when this region of the molecule is missing, a more diate dystrophinopathy cases generally stop ambulat- severe phenotype is likely. ing between 13 and 16 years of age. Age of Onset and Presenting Signs. Studies have shown Pattern and Progression of Weakness. BMD patients have significant overlap in the observed age of onset distribution of weakness similar to those with DMD between DMD and BMD (10). Although determination (10). Proximal lower limb muscles are involved earlier of the quantity and molecular weight of dystrophin in the disease course. Gradual involvement of the pec- has substantially improved the early differentiation toral girdle and upper limb musculature occurs 10\u201320 among BMD, \u201coutlier\u201d DMD, and the more common years from onset of disease. Extensors have been noted and rapidly progressive DMD phenotype, Bushby and to be weaker than flexors (10). The muscle groups that colleagues (54) found no clear correlation between are most severely involved earlier in the course of dis- abundance of dystrophin and clinical course within ease include the hip extensors, knee extensors, and the BMD group. neck flexors (10). A series of Bushby and Gardner-Medwin (54), Contractures. Early development of contractures does which included 67 BMD subjects, supported the pres- not appear to be a feature of BMD (10,54). As with ence of two major patterns of progression in BMD: BMD, nonambulatory BMD subjects may develop a \u201ctypical\u201d slowly progressive course and a more equinus contractures, knee flexion contractures, and \u201csevere\u201d and rapidly progressive course. All of the hip flexion contractures. Because of the tremendous \u201csevere\u201d BMD cases showed difficulty climbing stairs replacement of muscle in BMD subjects by fibrotic tis- by age 20, whereas none of the \u201ctypical\u201d BMD cases sue, it is likely that, as in DMD, a muscle with less- had difficulty climbing stairs before age 20. Abnormal than-antigravity extension strength, which is statically ECGs were seen in 27% of typical BMD subjects and positioned in flexion, is more likely to develop a flex- 88% of severe subjects. Bushby and Gardner-Medwin ion contracture subsequent to wheelchair reliance. (54) found BMD subjects to have a mean age of onset of 12 years in the typical group and 7.7 years in the Spine Deformity. Spinal deformity is not nearly as com- severe group. Some patients with BMD present with mon or severe in BMD, as compared with DMD. Spinal major muscle cramps as an isolated symptom (54). As instrumentation is rarely required by DMD patients in DMD, preclinical cases are often identified by the (10,54). finding of a grossly elevated CK value. There is also considerable overlap in CK values between DMD and Pulmonary Function. Compromised pulmonary function BMD cases at the time of presentation. Thus, CK val- is much less problematic in BMD as opposed to DMD ues cannot be used to differentiate DMD from BMD. (10,25,54). The percent predicted forced vital capac- ity does not appear substantially reduced until the Calf enlargement is a nonspecific finding in BMD, third to fourth decade. The percent predicted maximal as is the presence of a Gower\u2019s sign. The gait over time expiratory pressure appears relatively more reduced is similar to other neuromuscular disease conditions at younger ages than the percent predicted maximal with proximal weakness. Patients often ambulate with inspiratory pressure, a finding seen in DMD and other a lumbar lordosis, forefoot floor contact, decreased neuromuscular diseases (9,55,56,57). This may be stance-phase knee flexion, and a Trendelenburg\u2019s or caused by more relative involvement of the intercos- gluteus medius lurch, often described as a waddle. tals and abdominal musculature with relative sparing of contractile function in the diaphragm of BMD. As in Other atypical clinical presentations include a sole DMD and other neuromuscular disease, it appears that complaint of cramps on exercise in individuals with predicted maximal expiratory pressure (MEP) may be no muscle weakness (54). In addition, patients with a useful quantitative measure of impairment and per- focal wasting of the quadriceps, previously diagnosed haps disease progression early in the course of BMD. with quadriceps myopathy, have been diagnosed with BMD, based on molecular genetic testing and\/or dys- trophin analysis on muscle biopsy (10). Age of Transition to Wheelchair. The most useful clini- Cardiomyopathy. The pattern of occasional life-threat- cal criterion to distinguish BMD from DMD is the con- ening cardiac involvement in otherwise mild and tinued ability of the patient to walk into late teenage slowly progressive BMD has been reported by many years. Those with BMD will typically remain ambu- (54,58). A significant percentage of BMD cases develop latory beyond 16 years. Some patients may become cardiac abnormalities, and the rate of progression of wheelchair uses in their late teens or 20s, whereas oth- cardiac failure may on occasion be more rapid than ers may continue walking into their 40s, 50s, or later. the progression of skeletal myopathy (58). In fact,","Chapter 12 Neuromuscular Diseases 295 successful cardiac transplantation has been success- related protein (FKRP), telethonin, and titin. The most fully performed in BMD subjects with cardiac failure. common LGMD2 subtypes include sarcoglycanopa- Approximately 75% of BMD patients have been found thies, dysferlinopathies, calpainopathies, and FKRP to exhibit ECG abnormalities (10,59). The abnormal deficiencies. The distribution and pattern of weakness findings most typically reported include abnormal at onset most often affects the pelvic or shoulder girdle Q-waves, right ventricular hypertrophy, left ventricu- musculature or both. The rate of progression is slower lar hypertrophy, right bundle branch block, and non- than DMD (60,61,62). Clinical features of the most com- specific T-wave abnormalities. Unlike DMD, resting mon forms of LGMD2 are shown in Table 12.2. sinus tachycardia has not been a frequent finding. Echocardiography has shown left ventricular dilation Sarcoglycanopathies (LGMD 2C-2F) in 37%, whereas 63% have subnormal systolic function because of global hypokinesia (59). Thus, the cardiac Disruption of the sarcolemmal membrane cytoskele- compromise may be disproportionately severe, rela- ton is a common feature of the sarcoglycanopathies. tive to the degree of restrictive lung disease in some Most of the primary sargoglycan abnormalities lead to BMD subjects. The evidence for significant myocardial secondary deficiencies of alpha-sarcoglycan. Diagnosis involvement in BMD is sufficient to warrant screening of sarcoglycanopathies may be made with molecular of all of these patients at regular intervals using ECG genetic studies and immunohistochemical analysis of and echocardiography. The slowly progressive nature muscle biopsies. The age of onset of sarcoglycanopa- of this dystrophic myopathy, which is compatible thies ranges from 2 to 15 years. Progression is variable with many years of functional mobility and longevity, with both more severe and milder phenotypes. Loss makes these patients suitable candidates for cardiac of ambulation may vary from 10 years to young adult- transplantation if end-stage cardiac failure occurs. hood. Weakness involves proximal greater than distal musculature. Calf pseudohypertrophy scapular wing- Some cases with BMD may present with an iso- ing, progressive contractures, and scoliosis often occur lated cardiomyopathy with no clinical manifestation (61). A dilated cardiomypathy may occur, particularly of skeletal muscle involvement. The diagnosis can be in alpha-SG and delta-SG. Intelligence is often normal. established by demonstration of a deletion in the Xp21 gene or by muscle biopsy. Isolated cases of cardio- Dysferlinopathies (LGMD 2B) myopathy in children, particularly those with family histories indicative of X-linked inheritance, should be Dysferlin is a skeletal muscle protein localized in the screened for BMD with an initial serum CK estimation muscle cell membrane (63). It is involved in muscle con- and molecular genetic studies of the Xp21 gene. traction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting Cognition. Cognitive testing in BMD subjects have that it may be involved in membrane regeneration and shown large variability in IQ scores and neuropsycho- repair. Specific mutations in this gene have been shown logical test measures. Mildly reduced intellectual per- to cause autosomal-recessive limb girdle muscular dys- formance has been noted in a subset of BMD patients; trophy type 2B (LGMD2B) with proximal muscle involve- however, the degree of impairment is not as severe as ment as well as Miyoshi myopathy, which presents with noted in DMD (10). distal weakness involving the distal legs, including the gastrocnemius and soleus muscles (61). In LGMD 2B, Limb Girdle Muscular Dystrophy (LGMD) no specific genotype-phenotype correlations have been established. LGMD 2B presents from 12 to 39 years, with Before the advent of genetic testing, a group of patients early weakness of gastrocnemius, quadriceps and psoas commonly sharing a progressive pattern of proximal muscles, and atrophy of the pelvic and shoulder girdle greater than distal muscular weakness with either auto- muscles. There is no scapular winging. Patients have somal-recessive (LGMD2) or dominant (LGMD1) inher- difficulty tip-toeing and running. Weakness occurs in itance were termed limb-girdle muscular dystrophies. a distal lower extremity and\/or pelvifemoral distribu- Recent advances in molecular and genetic analyses tion. Progression is slow, with loss of ambulation 10 to have now identified a number of distinct genetic muta- 30 years after onset. Equinus contractures are common, tions in these patients. LGMD1 subtypes usually have and toe-walking may be a presenting sign. Respiratory later onset in adulthood. LGMD2 usually present dur- and cardiac muscles are spared. Intelligence is normal. ing childhood or adolescence, although some may pre- sent in early adulthood. Many of the LGMD2 subtypes Calpainopathies (LGMD 2A) have been linked to gene defects causing abnormal- ities of the sarcolemmal-associated proteins, includ- Heterogeneous dystrophies due to mutation of the cal- ing sargoglycans (alpha-SG, gamma-SG, beta-SG, and pain-3 gene are termed calpainopathy (62). Calpain-3 is delta-SG), dystroglycans, calpain-3, dysferlin, fukutin-","296 12.2 Characteristics of Autosomal Recessive Limb Girdle Muscul LGMD 2A LGMD 2B LGMD 2C U.S. prevalence 4,200 2,850 675 Inheritance AR AR XR Gene location 4p21 2p12\u201314 13q12 Protein Calpain-3 Dysferlin \u2425-sarcoglycan Onset Early: <12 years 12\u201339 years Mean 5 to 6 yrs C283Y Severity course Leyden-Mobius type: Mean 19 \u00b1 3 years mutation: <2 years 13\u201329 years Late: >30 years Slow progression Variable progression Mild weakness (some like DMD; others Variable like BMD) Mild phenotype in Death common in majority second decade Early onset has more severe progression Ambulation status Loss of ambulation Loss of ambulation: Loss of ambulation: 10 \u201330 years after 10 \u201330 years after 10 \u201337 years (mean onset onset; 16 years) Most walk until their Weakness Scapula pelvic girdle fourth decade Proximal > Distal and trunk weakness Patchy distribution with Proximal legs > arms Weakness in some mutations gastrocnemius, Quadriceps: spared Cardiac No involvement quadriceps, and psoas Occasional; especially Weakness in biceps late in disease course after legs No involvement","lar Dystrophies (LGMD) LGMD 2D LGMD 2E LGMD 2F LGMD 2I 105 1,260 675 AR 450 XR AR 5q33 17q21 4q12 \u2425-sarcoglycan XR \u2425-sarcoglycan \u2425 -sarcoglycan (Adhalin) 2\u201310 years 19q13.3 2 \u2013 15 years 3 years\u2013teens Intrafamilial Fukutin-related variability protein 0.5\u201327 years; 61% less than 5 years Variable Moderate Rapid progression Variable Death in 2nd Early onset: non s Absent adhalin: rapid progression and decade ambulant by teens Later onset: progression severity Loss of slowly ambulation: 9 \u201316 progressive, Reduced adhalin: years 30% non- Later onset and milder ambulant by fourth to sixth weakness decade Early onset: loss of Often in wheelchair adhalin by 10 \u201315 years; Later onset: reduced usually by 25 years adhalin Proximal > distal Proximal Proximal Proximal > Distal Symmetric Legs: Proximal h Symmetric quadriceps Arms: proximal Dilated Face: mild weakness cardiomyopathy weakness in older described; May patients Dilated Occasional occur without cardiomyopathy cardiomyopathy myopathy Dilated cardiomyopathy in 30%\u201350% of patients","Respiratory Rarely involved: PFTs Rarely involved: Functional vital capacit rarely < 80% of normal ranges from normal to severe Quality of life Unknown Unknown Muscle size Hyper trophy: Unknown Limbs, pelvic and uncommon Hypertrophy of calf and Musculoskeletal shoulder: tongue in some patients Atrophy of posterior Contractures: calf compar tment s (toe walking may be Lumbar hyperlordosis presenting sign) Scapular Winging Contractures: calf (toe walking may be No intellectual defect presenting sign) reported Hearing loss CNS Intelligence: Normal to No intellectual defect Myopathic Inflammation mild mental retardation reported occasional Severe disease: absent Muscle pathology Myopathic Myopathic \u2425-sarcoglycan Slowly Necrosis and Necrosis and progressive: Reduced Blood chemistry regeneration with fiber degeneration with \u2425-sarcoglycan and hematology size variability variable fiber size Dystrophin: Normal or Endomysial fibrosis \u25a1 Endomysial reduced Type I predominance connective tissue with increasing Absent or \u2193 dysferlin CK: Very high weakness staining Normal Dystrophin and Normal Dystrophin Sarcoglycan and Sarcoglycan CK: 7 to 80 times CK: 10 to 72 times normal normal AR-LGMD, autosomal recessive limb girdle muscular dystrophy. 297","ty Functional vital Variable respiratory Variable Variable capacity ranges from involvement: respiratory respiratory normal to severe involvement: involvement; Unknown some severe Unknown Prominent muscle Unknown d Calf hypertrophy in hyper trophy Calf hypertrophy Unknown Cramps s some patients Calf, tongue and Shoulders: scapular Scapular winging thigh hypertrophy Scapular winging winging and muscle Wasting in regions wasting of weakness No intellectual defect reported No intellectual defect No intellectual Contractures in reported defect reported ankles (especially in non-ambulant) Scoliosis No intellectual defect reported n: Myopathic Myopathic Myopathic Myopathic Degeneration and Sarcoglycans: Fiber degeneration Necrosis and regeneration usually absent Fiber regeneration degeneration Variable fiber size Dystrophin: often \u25a1 -S arcoglycan Variable fiber size Endomysial connective reduced, but not absent connective tissue tissue absent Other sarcoglycans Type 1 fiber Myopathic grouping of absent or reduced predominance fibers CK: Very high (often \u2193 staining for Absent or reduced >5,000) adhalin adhalin \u2425-sarcoglycan CK: 10 to 50 times CK : Very high CK: Very high (often normal 1,000 \u20138,000) >5,000)","298 Pediatric Rehabilitation a nonlysosomal calcium-dependent proteinase specifi- musculoskeletal system, but other CMDs are char- cally expressed in muscle. Muscle biopsies reveal that acterized by significant cerebral neuronal migration calpainopathy patients have normal dystrophin and defects and eye abnormalities. Classical CMDs are fur- sarcoglycan labeling but lack calpain-3. An early-onset ther subdivided according to the presence or absence form occurs before 12 years of age and has the most of merosin (laminin-2) (64). An additional subgroup severe progression. The \u201cLeyden Mobius\u201d subtype has with collagen VI abnormalities has been identified and an onset between 13 and 30 years. Others with later referred to as Ullrich\u2019s congenital muscular dystrophy. onset have been reported. Pelvic girdle weakness is present and symptomatic from the onset, but often with Merosin-Deficient CMD striking sparing of the hip abductors, even relatively late into the course of the disease. Scapular winging is This condition (CMD 1A) has been linked to chromo- usually present from the early stages. The rate of dete- some 6q22 and accounts for around half of classical rioration varies between families. Wheelchair depen- CMD (64). These children show a consistently severe dency typically occurs at 10\u201330 years after the onset phenotype with multiple contractures and joint defor- of symptoms. The disease is predominantly symmetri- mities (arthrogryposis) at birth. Weakness correlates cal and atrophic, with prominent calves seen in only a with level of residual merosin (laminin \u03b12) protein. If minority of cases. Achilles tendon contractures may be there is absent laminin \u03b12 protein, weakness is severe, an early sign, and spine deformity may also develop. symmetric, proximal greater than distal, and involves Respiratory, but not cardiac, complications have been the facial muscles. Contractures are present at multi- reported. ple joints. CK is mildly to moderately elevated. Infants may present with respiratory failure, but if adequately Fukutin-Related Protein supported, they can be weaned off ventilatory sup- port. A proportion will achieve independent sitting, This dystrophy is caused by pathogenic mutations in but independent standing or walking is almost never the gene for fukutin-related protein (FKRP), which is achieved if laminin \u03b12 is severely reduced. Progressive involved in the glycosylation of cell surface molecules spine deformity is common. The condition tends to in muscle fibers (63). The majority of the LGMD 2I remain relatively static, but some subjects may show patients carry a common C826A missense mutation slow progression. Mental development is usually nor- in the FKRP gene. In the LGMD 2I patients, different mal, although minor learning disabilities and seizures mutations in the FKRP gene are associated with several do occur. Brain MRI commonly shows diffuse white secondary muscle protein reductions, and the deficien- matter signal changes. Nerve conduction velocities are cies of \u03b12-laminin and \u03b1-DG on sections are prevalent, frequently slowed, reflecting the ubiquitous expression independent of the mutation type or the clinical sever- of merosin in basement membranes. Merosin (laminin ity. LGMD 2I has a relatively mild and variable course, \u03b12) is an extracellular glycoprotein that interacts with with the age at onset varying from the first to the fourth surface receptors on the sarcolemmal membrane of the or fifth decade of life. Progression is slow. Serum CK is muscle cell. The diagnosis of merosin-deficient CMD elevated and intelligence is preserved, although struc- is dependent on the demonstration of absent merosin tural brain changes have been reported. staining on muscle immunohistochemistry. Congenital Muscular Dystrophy Merosin-Positive CMD The term congenital muscular dystrophy (CMD) has This is generally a milder disorder than merosin-defi- been widely used for a group of infants presenting cient CMD and the clinical phenotype is more hetero- with hypotonia, muscle weakness at birth or within geneous. Intellectual function is normal and the brain the first few months of life, congenital contractures, magnetic resonance imaging (MRI) is normal. Most of and immunohistochemical finding of dystrophic these children present with weakness and hypotonia, changes on muscle biopsy (muscle fiber necrosis and and they achieve the ability to stand and walk inde- regeneration, increased endomysial connective tissue, pendently by age 4. The course is static, with little and replacement of muscle with fat tissue). The early or no progression; however, contractures and scoliosis contractures may include equinovarus deformities, may develop. Respiratory failure is uncommon, as is knee flexion contractures, hip flexion contractures, cardiomyopathy. and tightness of the wrist flexors and long finger flex- ors. The contractures can become more severe over Fukuyama CMD time with prolonged static positioning and lack of adequate passive range of motion and splinting\/posi- These patients present in infancy with severe hypo- tioning. Classical CMDs are clinically confined to the tonia, weakness, and wasting of the face and limbs,","Chapter 12 Neuromuscular Diseases 299 occasional spasticity, large cheeks, contractures, collagen VI abnormality (64). The term collagen myopa- kyphoscoliosis, microcephaly, seizures (50%), severe thy is increasingly being utilized to describe these con- mental retardation (IQ 30 to 50), and occasionally ditions. Three subunits of collagen VI have been found progressive hydrocephalus. Muscle biopsy shows dys- to be abnormal in these patients: collagen type VI, trophic changes. While rare in North America, the subunit \u03b11 (COL6A1) linked to chromosome 21q22.3; condition is common in Japan, with an incidence collagen type VI, subunit \u03b12 (COL6A2), also linked to approaching 40% of Duchenne muscular dystrophy chromosome 21q22.3; and collagen type VI, subunit (65). Brain malformations are frequently seen on MRI, \u03b13 (COL6A3) linked to chromosome 2q37. Inheritance including polymicrogyria, pachygyria, and agyria. for all three groups may be recessive or dominant. Frontal white matter lucencies are also evident on MR Clinical features are variable, as some patients show or computed tomography (CT) imaging. The gene loci severe weakness and some families with COL6A3 has been identified to be at 9q31\u201333. mutations have milder disease. Onset is often at birth, with congenital proximal contractures and arthrogry- Muscle-Eye-Brain Disease posis caused by reduced fetal movements, hypotonia, and early hyperlaxity of distal joints (Fig. 12.11). Knee This is a syndrome comprising congenital muscular contractures may limit walking in some. Spine rigid- dystrophy, marked mental retardation due to neuro- ity and kyphoscoliosis has been noted. Torticollis may nal migration defects, and ocular abnormality. Infants improve with increasing age. Weakness is diffuse and present with congenital hypotonia, muscle weak- affects distal muscles greater than proximal and neck ness, elevated CK, myopathic EMG, and a dystrophic flexors. A minority of patients walk by age 1 to 2 years, changes on muscle biopsy. Children with muscle-eye- but the majority never walk. Respiratory insufficiency brain disease are usually able to stand and ambulate. and hypoventilation may begin in the first decade, Severe visual impairment is present, caused by severe and respiratory failure is not correlated with degree myopia, retinal dysplasia, cataracts, and optic atro- of weakness. The course is slowly progressive. Death phy. Patients often deteriorate around 5 years of age has been reported in the first or second decade due with progressive occurrence of spasticity. CT scans to respiratory failure, but many patients live to adult- have shown ventricular dilatation and low density of hood. The skin is soft, lax, and a classic rash can often the white matter. Death is usually in the first or sec- be found described as \u201ckeratosis pilaris.\u201d Patients may ond decade, but some individuals survive well into also show keloids, atrophic scars, striae, and pete- adulthood. chiae. There is no associated cardiomyopathy, and intelligence is usually normal. Serum CK is normal Walker-Warburg Syndrome (WWS) to 10 times elevated, and EMG is usually myopathic. Muscle biopsy and skin biopsy should be obtained to This is a severe condition leading to blindness at make the diagnosis. Muscle biopsy shows varied mus- birth and early death. Infants present with congen- cle fiber size, some very small muscle fibers, and an ital muscular dystrophy, mental retardation, and increase in endomysial connective tissue. Rare or occa- consistent central nervous system abnormalities on sional necrotic muscle fibers may be found. Collagen imaging (type II lissencephaly, abnormally thick cor- tex, decreased interdigitations between white mat- ter and cortex, and cerebellar malformation). Ocular abnormalities and cleft lip or palate may also be present. Muscle involvement is less prominent in Walker-Warburg syndrome (WWS) than other CMDs. Several gene abnormalities with autosomal-recessive inheritance have been linked to WWS, including O-mannosyltransferase 1 (POMT1) linked to chromo- some 9q34.1 and O-mannosyltransferase 2 (POMT2) linked to chromosome 14q24.3. Ullrich Congenital Muscular Dystrophy Figure 12.11 Joint laxity in Ullrich congenital muscular dystrophy with collagen VI abnormality. An emerging common group of CMD patients have a unique combination of dystrophic changes on mus- cle biopsy in association with weakness, low tone, selected early joint contractures, and other joints and skin demonstrating clinical laxity caused by a primary","300 Pediatric Rehabilitation VI expression may be absent in skeletal muscle and fibers. Other fibers may be hypertrophied. Serum capillaries or absent on surface of muscle fibers but creatine kinase levels are normal or slightly elevated present in connective tissue. There has been no cor- in the majority of patients. Diagnosis is confirmed relation between pattern of pathology and clinical in more than 90% of cases by molecular genetic phenotype. testing. Congenital Muscular Dystrophy Facial weakness is an important clinical feature of With Early Spine Rigidity FSHD muscular dystrophy. The initial weakness affects the facial muscles, especially the orbicularis oculi, This is a recessive condition caused by a defect in zygomaticus, and orbicularis oris. These patients often selenoprotein N, 1 (SEPN1) and linked to chromosome have difficulty with eye closure but not ptosis. An indi- 1p35-p36. Clinical severity is variable, with early-onset vidual may assume an expressionless appearance and cases in infancy and later-onset cases in the later first exhibit difficulty whistling, pursing the lips, drinking decade. Patients present with hypotonia and poor head through a straw, or smiling (Fig. 12.12). Even in the control. The weakness is symmetric and involves the very early stages, forced closure of the eyelids can be neck, face, and proximal and distal musculature. easily overcome by the examiner. Masseter, tempora- lis, extraocular, and pharyngeal muscles characteristi- Respiratory function is compromised with vital cally are spared in FSHD. capacity below 55% by the end of the first decade. Patients often show signs of nocturnal hypoventilation and central apnea. Respiratory failure may develop. Some patients never develop walking. Muscle size is small, especially in the inner thighs and calves. Many children show early improvement, with development followed by nonprogressive or slow decline. The rigid spine develops by 3 to 7 years and is manifested by limited flexion of the neck and spine. Progressive sco- liosis occurs with onset 4 to 12 years. Contractures of the elbow flexors, hip extensors, ankles, and knees are common. The rate of insulin resistance is increased, and intelligence is normal. Serum CK is usually nor- mal. The muscle to biopsy can be best identified by MR imaging, with involved muscles often being the vastus lateralis and biceps femoris. Clinically, there is overlap with minicore congenital myopathy syndromes, and mutations in this SEPN1 gene also cause minicore con- genital myopathy, congenital myopathy with desmin inclusions, and congenital fiber type size dispropor- tion (small type I fibers). Fascioscapulohumeral Figure 12.12 Facial weakness and expressionless facies Muscular Dystrophy (FSHD) in fascioscapulohumeral muscular dystrophy. Both father and daughter demonstrate dif\ufb01culty whistling and pursing Facioscapulohumeral muscular dystrophy (FSHD) is their lips. a slowly progressive dystrophic myopathy with pre- dominant involvement of facial and shoulder girdle musculature (66). The condition has autosomal-dom- inant inheritance, with linkage to the chromosome 4q35 locus. Approximately 10% to 30% of cases are caused by sporadic mutations. FSHD is the third most common of the dystrophies, behind Duchenne and myotonic dystrophies, with an incidence of between 10 and 20 per million live births (7). Age of presen- tation is generally before age 20. Changes on muscle biopsy are relatively slight, with the most consistent finding being the presence of isolated small atrophic","Chapter 12 Neuromuscular Diseases 301 Scapular stabilizers, shoulder abductors, and by the late second or third decade. These individu- shoulder external rotators may be significantly als also have a progressive exudative telangiectasia affected, but at times the deltoids are surprisingly of the retina. Early recognition and photocoagula- spared if tested with the scapulae stabilized. Both tion of the abnormal retinal vessels may prevent loss the biceps and triceps may be more affected than the of vision. Several audiometry studies have demon- deltoids. Patients with FSHD show characteristic pat- strated hearing deficits in many later-onset FSHD terns of muscle atrophy and scapular displacement. patients in addition to those with Coates syndrome, Involvement of the latissimus dorsi, lower trapezius, suggesting that impaired hearing function is more rhomboids, and serratus anterior results in a charac- common than expected in FSHD muscular dystro- teristic appearance of the shoulders, with the scapula phy (68). Thus, all patients with FSHD should have positioned more laterally and superiorly, giving the screening audiometry and ophthalmologic eval- shoulders a forward-sloped appearance (Fig. 12.13). uation. Contractures are relatively uncommon in The upper border of the scapula rises into the trape- FSHD muscular dystrophy. FSHD patients with sco- zius, falsely giving it a hypertrophied appearance. liosis have mild and nonprogressive curves. Rarely, From the posterior view, the medial border of the severe and progressive hyperlordosis is associated scapula may exhibit profound posterior and lateral with FSHD. The patient with severe hyperlordosis winging. The involvement of shoulder girdle muscu- may utilize their lordotic posturing to compensate lature may be quite asymmetric. Some authors have for hip extensor weakness. found asymmetric weakness in the dominant upper extremity (67). Mild restrictive lung disease has been reported in nearly one-half of FSHD patients (66). The expi- A sensory neural hearing deficit was originally ratory muscles involved in respiration appear to be observed in Coates syndrome (early-onset FSHD). more affected than inspiratory muscles in FSHD These individuals have a myopathy that presents (67). Patients rarely require nocturnal ventilatory in infancy. The disease progression is fairly rapid, support. with most individuals becoming wheelchair-reliant The presence of cardiac abnormalities in FSHD muscular dystrophy is debated. While diverse ECG abnormalities have been noted, one study showed no abnormalities on ECG, chest radiography, Holter mon- itoring, and echocardiography (69). Nuclear scanning with thallium-201 has demonstrated diffuse defects consistent with diffuse fibrosis (32). Abnormalities in systolic time intervals on echocardiography and eleva- tions in atrial natriuretic peptide are consistent with subclinical cardiomyopathy. Cardiac complications in FSHD muscular dystrophy are rare, and patients in general have normal longevity. There is usually no associated intellectual involvement in this dystrophic myopathy. AB Figure 12.13 (A) Posterior and lateral scapular winging, high-riding scapula, and (B) hyperlordosis in fascioscapulohumeral muscular dystrophy.","302 Pediatric Rehabilitation Emery-Dreifuss Muscular below 50. EKG changes include slow heart rate, absent Dystrophy (EMD) or small P waves, AV block, and atrial fibrillation\/flut- ter. Evidence of cardiac arrhythmia, sometimes only Emery-Dreifuss muscular dystrophy (EMD) refers present at night, may be detected on 24-hour Holter to a group of muscular dystrophies with weakness, monitoring. A significant percentage of female carri- contractures and cardiac conduction abnormalities. ers have conduction defects and arrhythmias, so they Inheritance pattern is variable among subtypes. warrant monitoring with annual EKGs. Emery-Dreifuss 1 Laboratory evaluation is usually with molecu- lar genetic studies and\/or muscle biopsy. Serum CK Emery-Dreifuss 1 (EMD1) is an X-linked recessive pro- is mildly elevated to <10 times normal, and levels gressive dystrophic myopathy due to an abnormality decrease with age. MRI of posterior calf shows the of the protein \u201cEmerin\u201d with a gene locus identified at soleus to be involved and the gastrocnemius to be rel- Xq28 (70,71). The protein is associated with the subcel- atively spared. Muscle biopsy shows variable muscle lular nucleus and cytoplasm membranes, and is found fiber size, endomysial fibrosis, inflammation, type I in muscle, nerve, mucosal epithelium, skin, and car- fiber atrophy, type I or II predominance, and nuclear diac tissue. Patients usually present in teenage years, membrane pathology on electron microscopy. Other but age of presentation may vary from the neonatal muscle changes in some patients include rimmed period with hypotonia to the third decade. Early elbow vacuoles (\u201cIBM-like\u201d). Immunohistochemistry reveals flexion contractures are a hallmark of the disease. Emerin loss in muscle in >95% of patients. Severe contractures, including elbow flexion, ankle equinus, rigid spine, and neck extension contractures, Emery Dreifuss Muscular Dystrophy 2 are often more limiting than weakness, which begins in a sapulohumeral peroneal distribution. The biceps EMD2 is due to a lamin A\/C protein abnormality, and and triceps show wasting and weakness, and the del- it has been linked to chromosome 1q21.2. Inheritance toids and forearms are often more spared. The calf may be dominant or recessive, and lamin A\/C muta- frequently shows wasting. Ankle dorsiflexors often tions may be either frameshift or missense (70). Those are weaker than ankle plantar flexors leading to the with missense mutations have childhood onset, with a equinus contractures. Scapular winging is frequent. mean age of onset of 2.4 years. Weakness is in a scapu- Tightness of the cervical and lumbar spinal extensor loperoneal and facial distribution. Patients demonstrate muscles, resulting in limitation of neck and trunk flex- paravertebral weakness or rigidity, and tendon contrac- ion, with inability to flex the chin to the sternum and tures are common. Those with frameshift mutations to touch the toes, also has been reported in EMD. The producing a truncated protein have adult onset, with face is either spared or affected late. Functional dif- mean age of 30.5 years, and cardiomyopathy is more ficulties are experienced walking or climbing stairs. frequent than weakness (70). Contractures are rare, Progression is slow and loss of ambulation is rare. and weakness is in a limb girdle distribution. The dis- Some cases with EMD1 may show evidence of noctur- order is allelic with autosomal-dominant LGMD 1B. nal hypoventilation, as a result of restrictive expan- sion of the chest in association with the rigid spine, CONGENITAL MYOPATHIES and partly due to involvement of the diaphragm. The term congenital myopathy is used to describe a Progressive cardiac disese is almost invariably group of heterogenous disorders usually presenting present, with onset in the early second decade to the with infantile hypotonia due to genetic defects, caus- fourth decade. Arrhythmia may lead to emboli or sud- ing primary myopathies with the absence of any struc- den death in early adult life. The cardiomyopathy may tural abnormality of the central nervous system or progress to left ventricular myocardial dysfunction or peripheral nerves. A specific diagnosis of each entity four-chamber dilated cardiomyopathy due to fibrosis is made on the basis of specific histologic and elec- with complete heart block and ventricular arrhythmias tron microscopic changes found on muscle biopsy. (72). Initially, atrial arrhythmia usually appears prior While patients may be hypotonic during early infancy, to complete heart block. Reported features include they later develop muscle weakness that is generally first-degree heart block, followed by Wenckebach nonprogressive and static. The weakness is predom- phenomenon, and then complete atrial ventricular inantly proximal, symmetric, and in a limb girdle dissociation and atrial fibrillation or flutter with pro- distribution. gressive slowing of the rate (72). Frank syncope may develop in the late second and early third decade, and The serum creatine kinase values are frequently patients often require a cardiac pacemaker by age 30 normal, and the EMG may be normal or may show with an indication being bradycardia with heart rate mild, nonspecific changes, usually of a myopathic","Chapter 12 Neuromuscular Diseases 303 character (small-amplitude polyphasic potentials). The different modes of inheritance, but the most typical only congenital myopathy consistently associated with form is autosomal recessive. While the rods may be spontaneous activity is myotubular (centronuclear) easily overlooked on routine hematoxylin-and-eosin myopathy. In this disorder, the EMG reveals myopathic (H&E) staining, they can be rarely demonstrated with motor unit action potentials with frequent complex the Gomori trichrome stain. The rods are readily dem- repetitive discharges and diffuse fibrillation potentials. onstrated on electron microscopy. They are thought to These myopathies may be considered primarily struc- be an abnormal deposition of Z-band material of a pro- tural in nature and thus, patients do not actively lose tein nature and possibly alpha-actinin. The disease has muscle fibers, as is the case in dystrophic myopathies. been linked to at least seven distinct genes. The severe congenital form has been linked to \u03b1-Actin, nebulin, Central Core Myopathy and troponin T1 mutations. A milder childhood form has been linked to \u03b1-actin, nebulin, \u03b1-tropomyosin 3 This is an autosomal-dominant disorder with gene (TPM3), and \u2424-tropomyosin (TPM2) mutations. locus at 19q13.1, the same gene locus as the malig- nant hyperthermia gene (ryanodine receptor gene, A severe form of the disease may present in the RYR1). Indeed, these patients have a high incidence of neonatal period with severe weakness, respiratory malignant hyperthermia with inhalational anesthetic insufficiency, and often a fatal outcome. Most cases agents. Histologically, the muscle fibers have amor- present with a mild, nonprogressive myopathy with phus-looking central areas within the muscle that may hypotonia and proximal weakness. In more severe be devoid of enzyme activity. There are densely packed cases, swallowing difficulty may be present in the neo- disorganized myofibrils (\u201ccores\u201d) in the center of the natal period. Skeletal abnormalities, such as kyphosco- majority of type 1 fibers. Electron microscopy shows liosis, pigeon chest, pes cavus feet, high arched palate, the virtual absence of mitochondria and sarcoplasmic tent-shaped mouth, and an unusually long face has reticulum in the core region, reduced muscle enzymes been noted. Cardiomyopathy has been described in (cytochrome oxidase, NADH), a marked reduction in both severe neonatal and milder forms of the disease. the interfibrillary space, and an irregular zig-zag pat- Autosomal-dominant inheritance has been described tern (streaming) of the Z-lines. This gives rise to the in a few instances. characteristic central pallor. There is a predominance of high oxidative, low glycolytic type I fibers and a Centronuclear (Myotubular) relative paucity of type II fibers, resulting in a relative Myopathy (Non-X\u2013linked) deficiency of glycolytic enzymes. Patients with non-X\u2013linked myotubular myopathy Clinically, patients generally demonstrate mild have muscle biopsies that show a striking resemblance and relatively nonprogressive muscle weakness, either to the myotubes of fetal muscle. Patients typically pre- proximal or generalized, and arreflexia, which pres- sent with early hypotonia, delay in motor milestones, ents in either early infancy or later. There may be mild generalized weakness of both proximal and distal facial weakness but normal extraocular movements. musculature, and ptosis with weakness of the exter- Patients often achieve gross motor milestones, such nal ocular muscles, as well as weakness of the axial as walking, rather late, and they continue to have musculature. The author has seen severe cardiomyop- difficulty going upstairs. Proximal limb weakness is athy in an adult female with documented autosomal- typical, and patients may show a Gower\u2019s sign. The dominant inheritance. Nocturnal hypoventilation has disorder remains fairly static over the years. There been described. may be a frequent occurrence of congenital dislocation of the hip, kyphoscoliosis, and pes cavus. The condi- Several gene loci with autosomal-dominant inher- tion is largely nonprogressive, with affected children itance have been identified in centronuclear congen- remaining ambulatory into adult life. One-third show ital myopathy, including dynamin 2 (DNM2) linked anesthesia-related malignant hyperthermia. Central to chromosome 19p13.2, and MYF6 linked to chromo- core myopathy and familial malignant hyperthermia some 12q21. appear to be allelic, as the ryanodine receptor chain implicated in malignant hyperthermia has the same Severe X-linked Centronuclear locus. Individuals within the same family can exhibit (Myotubular) Myopathy one or both phenotypes. Cases with neonatal onset and severe respiratory insuf- Nemaline Myopathy ficiency have been identified with an X-linked reces- sive mode of inheritance. The gene for this disorder Nemaline myopathy, also referred to as rod body codes for myotubularin (MTM1), and has been linked myopathy, represents a varied group of disorders with to chromosome Xq27.3-q28. Muscle biopsy shows","304 Pediatric Rehabilitation characteristic fetal-appearing myotubes with rows of picture demonstrating type I fibers that are smaller centrally placed internal nuclei. than type II fibers by a margin of more than 12% of the diameter of the type II fibers. The mean reduction in Patients present with severe generalized hypoto- fiber diameter is 41% and ranges up to 78%. A number nia, associated muscle weakness, swallowing diffi- of disorders, such as congenital myopathies (nemaline culty, and respiratory insufficiency. They often become rod, centronuclear, and multi-minicore), Emery-Dreifuss ventilator-dependent at birth. If they are able to be MD and myotonic dystrophy 1, rigid spine syndromes, weaned from the ventilator, subsequent death due to congenital muscular dystrophy (SEPN1), LGMD 2A, pulmonary complications is not uncommon. Mean age and severe spinal muscular atrophy, all may show of death is 5 months, but some children survive for small type I fibers and should be excluded. The diag- many years with mechanical ventilation. Aspiration nosis of congenital fiber-type disproportion should be pneumonias are common. Additional clinical features made only in the presence of normal-sized or enlarged include congenital contractures, facial weakness with type II fibers and not in cases where both type I and an elongated expressionless face, tent-shaped mouth, type II fibers are small. Serum CK has been normal to high arched palate, weakness of the external ocular <3 times the upper limit of normal. muscles, and long digits. Progressive kyphoscolio- sis is common. Systemic features in some survivors Patients typically present with infantile hypoto- >1 year of age include pyloric stenosis, spherocyto- nia and delay in gross motor milestones. The severity sis, gallstones, renal stones or calcinosis, a vitamin has been noted to be quite variable, but it is generally K-responsive bleeding diathesis, rapid linear skeletal nonprogressive or improves with time. Limb weak- growth, advanced bone age, and hepatic dysfunction. ness of variable severity may be diffuse or affect Electromyography shows many fibrillations and posi- proximal muscles. Deep tendon reflexes are reduced. tive sharp waves. Ophthalmoplegia, facial weakness, and bulbar weak- ness are rare findings but associated with more severe Minicore Disease (Multicore Disease) cases. Intelligence is normal. There is generally short stature and low weight. Patients may exhibit a long, This is a relatively rare congenital myopathy with narrow face; high-arched palate; and deformities of muscle biopsies showing multiple small randomly the feet, including either flat feet or occasionally high- distributed areas in the muscle, with focal decrease arched feet. Kyphoscoliosis has been reported. Lenard in mitochondrial oxidative enzyme activity and focal and Goebel (74) documented a case with fairly severe myofibrillar degenerative change. Characteristic weakness and associated respiratory deficit, necessitat- changes are present on electron microscopy. There is a ing tracheostomy. The author has managed two cases predominance of type I fiber involvement. (a mother and son with presumed autosomal-dominant inheritance), who both developed nocturnal hypoven- Clinically, patients present with hypotonia, delays tilation requiring bilevel positive airway pressure. in gross motor development, and nonprogressive sym- metric weakness of the trunk and proximal limb mus- Patients with muscle biopsies indicative of con- culature. There may be mild facial weakness, ptosis, genital fiber-type disproportion and ptosis should and ophthalmoplegia. There is also associated dia- be evaluated for a congenital myasthenic syndrome, phragmatic weakness, placing patients at risk for noc- as the author has seen a number of cases in recent turnal hypoventilation. Subtle ultrastructural changes years of congenital structural neuromuscular junction allow this condition to be distinguished from central disorders that have associated nonspecific changes core disease. The cores are smaller in size (minicores) on muscle biopsy, interpreted to be congenital fiber- and not confined to the center of the fiber. Inheritance type disproportion. This is an important distinction, is usually autosomal-recessive, and two genes\u2014the as some of these patients with congenital myasthenia ryanodine receptor gene (RYR1), linked to chromo- respond to pharmacologic intervention. some 19q13.1, and the selenoprotein N, 1 (SEPN1) gene, linked chromosome 1p35-p36, account for 50% The mode of inheritance for congenital fiber-type of cases. disproportion is varied, with both autosomal-reces- sive and autosomal-dominant patterns of inheritance Congenital Fiber-Type Size reported. Disproportion MYOTONIC DISORDERS Congenital fiber-type size disproportion represents a heterogenous group of conditions most likely with var- Myotonic Muscular Dystrophy 1 (DM1) ied genetic defects. The condition was initially delin- eated by Brooke (73) on the basis of the muscle biopsy Myotonic muscular dystrophy 1 (DM1) is an auto- somal-dominant multisystem muscular dystrophy","Chapter 12 Neuromuscular Diseases 305 with an incidence of 1 per 8,000 (7). It represents the long-standing DM1 often has characteristic facial fea- most common inherited neuromuscular disease of tures. The long, thin face with temporal and masseter adults. The disorder affects skeletal muscle, smooth wasting is drawn and has been described by some as muscle, myocardium, brain, and ocular structures. \u201clugubrious.\u201d Adult males often exhibit frontal bald- Associated findings include baldness and gonadal ing. Children with congenital myotonic muscular atrophy (in males), cataracts, and cardiac dysrhyth- dystrophy often exhibit a triangular or so-called tent- mias. Insulin insensitivity may be present. The gene shaped mouth (Fig. 14B). has been localized to the region of the myotonin pro- tein kinase (DMPK) gene at 19q13.3. Patients dem- Myotonia, a state of delayed relaxation, or sus- onstrate expansion of an unstable CTG trinucleotide tained contraction of skeletal muscle is easily identified repeat within the region. Molecular genetic testing in school-age children, adolescents, and adults with is available for diagnosis. Normal individuals gener- DM1. Grip myotonia may be demonstrated by delayed ally have <37 repeats, which are transmitted from opening of the hand with difficult extension of the fin- generation to generation. DM1 patients may have 50 gers following tight grip. Percussion myotonia may be to several thousand CTG repeats with remarkable elicited by percussion of thenar eminence with a reflex instability. The age of onset is inversely correlated hammer, giving an adduction and flexion of the thumb by the repeat links (75). Mild, late-onset DM1 usually with slow return (see Fig. 12.4). Symptomatic myoto- is associated with 50\u2013150 repeats, classic adolescent nia may be treated with agents such as mexiletine or or young adult-onset DM1 shows 100\u20131,000 repeats, membrane stabilizers such as carbamazepine or dilan- and congenital DM1 patients show greater than 1,000 tin, which have been shown to affect the symptoms; repeats. The expanded CTG repeat further expands however, patients treated have shown little functional as it is transmitted to successive generations, pro- gain (76). viding a molecular basis for genetic anticipation. Both maternal-to-child and paternal-to-child trans- DM1 is one of the few dystrophic myopathies with mission occurs. Repeat size in offspring exceeding greater distal weakness than proximal weakness, 1,000 CTG repeats is generally seen in maternal although neck flexors, shoulder girdle musculature, rather than paternal transmission. Affected fathers and pelvic girdle musculature may become signifi- seldom transmit alleles larger than 1,000 copies to cantly involved over decades. Weakness initially is offspring owing to a lack of sperm containing such often most predominant in the ankle dorsiflexors, alleles. ankle everters and inverters, and hand muscles (77). As with other dystrophic myopathies, significant mus- Several characteristic facial features of DM1 may cle wasting may occur over time. In DM1 patients with be noted on inspection (Fig. 12.14A). The adult with infantile onset, a congenital club foot or talipes equi- novarus are fairly common deformities (Fig. 12.15). In patients with noncongenital DM1, contractures at the wrist, ankle, and elbows are relatively uncommon and AB Figure 12.14 (A) Typical facial characteristics in myotonic muscular dystrophy 1 (DM1) and congenital DM1. The symptomatic mother has 660 trinucleotide CTG repeats at the DM protein kinase (DMPK) gene loci in chromosome 19q13.3, while the child has 1,560 repeats. (B) Siblings with DM1.","306 Pediatric Rehabilitation Figure 12.15 Talipes equinus in congenital myotonic which may explain the occurrence of sudden death, muscular dystrophy 1 (DM1). which occurs in less than 5% of DM1 patients (78). Ventricular tachycardia may also contribute to the mild (77). Patients with congenital-onset DM1 may syncope and sudden death associated with DM1. develop spinal deformity requiring surgical spinal Some patients have required implantation of cardiac arthrodesis (77). pacemakers. Q-waves have been reported on screen- ing ECGs in DM1 patients, and this abnormality may Excessive daytime sleepiness is commonly seen reflect myocardial fibrosis (77,78). Occassionally, in DM1, and it is thought to be related to the loss of teenagers may present with atrial arrythmias. Any serotonergic neurons in the dorsal raphe and supe- DM1 patient with dyspnea, chest pain, syncope, or rior central nucleus of the brainstem. Treatment of the other cardiac symptoms should receive thorough hypersomnolence with modafinil has been helpful. cardiac evaluation. Endocrinopathies are frequently found in DM1. Individuals with congenital and noncongenital These include hypothyroidism, increased insulin DM1 have a very high incidence of restrictive lung resistance and type 2 diabetes, reduced insulinlike disease (77). Involvement of respiratory muscles is a growth factor-1 (IGF-1) levels, hypogonadism in males major cause of respiratory distress and mortality in with reduced testosterone levels and oilgospermia, affected infants with DM1. Swallowing difficulties that pituitary deficiency with reduced growth hormone produce aspiration of material into the trachea and release, and increased follicle-stimulatin hormone bronchial tree, along with weakened respiratory mus- (FSH) levels. DM1 patients should also be screened cles and a weak cough, have been reported as factors for diabetes mellitus, as insulin insensitivity is not that may result in pulmonary complications in DM1 uncommon. patients. Constipation is a fairly common complaint in congenital DM1, owing to smooth muscle involve- Cardiac involvement is common in DM1. ment. Care should be taken during general anesthesia Abnormalities on ECG and echocardiography are in DM1 due to risk of cardiac arrhythmias and malig- demonstrated in approximately 70% to 75% of nant hyperthermia. patients (77). Prolongation of the PR interval, abnor- mal axis, and infranodal conduction abnormalities Twenty-five percent of infants born to myotonic are all suggestive of conduction system disease, mothers have congenital DM1 and 10% to 15% of all DM1 patients have congenital presentations. CTG repeats in these cases may range from 1,000 to more than 4,000 repeats. Obstetric problems are inversely related to age of presentation of the mother with DM1, and they include polyhydramnios, decreased fetal movements, breech presentation, and preterm labor. Infants show hypotonia, failure to thrive due to an inability to suck, bilateral facial and jaw muscle weakness, craniofacial changes (including a tented upper lip and high-arched palate), neonatal respira- tory distress (50%), delayed motor milestones, and delayed speech. Equinovarus deformaties are com- mon. Most children are weaned from the ventilator and walk independently. Clinically, children with congenital DM1 usually show no myotonia over the first five years of life. Those with congenital DM1 usually show significantly reduced IQ, often in the mentally retarded range (77,79). The cognitive impairment is nonprogressive. Behavioral abnor- malities include hyperactivity attention-deficit and autistic behavior. Hydrocephalus may be seen in nearly half of patients with congenital DM1. MRI may show hypoplasia of corpus callosum and cere- bral white matter changes and diffuse cerebral atrophy. Diagnosis of congenital DM1 is made by molecular genetic studies, as EMG shows no myo- tonia and CK is usually normal. Muscle biopsy is normal or nonspecific.","Chapter 12 Neuromuscular Diseases 307 In noncongenital DM1, there is evidence for a gen- in releasing objects or difficulty walking or climbing erally lower intelligence of a mild degree (full-scale IQs stairs. Most patients do not show overt weakness. have been reported in the 86\u201392 range) (77). There is a Functional difficulties in climbing stairs may be pre- wide range of IQ values found in this population, with sent. The myotonia is exacerbated by prolonged rest many subjects scoring in the above-average range. or inactivity. There is a \u201cwarm-up\u201d phenomenon with Cognitive functioning also appears to be related to the reduced myotonia after repeated activity. Myotonia size of the CTG expansion at the DM1 gene locus. may be aggravated by cold, hunger, fatigue, and emo- tional upset. Patients may demonstrate grip myotonia Proximal Myotonic Myopathy or lid lag following upward gaze or squint and diplopia (PROMM; DM2) following sustained conjugate movement of the eyes in one direction. Nearly all have electrical myotonia Proximal myotonic myopathy, also referred to as myo- by EMG, but there is a warm-up phenomenon with the tonic muscular dystrophy 2 (DM2), is a disorder with myotonia reduced after a period of maximal contrac- clinical similarities to DM1 (80). The abnormal pro- tion. Half of individuals have percussion myotonia. tein in this autosomal-dominant disorder is the zinc Patients may be symptom-free for weeks to months. The finger protein 9 (ZNF9) with genetic loci at chromo- other common feature of myotonia congenita is mus- some 3q21. Clinical severity is unrelated to variable- cle hypertrophy. Patients may exhibit a \u201cHerculean\u201d size CCTG repeats. The prognosis is more benign than appearance. Patients have shown some benefit from DM1, and there is not a severe congenital onset form. treatment with quinine, mexiletine, dilantin, procain- Onset is 8 to 60 years, and there is intrafamilial var- amide, carbamazepine, and acetazolamide. iability. Patients present with muscle stiffness and pain. Weakness involves the proximal legs (hip flex- A recessive form of myotonia congenita (Becker ors and extensors) greater than the proximal legs as form) also exists with later onset (ages 4 to 12), more well as thumb and finger flexors. Facial weakness is marked myotonia, more striking hypertrophy of mus- seen in a minority of patients. Distal legs and respi- cles, and associated weakness of muscles, particularly ratory muscles are not clinically affected. A hallmark with short exercise. EMG shows myotonia in distal is the enlargement of calf muscles. Muscle pain may muscles and less myotonia after maximal contrac- be exercise-related, or at rest and increases with cold. tion. On repetitive stimulation, there is a decremental The myotonia is severe, asymmetric, and intermittent CMAP response at high stimulation frequency (30 Hz) from day to day. The myotonia actually inceases with and following exercise. The dominant form seems warmth and decreases with cold. There is both grip more prone to aggravation of the myotonia by cold. and percussion myotonia. Cataracts are noted in all Diagnosis is suspected based on clinical information patients over 20 years with slit lamp examinations. and the presence of classical myotonic discharges on Cardiac conduction defects are present in 20%, dia- EMG. Diagnosis is confirmed with molecular genetic betes mellitus in 20%, and hearing loss in 20%. MRI testing. Muscle biopsy is essentially normal, apart from shows white matter hyperintensity on T2-weighted the presence of hypertrophy of fibers and an absence images. CK is normal to less than 10 times elevated. of type II-B fibers. EMG shows profound myotonia and compound muscle action potential (CMAP) amplitudes increment by 60% Paramyotonia Congenita with exercise and reduce by 40% with rest. There is no decrement on short exercise or slow or rapid repeti- Paramyotonia congenita is an autosomal-dominant tive stimulation. Myopathic motor units are seen prox- myotonic condition with at least two distinct genetic imally. MRI shows selective muscle involvement of the etiologies involving the sodium channel: \u03b1 subunit erector spinae and gluteus maximus. Diagnosis is con- (SCN4A) located at chromosome 17q35 and a mus- firmed by molecular genetic studies. cle chloride channel (CLCN1) located at chromosome 7q35. The worsening of the myotonia with exercise Myotonia Congenita is referred to as paradoxical myotonia. Weakness or stiffness may occur together or separately, there is Myotonia congenita (Thomsen\u2019s disease) presents in cold and exercise aggravation, hypertrophy of mus- infancy and is inherited as an autosomal-dominant culature, and more severe involvement of hands and condition. There is an abnormality of the muscle chlo- muscles of the face and neck. Myotonic episodes usu- ride channel, and the disease is linked to the 7q35 loci. ally subside within a matter of hours, but may last There is variable penetrance. Symptoms may be pre- days. Some patients become worse with a potassium sent from birth, but usually develop later. The myo- load. On electrodiagnostic studies, there is a drop in tonia is relatively mild and may manifest as difficulty CMAP amplitude with cooling. Dense fibrillations dis- appear below 28 degrees Celsius, myotonic bursts dis- appear below 20 degrees Celsius, and electrical silence","308 Pediatric Rehabilitation may occur below 20 degress Celsius. Treatment has defects (coenzyme Q10 deficiency, complex I deficiency, involved mexiletine or tocainide. complex III deficiency, and complex IV deficiency). While an exhaustive review of metabolic myopathies Schwartz-Jampel Syndrome is not presented here, two prototypical metabolic myo- (Chondrodystrophic Myotonia) pathies\u2014McArdle\u2019s disease and Pompe\u2019s disease\u2014 deserve mention. Schwartz-Jampel syndrome is an autosomal-reces- sive disorder with myotonia, dwarfism, diffuse bone Myophosphorylase Deficiency disease, narrow palpebral fissures, blepharospasm, micrognathia, and flattened facies (see Fig. 12.10). The most common glycogen storage disease is myo- Onset is usually before age 3. Patients have respiratory phosphorylas deficiency, also known as McArdle\u2019s and feeding difficulties with impaired swallowing. disease or glycogenosis type 5. The autosomal-reces- Limitation of joint movement may be present along sive disorder has been linked to chromosome 11q13, with skeletal abnormalities, including short neck and and more than 65 different disease-causing muta- kyphoscoliosis. Muscles are typically hypertrophic tions have been identified. Initial onset of symptoms and clinically stiff. There is a characteristic facies with often occurs during childhood and consists of poor pursed lips, micrognathia, and small mouth. Patients endurance, fatigue, and exercise-induced cramps and may be difficult to intubate. Ocular changes include myalgia that mainly affects active muscle groups. myopia and cataracts. There may be hirsutism and Myoglobinuria may also be absent during childhood, small testes. The symptoms are not progressive. The with prevalence of fixed muscle weakness increas- protein perlecan with gene loci at chromosome 1p34- ing as patient ages. Symptoms can be precipitated by p36 has been implicated. activities such as lifting heavy weights or climbing long flights of stairs. The \u201csecond wind phenomenon\u201d Electrodiagnostic studies show continuous electri- is characteristic of this disorder. With the onset of cal activity, with electrical silence being difficult to myalgia, patients who rest briefly are then able to con- obtain. There is relatively little waxing and waning tinue their physical activity with few or no symptoms. in either amplitude or frequency of complex repetitive The normal function of muscle myophosphorylase is discharges. Abnormal sodium channel kinetics in the to catalyze the removal of 1,4-glycosyl residues from sarcolemma of muscle has been demonstrated. Some glycogen to produce glucose-1-phosphate. Its absence therapeutic benefit has been reported with procain- leads to decreased metabolic substrate for glycolysis amide and carbomezapine. to produce adenosine triphosphate. CK is persistently elevated between episodes of myoglobinuria. EMG is METABOLIC MYOPATHIES normal when patients are asymptomatic, but can show myotonic discharges and fibrillation potentials during Inborn errors of glycogen metabolism and fatty acid an acute attack. Nonischemic forearm exercise testing metabolism may result in neuromuscular disorders. shows only an increase in ammonia and stable levels The major clinical presentations include fixed and pro- of lactic acid and pyruvate. Diagnosisis made by dem- gressive weakness or exercise intolerance, cramps and onstrating absence of myophosphorylase on muscle myalgias, and myoglobinuria. biopsy or by genetic mutation analysis. Possible treat- ments include high protein diet, pyridoxine, and crea- Fixed and progressive weakness may be caused tine monohydrate. by glycogenoses (acid maltase deficiency or \u201cPompe disease,\u201d debrancher deficiency, brancher deficiency, Acid Maltase Deficiency and aldolase A deficiency), or disorders of lipid metab- olism (primary systemic carnitine deficiency, primary Acid maltase deficiency, also referred to as glycogeno- myopathic carnitine deficiency, secondary carnitine sis type 2 or Pompe\u2019s disease, is caused by a deficiency deficiency, short-chain acyocoenzyme A synthetase of acid \u03b1-1,4-glucosidase (GAA). Inheritance is auto- defiency [SCAD], medium-chain acylocoenzyme A somal recessive, with linkage to chromosome 17q23. synthetase dehydrogenase deficiency [MCAD], etc.). Disease incidence is 1 in 40,000 to 50,000 live births. The level of residual enzyme activity correlates with Exercise intolerance, cramps\/myalgias, and myo- the severity of disease. Those with infantile onset globinuria may be caused by glycogenoses (myo- (birth to 1 year) show <1% GAA activity, childhood phosphorlase deficiency or \u201cMcArdle\u2019s disease,\u201d and juvenile onset (1 year to teens) show 2% to 6% phosphorylase kinase defiency, phosphofructokinase GAA activity, and those with adult onset (third decade [PFK] deficiency, phosphoglycerate mutase deficiency or later) show 1% to 29% GAA activity. There is no [PGAM], etc.); disorders of lipid metabolism (carnitine clear correlation with residual activity within adult palmitoyltranferase II deficiency [CPT II], VLCAD defi- ciency, and TP deficiency, etc.); and respiratory chain","Chapter 12 Neuromuscular Diseases 309 population. There is glycogen accumulation in tissues. Mitochondria are essential cellular organelles that Clinically in those with infantile onset, symptoms and convert carbohydrates, lipids, and proteins into usable signs usually present within the first six months, with energy in the form of adenosine triphosphate (ATP) hypotonia, weakness, cardiomegaly, congestive heart via aerobic metabolism. Although the human mito- failure, and arrhythmia. There is liver involvement and chondrial genome is only 16.5 Kb and encodes 13 pro- pulmonary involvement. Anesthesia risks with suc- teins, many different clinical syndromes can result cinylcholine include arrhythmia, hyperkalemia, and from mutations of these genes. Mutant mitochondrial rhabdomyolysis. Propofol also produces risks. Safer DNA can be present in different proportions in vari- anesthetics include ketamine and etomidate. Death ous cell populations in a phenomenon known as het- occurs within the first year of life in 80% to 95% of eroplasmy. The pathogenic effect of the mutation will untreated patients. In childhood onset, there is mildly only be manifested when a critical level of mutation enlarged tongue, symmetric proximal weakness, and is reached. Mutant and normal mitochondrial DNA calf hypertrophy. Death occurs between 3 to 24 years segregate randomly during cell division, thus chang- due to respiratory failure. There is glycogen accumula- ing the proportion of mutant DNA in different cells tion mainly in muscle. In adult-onset Pompe\u2019s, patients over time. All mitochondria and mitochondrial DNA present with lower extremity weakness, restrictive are derived from the mother\u2019s oocyte. Thus, a family lung disease from diaphragm involvement, headache, history compatible with maternal inheritance is strong somnolence, and increased dyspnea when supine. evidence for a primary mitochondrial DNA mutation. Sleep-disordered breathing is common. Expiration is Different family members in the maternal lineage may more involved than inspiration due to chest wall mus- be asymptomatic or oligospermatic. cle involvement. Nocturnal noninvasive ventilation is occasionally necessary. There is atrophy of paras- Of the many clinical features of mitochondrial pinous muscles and scapular winging. The disease disorders that involve multiple organ systems, some course is one of slow progression over years. Pain, are frequently present together and should alert the fatigue, and cramps are common complaints. There clinician to a mitochondrial etiology. Ptosis, progres- may be mild calf hypertrophy and diffuse muscle atro- sive external ophthalmoplegia (PEO), or both are hall- phy more proximally. Progressive disability is related marks of Kearns-Sayre syndrome, which produces to disease duration rather than age of onset. Eventual diplopia and blurred vision. Myopathy is common respiratory involvement is common, and many need among patients with mitochondrial disorders. Neck wheelchairs or walking devices. Death is most often flexors may be affected earlier and more severely than due to respiratory failure. neck extensors. Progressive fixed proximal weakness is more common, and patients may develop decreased Diagnosis of Pompe\u2019s disease is confirmed with muscle bulk. Premature fatigue, exercise intolerance, either molecular genetic studies or biochemical analysis myalgia, and recurrent myoglobinuria can be symp- of acid maltase activity with muscle biopsy. However, toms of mitochondrial disorders. Serum lactate and new methods using blood samples to measure GAA pyruvate often are elevated at rest, and these levels activity are rapidly becoming adopted because of their may increase significantly after moderate exercise. speed and convenience (81,82). Typically, serum CK is Sensorineural hearing loss is frequently associated elevated (less than 10 times) in infants and less ele- with mitochondrial encephalomyopathies. The hear- vated in adults. EMG shows an irritative myopathy ing loss may be asymmetric and fluctuating in sever- with fibrillations, complex repetitive discharges, and ity. Maternally inherited deafness and diabetes (DAD) myotonic discharges. Treatment now involves enzyme is another phenotypic combination in patients with replacement with intravenous administration of recom- mitochondrial DNA mutations. Dementia can be a binant \u03b1-glucosidase (Genezyme). Better outcomes are prominent feature in mitochondrial cytopathy. seen with earlier initiation of therapy. Genzyme has been shown to benefit infantile disease and possibly The diagnostic workup of a mitochondrial disorder late-onset disease with improved strength of distal often includes a complete blood count, serum electro- and proximal muscles, improved pulmonary function, lytes (including calcium and phosphate), liver function improved cardiomyopathy, and improved survival tests, blood urea nitrogen, creatinine, blood lactate (83,84). and pyruvate, ECG, lumbar puncture for CSF protein, glucose, lactate, pyruvate, EMG and nerve conduction MITOCHONDRIAL DISORDERS study, brain imaging with MRI, and muscle biopsy for histology and electron microscopy. Histochemical Mitochondrial encephalomyopathies, also referred stains for mitochondrial enzymes (SDH, NADH-TR, to as mitochondrial cytopathy, represent a complex and COX) may be obtained, and the activities of mito- group of disorders that affect multiple organ systems. chondrial respiratory chain enzymes can be mea- sured in muscle tissue. The identification of numerous mitochondrial DNA (mtDNA) mutations, including","310 Pediatric Rehabilitation duplications, deletions, multiple deletions, and more both as manifestations of the respiratory chain defects. than 100 pathgenic point mutations, provides specific Other frequent clinical features include normal early genetic diagnoses. development, myogenic limb weakness, ataxia, myoc- lonus, migrainelike headaches, recurrent nausea and Treatment is symptomatic for seizures (with avoid- vomiting, and hearing loss. The abrupt-onset strokes ance of valproic acid, which is contraindicated because often affect the occipital cortex, but may involve other of depletion of carnitine and direct inhibitory effects regions of the brain. These patients often describe an on the mitochondrial respiratory chain). Electrolyte antecedent history of migraine headaches that often disturbances related to hypoparathyroidism and dia- occur prior to the strokelike event. Patients may expe- betes mellitus are corrected. Thyroid replacement alle- rience improvement over weeks to months, but events viates hypothyroidism, Cardiac pacemaker placement virtually always recur. The lesions do not conform to prolongs life in Kearns-Sayre syndrome (KSS) with territories of large vessels, a finding that favors the conduction defects. Impairments in the oxidative phos- term strokelike episodes. Dementia may occur and phorylation pathway may generate increased amounts be progressive. There is infrequent occurrence of the of free radicals; therefore, antioxidants are prescribed, full syndrome in more than one member of a pedi- which include \u2424-carotene, vitamin C, vitamin E, and gree. Based on the hypothesis that MELAS is caused CoQ10. CoQ10 shuttles electrons from complex I and II by impaired vasodilation in an intracerebral artery, to complex III and may stabilize the oxidative phopho- investigators have evaluated the effects of adminis- rylation enzyme complexes within the inner mito- tering L-arginine, a nitric oxide precursor to patients chondrial memebrane. The dose for CoQ in adults is acutely with the first signs of strokelike episodes. Oral L-arginine administration within 30 minutes of a 10 stroke was shown to significantly decrease frequency and severity of strokelike episodes (85). 50 to 100 mg, three times per day. L-xarnitine is also recommended. Dicholroacetate increases the pyruvate Neuropathy Ataxia and Retinis Pigmentos dehydrogenase complex and reduces lactate. Aerobic training is recommended for some conditions. This disorder consists of the variable combinations of proximal neurogenic limb weakness, sensory neu- More common mitochondrial disorders presenting ropathy, ataxia, pigmentary retinopathy, developmen- in childhood are discussed in the following sections. tal delay, dementia, and seizures. The onset occurs in teens and young adults, and the course is gradually Kearns-Sayre Syndrome progressive. These patients show progressive external ophthal- Mitochondrial Neurogastrointestinal moplegia, retinitis pigmentosa on fundoscopic exam- Encephalomyopathy ination, and complete heart block. Onset is usually before 20 years of age. Cerebellar findings may be pre- This syndrome is clinically recognized by the unusual sent on physical examination, and patients may show combination of six features: PEO, severe gastrointes- limb weakness, hearing loss, diabetes mellitus, hypo- tinal dysmotility, cachexia, peripheral neuropathy, parathyroidism, irregular menses, and growth hor- diffuse leukoencephalopathy on MR imaging, and evi- mone deficiency. Dementia may be progressive. CSF dence of mitochondrial dysfunction (histologic, bio- protein is frequently greater than 100 mg\/dL. chemical, or genetic). The peripheral neuropathy and the prominent gastrointestinal dysmotility are defining Myoclonus Epilepsy With Ragged-Red Fibers features. Lactic acidosis at rest is present in two-thirds of patients. Both axonal and demyelination polyneu- This clinical syndrome is defined by the presence of ropathy is frequent. Muscle biopsy reveals ragged red myoclonus, generalized seizures, ataxia, and ragged fibers (RRFs) and neurogenic changes. red fibers on muscle biopsy. Symptoms usually begin in childhood. Other common clinical manifestations NEUROMUSCULAR JUNCTION include hearing loss, dementia, exercise intolerance, DISORDERS and lactic acidosis. Multiple lipomatosis is common. Multiple members of a pedigree usually show the full Transient Neonatal Myasthenia syndrome. Transient neonatal myasthenia occurs in about 10% Mitochondrial Encephalopathy, Lactic Acidosis, to 15% of infants born to myasthenic mothers and is and Strokelike Episodes This clinical syndrome is characterized by stroke- like epidodes at a young age and typically before 40 years; encephalopathy evident as seizures, dementia, or both; lactic acidosis, ragged-red fibers on biopsy, or","Chapter 12 Neuromuscular Diseases 311 due to transplacental transfer of circulating acetylcho- or the \u201cmotor point.\u201d For in vitro electrophysiologic and line receptor (AChR) antibodies from the myasthenic immunocytochemical studies of the neuromuscular mother to the fetus. Symptoms appear within the junction, a short muscle usually is removed from ori- first few hours of birth; however, occasionally onset gin to insertion along with its motor branch and NMJ (a may be delayed for three to four days. Typical clinical \u201cmotor point biopsy\u201d). Muscles obtained have included characteristics include feeding difficulty, generalized the anconeus muscle near the elbow, the external inter- weakness and hypotonia, respiratory difficulties, fetal costal muscle in the fifth or sixth intercostal space near cry, facial weakness, and, less frequently, ptosis. the anterior axillary line, or the peroneus tertius muscle in the lower extremity. Such in vitro electrophysiologic The author prefers diagnostic confirmation by studies allow specific delineation of the congenital myas- evaluating the response to edrophonium or neostig- thenic syndrome into one of the numerous specific sub- mine, with repetitive nerve stimulation studies per- types. More recently, the diagnostic evaluation of CMS formed at baseline and subsequent to infusion of the has increasingly relied upon molecular genetic studies. anticholinesterase agent. A response decrement with slow rates of stimulation (2\u20135 Hz) over a train of four For treatment of a CMS subtype, a definitive diag- to five stimuli may be repaired by the edrophonium nosis is important because some CMS syndromes deteri- (Tensilon) or neostigmine. orate with empiric treatment with AChE inhibitors such as pyridostigmine (Mestinon). For example, slow chan- Treatment is largely supportive and the condition nel syndromes may deteriorate on pyridostigmine and itself limiting, with resolution generally occurring endplate acetylcholinesterase deficiency may deteriorate within two to three weeks, although occasional cases or show no response. Some presynaptic syndromes may may persist longer. show response to 3,4-diaminopyridine, which increases release of acetylcholine at the presynaptic terminal. Congenital Myasthenic Syndromes This drug has been used in Lambert-Eaton syndrome and in presynaptic CMS on a compassionate-use basis. Congenital myasthenia syndrome (CMS) is a term used for a heterogenous group of disorders that are genetically Autoimmune Myasthenia Gravis determined rather than autoimmune-mediated. Patients may present in the neonatal period, later in childhood, This disorder is similar to the autoimmune myasthenia or even in adult life. Patients often exhibit ptosis, exter- gravis observed in adults. The onset is often insidious, nal ophthalmoparesis, facial weakness, general hypoto- but at times, patients may present with acute respiratory nia, proximal greater than distal muscle weakness, and difficulties. Patients usually present with variable degrees variable degrees of functional impairment. Patients show of ophthalmoparesis and ptosis. In addition, patients may absence of anti-AChR antibodies. More than 20 subtypes exhibit facial weakness, swallowing difficulties, speech have been described, and congenital myasthenia may problems, and weakness of the neck, trunk, and limbs. be classified according to the following: 1) presynaptic Proximal muscles are more affected than distal, and the defects (eg, choline acetyltransferese [CHAT] deficiency upper limits are more affected than the lower. causing CMS with episodic apnea, paucity of synap- tic vesicles and reduced quantal release, or congenital Fluctuation in the disease course with relapse Lambert-Eatonlike syndrome), 2) synaptic basal lamina and remission is common. Patients often complain of defects (eg, endplate acetylcholinesterase [AChE] defi- fatigue and diplopia, as well as progressive difficulty ciency at neuromuscular junctions [NMJs]), and 3) post- with chewing or swallowing. Patients are often worse synaptic defects (eg, AChR disorders involving \u03b1, \u2424, \u2426, e with fatigue towards the end of the day. Thymoma, subunits; kinetic abnormalities in AChR function caused which occurs in about 10% of adult cases, is not a fea- by AChR deficiency; slow AChR channel syndromes; fast- ture of the childhood-onset disease. channel syndromes; endplate rapsyn deficiency, etc.). Serum AChR antibodies are an important diag- Several congenital myasthenic syndromes have nostic screening tool. Anti-AChR antibodies can be been associated with arthrogryposis syndromes. For detected in the serum in about 85% to 90% of patients example, \u201cmultiple pterygium syndrome\u201d (Escobar\u2019s with generalized myasthenia gravis and greater than syndrome) has been associated with AChR gamma, 50% of those with ocular myasthenia. The most com- alpha 1, and delta subunit mutations. mon antibodies detected are AChR binding, followed by AChR modulating and then striational AChR anti- For diagnostic workup, standard EMG with repet- bodies. Muscle-specific kinase (MUSK) antibodies are itive nerve stimulation is utilized initially, and subse- an additional marker present in some seronegative quently stimulated single-fiber EMG may be useful. patients and many patients with ocular myasthenia. Ultrastructural evaluation of the neuromuscular junc- tion with electron microscopy usually is performed on Diagnosis may also be confirmed by clinical response a biopsy of the deltoid or biceps, including the muscle to an anticholinesterase drug such as edrophonium region containing the neuromuscular junction (NMJ) (Tensilon) Alternatively, neostigmine, a longer-acting","312 Pediatric Rehabilitation agent, can be used. Repetitive nerve stimulation studies with autoimmune etiology. Motor axons are affected show a characteristic decrement in the compound mus- more than sensory axons. Incidence in children is cle action potential with slow stimulation rates (2\u20135 Hz) similar to that seen in adults. Children often have a over a train of four to five stimuli. A decrement greater prodromal respiratory or gastrointestinal infection than 12% to 15% is often noted. Electrophysiologic stud- occurring within one month of onset. Common precipi- ies may be more sensitive with proximal muscle groups tating infections include Mycoplasma, cytomegalovirus, such as the accessory nerve to the trapezius or study of Epstein-Barr virus, Campylobacter jejuni, and various the facial nerve. Abnormal repetitive nerve stimulation vaccinations. Weakness generally begins distally in the studies may also be seen in Lambert-Eaton syndrome, lower extremity, with a progressive ascending paraly- botulism, and congenital myasthenic syndromes. Single- sis ultimately involving the upper limbs. Pain and sen- fiber EMG is usually impractical in children; however, sory symptoms are not uncommon. The most common stimulated single-fiber EMG may be performed under cranial nerve abnormality is an ipsilateral or bilateral anesthesia. Management may include treatment with lower motor neuron facial paralysis. Objective sensory anticholinesterase drugs, such as pyridostigmine, corti- loss has been documented in the minority of children costeroids (prednisone), intravenous (IV) immunoglob- (85). In one series, only 15% required mechanical venti- ulin, immunosuppressants (azathioprine, cyclosporine, lation (86). The maximal degree of weakness generally mycophenolate mofetil, or cyclophosphamide), plasma reaches a peak within two weeks of onset, and time to exchange, or thymectomy. maximum recovery was 7 months \u00b1 5 months in one series (87). Complete recovery occurs in most children. Infantile Botulism Classic criteria for poor recovery in adults (low-median CMAPs and fibrillation potentials) may not apply to Infants with botulism usually present between 10 days children (87). to 6 months, with an acute onset of hypotonia, dys- phagia, constipation, weak cry, and respiratory insuf- Disturbances of the autonomic nervous system are ficiency. The neurologic examination shows diffuse common in children, including transient disturbances hypotonia and weakness, ptosis, ophthalmoplegia of bowel and bladder, excessive sweating or vasocon- with pupillary dilation, reduced gag reflex, and rel- striction, mild hypertension or hypotension, and occa- ative preservation of deep tendon reflexes. The diag- sionally cardiac arrhythmias. nosis may be made by electrodiagnostic studies (see Chapter 7) or by measuring Clostridium botulinum The acute motor axonal neuropathy (AMAN) toxin in a rectal aspirate containing stool. involves predominantly motor nerve fibers with a phys- iologic pattern suggesting axonal damage, whereas the Noninfantile Acquired Botulism acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers Older children and adults acquire botulism through with a physiologic pattern suggesting demyelination. poorly cooked, contaminated food with the toxin or Another clinical variant is the Miller-Fisher syndrome through a cutaneous wound that becomes contami- characterized by acute onset ataxia, ophthalmopare- nated with soil-containing Clostridium botulinum. The sis, and areflexia. toxin can often be identified in the serum and the food source. Clinical findings include acute onset of consti- Diagnosis is generally confirmed by electrodiag- pation, ptosis, diplopia, bulbar weakness, respiratory nostic studies (see Chapter 7), and the CSF protein is difficulties, ophthalmoparesis, pupillary dilation, and characteristically elevated in a majority of children. diminished deep tendon reflexes. Recovery may take Serum autoantibodies that may be elevated include months. The diagnosis is generally made from elec- IgM and IgG versus beta-tubulin and heparin sulfate. trodiagnostic studies. AMAN patients may show increased IgG antibodies to GM1 ganglioside. The Miller-Fisher syndrome is asso- PERIPHERAL NERVE DISORDERS ciated with a high frequency of the IgG GQ1b antibod- ies. The major considerations in differential diagnosis Acute Inflammatory Demyelinating of AIDP or AMAN include transverse myelitis, toxic Polyradiculoneuropathy (Guillain-Barr\u00e9 neuropathies, tick paralysis, infantile botulism, myas- Syndrome) thenia gravis, and dermatomyositis. Acute inflammatory demyelinating polyradiculoneu- Treatment has typically included corticosteroids, ropathy (AIDP) is a primarily demyelinating neuropathy plasma exchange, or, more recently, intravenous immune globulin (88,89,90,91). AIDP patients respond to both plasma exchange and intravenous immuno- globulin (IVIG). Patients with AMAN respond preferen- tially to IVIG over plasma exchange. Recovery is often quite good in children without treatment. After stan- dard intravenous immunoglobulin therapy, children","Chapter 12 Neuromuscular Diseases 313 with axonal forms of Guillain-Barr\u00e9 syndrome (GBS) In general, in most CMT subtypes, onset is usually recover more slowly than those with the demyelin- during the first or second decade of life. Both motor ating form, but outcome at 12 months appears to be and sensory nerve function are affected. The clinical equally favorable in two groups (92). features include distal muscle weakness, impaired sen- sation, and absent or diminished deep tendon reflexes. Chronic Inflammatory Demyelinating Weakness usually is greatest initially present in the Polyradiculoneuropathy foot and hand intrinsics and distal lower extremities, and subsequently in the distal upper extremities. Slow Children with chronic inflammatory demyelinating progressive weakness, more proximally in the knees, polyradiculoneuropathy (CIDP) often have a presen- elbows, and pelvic and shoulder girdles may occur tation similar to AIDP; however, the disorder contin- over decades (56). There is variable penetrance in ues with a chronic or relapsing course. The disorder most subtypes. The various gene locations and known may begin as early as infancy, but is seen in children protein abnormalities associated with various forms of and adults. Electrophysiologic studies show focal con- CMT (HMSN) are given in Table 12.3. duction block, temporal dispersion of CMAPs, pro- longation of distal motor latencies, markedly slow The majority of CMT 1 pedigrees (70%) demon- conduction velocities, and absent or prolonged H-wave strate linkage to chromosome 17p11.2\u201312 and are des- and F-wave latencies. CIDP cases often demonstrate ignated CMT 1A (95). CMT 1A duplication results in axonal loss on EMG. The CSF protein is elevated in increased expression of peripheral myolin protein-22 most cases. (PMP-22). Conduction velocities are uniformly slow in all nerves, with a mean of 17\u201320 M\/s and a range of The differential diagnosis usually includes CMT 5\u201334 M\/s. Onset is typically in the first decade, with types I and III. The presence of acute relapsing epi- leg arreflexia, gait disorder (toe-walking or steppage sodes point towards CIDP. Due to the more severe gait), foot muscle atrophy or pes cavus, occasionally involvement of proximal nerves and nerve roots, a dis- short Achilles tendons, and enlarged nerves owing to tal sural nerve biopsy may not always show inflamma- onion bulb formation in half of patients. Distal weak- tory changes and demyelination. ness develops initially in intrinsic muscles of the feet and hands with development of wasting of muscula- Treatment may include corticosteroids (predni- ture occurring slowly over time (Fig. 12.16). Ankle dor- sone) and IVIG as first-line approaches and subse- siflexion, ankle eversion, and extensor hallucis longus quently plasma exchange. weakness develops with more normal strength proxi- mally. Progressive cavus foot deformities with claw- Charcot-Marie-Tooth (Hereditary ing of the toes often develop (Fig. 12.17). Orthopedic Motor Sensory) Neuropathy procedures are limited to soft tissue procedures and correcting wedge osteotomies, and joint fusion should Charcot-Marie-Tooth (CMT) neuropathy (also called be avoided if possible to avoid late pain. Late in the hereditary motor sensory neuropathy or HMSN) is disease, diaphragm or bulbar weakness may develop a heterogenous group of inherited disease of periph- in rare cases. Progression is slow over many decades. eral nerve that affects both children and adults and Defects in the human myelin zero gene (P0) on chromo- causes significant progressive neuromuscular impair- some 1q22-q23 leads to CMT 1B. P0 is the major protein ment (93,94). It has been estimated that 1 per 2,500 to structural component of peripheral nervous system 3,000 persons has a form of CMT. CMT 1 denotes indi- myelin. The clinical presentation is similar to CMT1A; viduals with a hypertrophic demyelinating neurop- however, onset may lag into the second to third decade athy (\u201conion bulbs\u201d) and reduced nerve conduction in a minority of patients and there is more variabil- velocities, whereas CMT 2 refers to individuals with ity in severity. Nerve conduction velocities are usu- an axonal neuropathy and normal or slightly reduced ally less than 20 m\/s. P0 mutations may lead to other nerve conduction velocities. Individuals with CMT 3 clinical variants, referred to as CMT 1E (demyelinating (Dejerine-Sotttas disease) have a primarily demyelin- CMT with deafness), and predominantly axonal neu- ating peripheral neuropathy with a more severe phe- ropathy with late adult-onset (eg, CMT 2I, and CMT 2J notype presenting in infancy. Historically, types 1, 2, with hearing loss and pupillary abnormalities). and 3 were felt to be autosomal-dominant conditions, with type 3 CMT patients exhibiting point muta- CMT 2 is a less common disorder than CMT 1. tions with frameshift and either dominant or reces- Generally, CMT 2 patients demonstrate later age of sive inheritance. CMT 4 refers to autosomal-recessive onset, less involvement of the small muscles of the CMT. However, recently, axonal forms of CMT have hands, and no palpably enlarged nerves. Wasting in been identified with autosomal recessive inheritance the calf and anterior compartment of the leg may give (deemed AR-CMT 2A, 2B, etc.) rise to an \u201cinverted champagne bottle\u201d or \u201cstork-leg\u201d appearance. Conduction velocities are mildly reduced,","314 Pediatric Rehabilitation 12.3 Hereditary Motor Sensory Neuropathy (HMSN) Types: Comparison of Clinical Features EARLY OR DISTINCT TENDON AVERAGE DISORDER GENE LOCATION USUAL ONSET SYMPTOMS REFLEXES NCVS CMT1: Dominant; Demyelinating CMT 1A PMP-22 17p11 1st decade Distal weakness Absent 15 to 20 M\/s 1st decade Distal weakness Absent <20 M\/s CMT 1B P0 1q22 2nd decade Distal weakness Reduced 16 to 25 M\/s 2nd decade Distal weakness Absent 26 to 42 M\/s CMT 1C LITAF 16p13 2nd decade Distal weakness Absent distal 25 to 40 M\/s 3rd decade Focal episodic weakness Normal Entrapments CMT 1D EGR2 10q21 2 years Severe weakness Absent <10 m\/s CMT X (S-D*) Connexin-32 Xq13 HNPP PMP-22 17p11 Dejerine-Sottas PMP-22 17p11 (HMSN 3) 8q23 8q23 EGR2 10q21 CMT Intermediate DNM2 19p12 1st or 2nd decade Distal weakness 25 to 50 M\/s NCV 0q24 10q24 1p34 1p34 P0 1q22 CMT-X Xq13 CMT2: Dominant; Axonal CMT 2A KIF1B\u2424 1p36 10 yrs Distal weakness Absent distal > 38 M\/s 1 Mitofusin 2 3q13 2nd decade CMT 2B RAB7 1st decade Distal weakness Sensory Absent distal Axon loss loss Acromutilation CMT 2C 12q23-q24 16 to 30 yrs Vocal cord and Distal Absent > 50 M\/s weakness CMT 2D GARS 7p15 1 to 40 yrs Distal weakness Arms Reduced Axon loss 6 to 54 years > legs CMT 2E NF-68 8p21 Distal weakness Reduced Axon loss CMT 2F\/ Distal HMN HSPB1 7q11 15 to 25 years Difficulty walking Reduced Axon loss (HSP 27) 15 to 33 years ankle CMT 2G 12q12 17 to 50 yrs Distal weakness Reduced 42 to 58 M\/s CMT 2L HSPB8 12q24 Distal weakness Reduced Axon loss HMSN-P 3q13 13 to 27 yrs Proximal weakness, Absent Axon loss 37 to 61 years cramps HSMN + Ataxia P0 7q22 Gait ataxia Absent Axon loss CMT 2 P0 1q22 Leg weakness Pupil or Reduced < 38 M\/s to Hearing Normal AR-CMT2: Recessive; Axonal AR-CMT2A Lamin A\/C 1q21 2nd decade Distal weakness Reduced Axon loss 19q13 Distal weakness AR-CMT2B 3rd and Absent distal Axon loss Autosomal 4th decade Distal weakness AR-CMT2 Ouvrier Reduced Axon loss 1st decade Continued","Chapter 12 Neuromuscular Diseases 315 12.3 Continued EARLY OR DISTINCT TENDON AVERAGE DISORDER GENE LOCATION USUAL ONSET SYMPTOMS REFLEXES NCVS HMSN 3: Infantile P0 Autosomal 2 years Severe weakness Absent <10 m\/s PMP-22 Dominant\/ Dejerine-Sottas Periaxin recessive <10 m\/s (HMSN 3) Slow Congenital P0 Autosomal Birth Severe weakness Absent Slow Hypomyelinating EGR2 Recessive 15 to 30 m\/s Neuropathy PMP-22 14 to 32 M\/s 10 to 20 M\/s CMT4: Recessive; Demyelinating 9 to 20 M\/s Absent CMT 4A GDAP1 8q13 Childhood Distal weakness Reduced < 15 M\/s 11q22 2 to 4 yrs Distal and Proximal Absent 20 to 34 m\/s CMT 4B MTMR2 weakness 11p15 1st 2 decades Distal weakness Sensory Absent CMT 4B2 SBF2 loss 5q23 5 to 15 yrs Delayed walking Reduced CMT 4C KIAA1985 8q24 1 to 10 yrs Gait disorder Absent CMT 4D (Lom) NDRG1 10q21 Birth Infant hypotonia Absent CMT 4E EGR2 19q13 1 to 3 yrs Motor delay Absent CMT 4F Periaxin 12q12 10 to 24 mo Walking delay Absent CMT 4H FGD4 18q23 1st or 2nd decade Distal leg weakness Reduced CCFDN CTDP1 and CMAP amplitudes and sensory nerve action poten- in either the PMP-22, P0 or EGR2 gene (95). While this tial (SNAP) amplitudes are usually reduced. CMT 2A2 disorder was previously felt to be autosomal-recessive, with mitofusin abnormality accounts for approxi- many cases are due to denovo point mutations and mately 20% of CMT 2 probands. CMT 2C linked to actually have dominant inheritance. chromosome 12q23-q24 has interesting features of early onset in the first decade and diaphragm and Congenital hypomyelinating neuropathy is a intercostal weakness producing shortness of breath. severe and often fatal newborn disorder that often Vocal cord paralysis may alter the voice of these presents with respiratory distress in the delivery room. patients. The disease may progress to proximal and These infants often have severe generalized hypotonia facial muscles. Arthrogryposis is present in some and associated arthrogryposis. Diagnostically, these patients. Phrenic nerve CMAPs are often reduced. infants have absent sensory nerve action potentials CMT 2E with abnormality in neurofilament light chain (SNAPS) or low-amplitude SNAPS with prolonged dis- (NFL) linked to chromosome 8p21 may have associ- tal latencies. Compound muscle action potentials are ated hearing loss in 30% of cases. While most axonal either absent or low-amplitude, with motor conduction CMT is autosomal-dominant, emerging pedigrees are velocities ranging from 3\u201310 meters per second. The being identified with recessive inheritance. disorder has been linked to PMP-22, P0, and EGR2 genes. Sural nerve biopsy may be useful. Inheritance Dejerine-Sottas disease (CMT 3) is a severe hyper- is usually autosomal-recessive, with some dominant trophic demyelinating polyneuropathy with onset inheritance linked to EGR2. in infancy or early childhood. Most patients achieve ambulation, but some may subsequently progress to Autosomal recessive CMT 4 is relatively rare. Most wheelchair reliance. Nerve conduction velocities are are demelinating with more severe phenotypes, and greatly slowed (often below 10 m\/s), and elevations in onset is often in childhood. CMT 4C linked to 5q23 is cerebrospinal fluid protein may be present. Dejerine- a relatively more common form of CMT 4. Sottas disease may be associated with point mutations Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder","316 Pediatric Rehabilitation A Figure 12.17 Progressive cavus foot deformities with clawing of the toes on Charcot-Marie-Tooth syndrome. B Patients with an X-linked dominant form of CMT (CMT-X) have been described. Male-to-male Figure 12.16 Distal weakness of intrinsic muscles of the transmission is not observed, and the disorder gen- feet (A) and hands (B) with wasting in Charcot-Marie-Tooth erally shows earlier onset and faster rate of progres- syndrome. sion. The gene locus code for connexon 32 protein is Xq13, which encodes a major component of gap that produces episodic recurrent nerve entrapments junctions, which provides a pathway for the transfer with focal demyelination. Patients may present with of ions and nutrients around and across the myelin peroneal palsies, carpal tunnel syndrome, and other sheath. entrapment neuropathies. A positive family history of entrapments often exists. Peripheral nerve biopsies DNA testing for many of the CMT subtypes (par- may demonstrate segmental demyelination and tomac- ticularly CMT 1) is available, but the ordering of ulous or \u201csausagelike\u201d formations. A deletion at the extensive CMT batteries is expensive unless guided PMP-22 gene locus (chromosome 17p11.2\u201312) causes by nerve conduction study findings. Nerve conduc- this autosomal-dominant condition, in contrast to a tion studies may be more expeditiously carried out duplication of this gene, which causes CMT 1A. on an affected parent to guide the molecular genetic workup of an affected child. Given the overlap of some gene abnormalities with several CMT clinical subtypes, it is often difficult to make a definitive diag- nosis on genetic study results without the additional information provided by nerve conduction testing. Hereditary motor sensory neuropathy remains one clinical entity that continues to warrant electrodiag- nostic evaluation. Toxic Neuropathies Toxic polyneuropathies are rare occurrences in chil- dren in North America. Toxic exposure to heavy met- als and environmental toxins may be more common in other regions of the world. Expeditious diagnosis is critical to identify and remove the source of the tox- icity and to establish treatment with agents such as penicillamine. Arsenic polyneuropathy is a sensori- motor neuropathy that may be axonal or, at times, pre- dominantly demyelinating, simulating Guillain-Barr\u00e9 syndrome or CIDP. Gastrointestinal (GI) symptoms are common, as well as tachycardia and hypotension. Mee\u2019s lines may be seen in nails, along with other skin changes and allopecia. The diagnosis is established by","Chapter 12 Neuromuscular Diseases 317 obtaining levels of arsenic in blood, urine, hair, and electrophysiologic studies or nerve biopsy are usually nail samples. not necessary. The neuropathy usually improves with discontinuation of the medication, although signifi- Lead polyneuropathy is most commonly observed cant electrophysiologic abnormalities (reduced CMAP in children who have ingested old lead-based paint. amplitudes and neuropathic recruitment) may persist. Acute exposures cause lead encephalopathy more Vincristine may be particularly troublesome for chil- commonly. Clinical findings may include anorexia, dren with hereditary motor sensory neuropathy. nausea and vomiting, gastrointestinal disturbance, fatigue, clumsiness and ataxia, and occasionally cog- Metabolic Neuropathies nitive impairment, seizures, mental status changes, papilledema, and coma. The weakness is predomi- Uremic neuropathy often occurs in children with nantly in the lower limbs, but the upper limbs may be end-stage renal disease. If clinical manifestations are involved. Electrophysiologic studies show a primarily present, they consist of a predominantly distal motor axonal degeneration affecting motor greater than sen- and sensory polyneuropathy with glove and stocking sory axons. A microcytic hypochromic anemia with loss of sensation, loss of vibratory sense, and distal basophilic stippling of red blood cells establishes the weakness, particularly involving peroneal innervated diagnosis. Lead lines may be evident in long bone musculature. With successful renal transplantation, films. Lead levels may or may not be elevated in urine clinical findings and electrophysiologic abnormalities and blood, but levels of delta aminolevulinic acid are normalize (143). Diabetic polyneuropathy usually is a usually elevated in the urine. mixed motor and sensory polyneuropathy with both axonal changes and mild demyelination. The poly- Mercury poisoning may occur from the ingestion neuropathy is less common in children with diabetes of mercuric salts, exposure to mercury vapor, or use mellitus, as compared with adults. The severity of the of topical ammonia mercury ointments. Patients pre- neuropathy may be related to the degree of glucose sent with a generalized encephalopathy, fatigue, and control (96). occasionally a skin rash. A predominantly distal motor axonal neuropathy occurs. Deep tendon reflexes may MOTOR NEURON DISORDERS be absent, and the gait is often ataxic. Sensory exam- ination is often normal, although patients may com- Predominantly Proximal Spinal plain of distal paresthesias. Electrophysiologic studies Muscular Atrophy show motor axonal degeneration with normal sensory conduction studies. Spinal muscular atrophy (SMA) is a term used to describe a varied group of inherited disorders char- Organophosphate poisoning may be due to expo- acterized by weakness and muscle wasting, second- sure to insecticides or high-temperature lubricants or ary to degeneration of both anterior horn cells of the softeners used in the plastic industry. Patients pre- spinal cord and brainstem motor nuclei without pyra- sent with an encephalopathy manifested by confusion midal tract involvement. Three subtypes of autosom- and coma. In acute-exposure cholinergic crisis, mani- al-recessive predominantly proximal SMA have been fested by sweating, abdominal cramps, diarrhea, and described, all linked to chromosome 5q. A common constricted pupils, may be present. A predominantly nomenclature subdivides SMA into types I, II, and III, motor polyneuropathy is a late effect. However, the based on age of onset and age of death, whereas the disorder may present as a rapidly progressive polyneu- other approach classifies cases as severe, intermedi- ropathy mimicking Guillain-Barr\u00e9 syndrome. Severe ate, and mild, based on ability to achieve indepen- paralysis with respiratory failure requiring ventilatory dent sitting, independent standing, and walking. The support may occur, and in this situation there may be International Consortium on SMA attempted to stan- a superimposed postsynaptic defect in neuromuscular dardize the classification of childhood SMA to provide transmission. a rational basis for linkage studies and therapeutic tri- als (Table 12.4) (97). Glue-sniffing (N-hexane) neuropathy may be seen in teenage recreational glue sniffers. Repeated use may SMA type I (Werdnig-Hoffman, severe form) was cause symptoms and signs of a predominantly distal defined by the International Consortium on SMA as motor and sensory polyneuropathy, which is predom- follows: onset from birth to 6 months, no achievement inantly demyelinating. Motor and sensory nerve con- of sitting without support, and death usually prior to duction studies demonstrate moderate slowing. age 2 years. In SMA type II (intermediate form), onset is before 18 months, sitting is usually obtained, but Chemotherapeutic agents, in particular, vincris- standing and ambulation are never obtained and death tine, often produce a relatively pure motor axonal polyneuropathy. Severity is dose-dependent. Clinical findings include distal weakness, absent deep ten- don reflexes, and at times foot drop. The disorder is often readily apparent by clinical examination, and","318 Pediatric Rehabilitation 12.4 Childhood Onset Proximal Spinal Muscular Atrophy (SMA) SMA I (WERNIG HOFFMAN) SMA II (INTERMEDIATE SMA) SMA III (KUGELBERG WELANDER) Onset <6 months 6 to 18 months >8 months Genetics IIIa <3 years Phenotype SMN1: AR homozygous SMN1: AR homozygous IIIb >3 years Milestones SMN2: <3 copies SMN2: three copies Severe hypotonia, weak suck, weak Hypotonia, proximal weakness, muscle SMN1: AR homozygous Life cry, proximal weakness, absent wasting, contractures, scoliosis, SMN2: 4\u20138 copies Expectancy refexes, respiratory failure common absent reflexes, tongue fasiculations Poor head control; Sit with head control; Proximal symmetric weakness, Never sit independently never stand unassisted; lordotic gait, Gowers\u2019s sign, decreased may require ventilatory support reflexes, tremor, tongue fasiculations 1 to 2 years 10% living at age 20 Most live to 3rd decade; many live to Stand and walk unassisted; may lose 4th to 5th decade standing or continue to walk IIIa: onset 18 mo to <3 years (80% not walking at age 40) IIIb: onset > 3 years (40% not walking at age 40) Normal life expectancy occurs above the age of 2 years, usually much later in understanding of the genetic basis for SMA (100\u2013105). adulthood. In SMA type III (Kugelberg-Welander, mild A detailed analysis of the 5q13 region revealed that form), the onset is after the age of 18 months, patients this chromosomal region in humans contained a large develop the ability to stand and walk, and death is in inverted duplication, with at least two genes present in adulthood. telomeric and centromeric copies. There is considerable variability and severity Further studies have identified the SMA causative within each of the three groups, and occasionally some gene as the survival motor neuron (SMN) 1 gene (SMN1, overlap exists. For example, patients with onset prior telomeric copy), along with a disease-modifying gene to 6 months may exhibit prolonged survival well past 4 (SMN2, centromeric copy) (100\u2013102). Briefly, the two years of age. Patients with onset between 6\u201318 months SMN genes are nearly identical, except for a difference may ultimately achieve standing and independent of only five nucleotides in their 3' regions, without any ambulation. An adult-onset type of SMA with mild alteration of the amino acid sequence of the protein. disease phenotype presenting usually in the second However, the critical difference between the SMN1 and or third decade has been recognized. These patients SMN2 genes is a C-T transition located within the exon- usually are able to ambulate with minor motor impair- splicing region of the SMN2 that affects the splicing of ments. Although the adult-onset SMA was not classi- exon 7. This change results in frequent exon 7 skip- fied formally by criteria set forth by the consortium, ping during the splicing of SMN2 transcripts (107,108). among clinicians, SMA type IV has been used widely It is thought that the resulting truncated SMN protein, to classify later-onset patients with mild disease fea- without its exon 7 contribution, is a less stable form tures. A modified classification has been proposed by of SMN protein, and, therefore, rapidly degraded. In Zerres and Rudnik-Schoneborn, which defines adult about 95% of SMA patients, both copies of SMN1 exon SMA as type IV (98). 7 are absent because of mutations. In the remaining SMA-affected patients, other small or subtle mutations The carrier frequency for SMA in the general have been identified (101). population is estimated at about 1 in 40 to 50 indi- viduals. Autosomal-recessive inheritance has long Genetic studies have now established that SMA been documented in proximal SMA with childhood is caused by mutations in the telomeric SMN1 gene, onset. In 1990, all three forms of SMA were mapped with all patients having at least one copy of the centro- to chromosomal region 5q13, indicating that allelic meric SMN2 gene. At least one copy of the SMN2 gene variance of the same disease locus accounts for the must be present in the setting of homozygous SMN1 clinical heterogeneity (99,100). During the past two mutations; otherwise, embryonic lethality occurs. The decades, tremendous advances have been made in our copy number of SMN2 varies in the population, and","Chapter 12 Neuromuscular Diseases 319 this variation appears to have some important mod- Tongue fasciculations have been reported in 56% to ifying effects on SMA disease severity (109\u2013111). All 61% of patients (113), so the absence of this finding SMA patients have >2 SMN2 genes. It appears that a does not necessarily exclude the disease. In one series higher number of SMN2 copies in the setting of SMN1 (113), deep tendon reflexes (DTRs) were absent in all mutations is associated with a less severe clinical SMA four extremities in 74% of cases. Thus, the preser- phenotype: SMA I (severe): two or three gene copies of vation of DTRs does not exclude the diagnosis of SMA. SMN2; SMA II: three copies of SMN2; SMA III: four to Appendicular muscle fasciculations and distal tremor eight copies of SMN2. However, substantial variations are also associated examination findings. Extraocular in SMA phenotype and disease severity can exist with muscles are spared, as is the myocardium. Mild to a given SMN2 copy number, so it is not recommended moderate hip flexion, knee flexion, and elbow flexion that disease severity be predicted based soley on SMN2 contractures may be observed in some patients, along copy numbers. Although we now know that SMN pro- with wrist contractures and ulnar drift of the fingers. tein is expressed widely in many tissues throughout Severe arthrogryposis is not typically observed. the body, its function is still not completely under- stood at this time (112). Diagnosis is confirmed by a consideration of clin- ical findings, molecular genetic studies, and, occa- Spinal Muscular Atrophy I sionally, electrodiagnostic studies. Muscle biopsy is (Werdnig-Hoffman Disease) generally not required to confirm the diagnosis. The majority of cases of SMA I present within the first In a large series from Germany (98), 197 patients two months, with generalized hypotonia and sym- classified as type I (never sits alone) had the following metrical weakness. The age of onset of symptoms is survival probabilities: 32% at age 2; 18% at age 4; 8% less than 4 months in the vast majority of cases. Weak at age 10; and 0% at age 20. sucking, dysphagia, labored breathing during feeding, frequent aspiration of food or secretions, and weak cry Spinal Muscular Atrophy II are frequently noted by history. Spinal muscular atrophy II disease onset is usually Examination shows generalized hypotonia and more insidious than that of SMA I. The findings of symmetric weakness involving the lower extremities generalized hypotonia, symmetrical weakness, and earlier and, to a greater extent, in the upper extremi- delayed motor milestones are hallmarks of SMA II. ties. Proximal muscles are weaker than distal extrem- Weakness also involves proximal muscles more than ities. In the supine position, the lower extremities may distal muscles and lower extremity more than upper be abducted and externally rotated in a \u201cfrog-leg\u201d posi- extremity. A fine tremor of the fingers and hands tion. The upper extremities tend to be adducted and occurs in a minority of patients. This \u201cpolyminimyo- externally rotated at the shoulders with a semiflexed clonus\u201d may be attributed to spontaneous, repetitive elbow. Volitional movements of fingers and hands per- rhythmical discharges by the motor neurons that sist well past the time when the shoulders and elbows innervate a large territory of muscle. Wasting tends to cannot be flexed against gravity. The thorax is flat- be more conspicuous in SMA II versus SMA I. DTRs are tened anteroposteriorly and bell-shaped as a result of depressed and usually absent in the lower extremities. intercostal weakness. Pectus excavatum may be vari- Appendicular or thoracic muscle wall fasciculations ably present. The diaphragm is usually preserved, rel- may be observed. Tongue fasciculations have been ative to the intercostal and abdominal musculature. observed in 30% to 70% of SMA II patients (97,113,114) This results in a diaphragmatic breathing pattern dur- Progressive kyphoscoliosis and neuromuscular restric- ing respiration with abdominal protrusion, paradox- tive lung disease is almost invariably seen in the late ical thoracic depression, and intercostal retraction. first decade. Contractures of the hip flexors, tensor fas- Neck flexor weakness may result in persistent poste- ciae latae, hamstrings, triceps surae, and elbow and rior head lag when the trunk is lifted forward from the finger flexors are quite common. Hypotonic hip dislo- supine position. Neck extensor weakness may result cations have been noted commonly in SMA II patients. in forward head lag when the infant is positioned in Sensory examination is completely normal, and extra- the horizontal prone position. With advanced disease, ocular muscles and the myocardium are spared. In a the mouth may remain open as a result of mastica- large series from Germany (98), of 104 cases classified tory muscle weakness. Facial weakness may be noted as SMA II (sits alone, never walks), 98% survived to in up to half of patients. The diagnostic criteria for the age of 10 and 77% to the age of 20. Thus, a longer SMA outlined by the International SMA Consortium lifespan is possible with adequate supportive care. (97) lists marked facial weakness as an exclusionary criterion for SMA, but this is not an absolute criterion. SMA II is a slowly progressive condition affecting proximal musculature more than distal. The calculated grade of progression for SMA may be less than one-half manual muscle testing units decline per decade (69).","320 Pediatric Rehabilitation Longitudinal series of 12\u201339 months\u2019 duration have ambulatory 20 years after onset of weakness, whereas shown essentially stable strength measurements but 89% of \u201cIIIb\u201d patients remained ambulatory after a slow loss of function (115,116). similar 20-year duration. Pathologic changes on muscle biopsy have been Distal Spinal Muscular Atrophy consistent with hypotrophic change in fetal muscle development. Other changes are consistent with a Distal spinal muscular atrophy is an increasingly rec- more active denervating process. Thus, SMA includes ognized group of rare diseases with varied genetic eti- a component of myofiber atrophy comparable to that ologies. More than 20 distinct genetic subtypes have seen in other denervating diseases and is not a pure been identified. The patients may be clinically misdi- hypotrophic process occurring during early fetal agnosed as having CMT due to the distal weakness of development. the foot and hand intrinsics. Some subtypes of distal SMA have predominant upper extremity involvement. Spinal Muscular Atrophy III Other variants of distal SMA may present initially with (Kugelberg-Weilander Syndrome) distal lower extremity weakness. Sensory function is always normal clinically and electrodiagnostically. In more chronic SMA III, also referred to as Kugelberg- The course is usually slowly progressive, although Welander syndrome, weakness usually initially occurs some patients may experience a prolonged period of between the ages of 18 months and late teens. Motor stability. Other associated features in some subtypes milestones may be delayed in infancy. Proximal weak- include vocal cord paralysis and diaphragm weakness. ness is observed, with the pelvic girdle being more Some subtypes have associated pyramidal signs. affected than the shoulder girdle (57). There is an exaggerated lumbar lordosis and anterior pelvic tilt Juvenile Segmental SMA (Benign owing to hip extensor weakness. There is also a wad- Focal Amyotrophy; Hirayama Disease) dling gait pattern with pelvic drop and lateral trunk lean over the stance-phase side, secondary to hip This disease was originally described by Hirayama abductor weakness. If ankle plantar flexion strength is as a slowly progressive focal motor neuron disease sufficient, the patients may show primarily forefoot or affecting the upper extremities. Most cases occur on toe contact and no heel strike similar to patients with a sporadic basis. The onset of this syndrome is typi- Duchenne dystrophy. This is a compensatory measure cally between 15 and 25 years, with a range of 2 to 30. for knee extensor weakness to maintain a stabilizing Wasting and weakness develop segmentally in C8\u2013T1 knee extension moment at the knee. The patient may hand and forearm muscles and unilaterally and often exhibit a Gower\u2019s sign when arising from the floor; but not always in the dominant extremity. Sensation stair climbing is difficult due to hip flexor weakness. is completely normal. The disease progresses to more Facial weakness is sometimes noted. Fasciculations are proximal upper extremity muscles. The lower extrem- noted in about half of the patients (97) and are more ities are never affected, and typically the disease pro- common later in the disease course. Fasciculations in gession plateaus after two to six years. Symptoms the limb muscles and thoracic wall muscles are com- worsen in the cold (\u201ccold paresis\u201d). Tremor may occur mon. Calf pseudohypertrophy has been occasionally due to distal weakness. Hyperhidrosis of the involved noted, but wasting of affected musculature is more limb is a common complaint. Reflexes are typically prominent. Deep tendon reflexes are diminished and spared but not brisk. EMG studies are consistent with often become absent over time. Contractures are gen- an anterior horn cell disorder. MR imaging abnormal- erally mild as long as patients remain ambulatory. ities of the cervical spinal cord (segmental atrophy, Scoliosis may be observed in SMA III, but it occurs less stenosis, or foraminal narrowing) have been described frequently and is less severe than scoliosis and SMA II. in a proportion of patients. The disease is more com- While no survival data exist for patients with SMA III, mon in Asian populations. cases have been followed into the eighth decade with- out mechanical ventilation (57,98). Ventilatory fail- Progressive Bulbar Paralysis of ure due to neuromuscular restrictive lung disease is Childhood (Fazio-Londe Disease) a rare event in SMA III, occurring only in adulthood (57,117). Fazio-Londe disease, or progressive bulbar paralysis of childhood, is a progressive bulbar paralysis that is Zerres and Rudnik-Schoneborn (98) have proposed probably genetically transmitted. This is a disorder of further subtypes, including SMA IIIa (walks without bulbar motor neurons. Patients present with cranial support; age of onset less than 3 years) and SMA IIIb nerve findings, including ptosis, facial weakness, (walks without support; age of onset 3\u201330 years). In their series, only 44% of SMA \u201cIIIa\u201d patients remained","Chapter 12 Neuromuscular Diseases 321 dysphagia, normal hearing, and respiratory stridor. deformity than others. Those Friedreich\u2019s ataxia cases They may show hyperreflexia. Dominant transmis- with onset of disease before the age of 10 years gen- sion is rare. One group with recessive inheritance had erally have more severe progressive scoliosis. Those early onset in infancy and rapid progression, with with the onset of disease during or after puberty have death from respiratory failure less than two years later onset spinal deformity, which may not require from the age of onset. Another group with recessive surgical intervention. inheritance shows later onset (3 to 12 years), less respiratory involvement but slowly progressive dysar- Frataxin is a mitochondrial protein located on the thria, dysphagia, and facial weakness. These patients inner mitochondrial membrane. It is likely required may have progressive motor neuron disease with pri- for maintenance of mitochondrial genome, and it mary involvement of the anterior horn cells in the is involved in iron homeostasis and iron transport cervical and upper thoracic core segments. In add- into mitochondria. Idebenone is a powerful antiox- ition, there may be widespread degenerative changes idant and a synthetic analogue of coenzyme Q. It in the brainstem. Cranial nerve VII is almost always may improve iron homeostasis and mitochondrial affected. These patients develop dysphagia second- function in Friedreich\u2019s ataxia. In randomized clin- ary to cranial nerve XII involvement. The nuclei of ical trials, longer-term idebenone treatment has cranial nerves III, IV, VI, and X may also be involved; been shown to prevent progression of cardiomy- however, clinical impairment of extraocular move- opathy and cardiac hypertrophy in both pediatric ment is rare. and adult patients with Friedreich\u2019s ataxia. Its sta- bilizing effect on neurological dysfunction has been SPINOCEREBELLAR shown to be present only in the pediatric popula- DEGENERATION DISEASES tion, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may Friedreich\u2019s Ataxia be an important factor in the effectiveness of the therapy (118). Friedreich\u2019s ataxia is a spinocerebellar degenera- tion syndrome with the onset of symptoms before Other Hereditary Ataxias age 20 years. This autosomal-recessive condition has been linked in one subtype to chromosome 9q13\u201321.1 The hereditary ataxias are a group of genetic dis- (FRDA), with the protein implicated being termed orders characterized by slowly progressive inco- \u201cfrataxin.\u201d A second subtype referred to as FRDA2 is ordination of gait and often associated with poor linked to chromosome 9p23-p11. coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The The incidence of Friedreich\u2019s ataxia is 1 in 25,000 hereditary ataxias are categorized by mode of inher- to 50,000. Carrier frequency is 1 in 60 to 110. Age of itance and causative gene or chromosomal locus. onset is usually <20 years, typically around puberty, The genetic forms of ataxia are diagnosed by family with a range from 2 to 25 years. Obligate signs and history, physical examination, and neuroimaging. symptoms include progressive ataxic gait, cerebellar Molecular genetic tests are available for the diagnosis dysfunction with tremor and dysmetria, dysarthria, of many but not all spinocerebellar ataxias (SCAs). decreased proprioception or vibratory sense (or both), At least 28 genetically distinct autosomal-dominant muscle weakness, and absent deep tendon reflexes. SCA subtypes and four other autosomal-dominant Other common signs include cavus foot deformity, car- hereditary ataxias have been identified. Childhood diomyopathy, scoliosis, and upper motor neuron signs onset has been found commonly in SCA7, SCA13, such as a Babinski\u2019s sign and spasticity. Weakness SCA17, and SCA21 and more rarely in SCA1, SCA2, is progressive, affecting lower extremities and small SCA3, SCA5, SCA 21, and SCA 22. Other pedigrees muscles in the hands and feet. Sensory loss is typi- of SCA with childhood onset have been identified in cal and especially affects vibration and joint position only single families. Autosomal-dominant episodic sensation. Tendon reflexes are often absent. An occa- ataxia 1 (EA1) with episodic attacks of myokymia sional patient may have chorea without ataxia. With and ataxia and linkage to chromosome 12p13.3 has electrodiagnostic studies, sensory nerve potentials onset in the first decade. At least seven autosomal- may be absent or reduced. Progression is slow, with recessive ataxias in addition to Friedreich\u2019s ataxia mean time to wheelchair 15 years of age and death have been identified, most of which have childhood from cardiomyopathy ranges from the third to seventh onset. The most common of these is ataxia-telangi- decade. ectasia, with linkage to chromosome 11q22.3, which presents in the first decade with ataxia, dysarthria, The prevalence of scoliosis approaches 100%, ocular telangiectasias, immune deficiency, and risk but some cases have more severe progressive spinal of cancers.","322 Pediatric Rehabilitation MANAGEMENT OF CHILDHOOD instances that have raised concerns regarding over- NEUROMUSCULAR DISEASES work weakness in dystrophic myopathies. The domi- nant upper limb has been found to be weaker in persons Diseases affecting the lower motor neuron, including with FSHD muscular dystrophy than the nondominant, those primarily affecting anterior horn cell, peripheral providing circumstantial evidence for overwork weak- nerve, neuromuscular junction (presynaptic or post- ness (67,121). A single subject with scapuloperoneal synaptic) or muscle, ultimately lead to progressive loss muscular dystrophy had a reversal of rapid strength of functional muscle fiber over time. This loss of func- decline after reducing daily physical activity. Other tional muscle fiber may lead to progressive weakness, studies evaluating strengthening intervention in DMD decreased endurance, limb contractures, spine defor- subjects have shown maintenance of strength or even mity, body composition changes, decrease in mobility, mild improvement in strength over the period of the decreased pulmonary function, and occasionally car- investigation. However, these studies are limited by diac impairment if the myocardium is affected. Genetic use of primarily nonquantitative measures (122), lack defects causing CNS structural protein alterations of a control group (123), and use of the opposite limb may lead to intellectual impairment. Rehabilitation as a control without considering the effects of cross approaches directed at improving impairment and\/ training (124). Animal work utilizing dystrophic dogs or resultant disability may substantially improve the has shown significant increases in creatine kinase val- quality of life and community integration of children ues immediately following exercise. with neuromuscular diseases. The following discussion emphasizes general principles in the rehabilitation man- No systemic studies using the DMD population agement of childhood neuromuscular disease, with sev- have shown any deleterious effects of resistance exer- eral specific conditions used to illustrate key concepts. cise. Based on the theoretic susceptibility of the dystro- phin-deficient sarcolemmal membrane to mechanical Exercise in Neuromuscular Disease injury and the relative paucity of investigations, it is prudent to recommend a submaximal strengthening Exercise prescriptions and recommendations in child- program in DMD and other rapidly progressive dys- hood neuromuscular disease need to consider the spe- trophic disorders. A great concern is how to incorpo- cific disease condition as well as the developmental rate these activities effectively into the daily routine and maturational status of the child. of the child, avoiding use of mundane and tedious regimens that employ progressive resistive exercises. Strengthening Exercise in Incorporation of the activity into recreational pursuits Rapidly Progressive Disorders and aquatic-based therapy are probably the most rea- sonable approaches for the preadolescent child. The more rapidly progressive neuromuscular disor- ders of childhood generally include the dystrophic Strengthening Exercise in Slowly myopathies. The inherent instability of the sarco- Progressive Neuromuscular Diseases lemmal membrane predisposes to membrane injury due to mechanical loads. Theoretically, eccentric or Only supervised strengthening programs in this pop- lengthening contractions produce more mechanical ulation have been advocated. Recently, a moderate stress on muscle fiber than concentric or shorten- resistance home exercise program (using a less super- ing contractions. Indeed, many of the muscle groups vised approach) was devised that demonstrated similar that show the greatest weakness early in the course strength gains in both neuromuscular disease patients of Duchenne muscular dystrophy are muscle groups and normal control subjects without evidence of over- that perform a great deal of eccentric activity, such as work weakness (125). Based on this encouraging result, the hip extensors, knee extensors, and ankle dorsiflex- the home program was advanced to high resistance ors. In addition, lower extremity muscles in this pop- training in similar subjects without apparent additive ulation experience more mechanical loads than upper beneficial effects; in fact, eccentrically measured elbow extremity muscle groups, and weakness in the lower flexor strength actually decreased significantly (126). extremities generally predates weakness in the upper extremities. Edwards and colleagues (119) proposed Based on these investigations, the author believes that routine eccentric contractions occurring during that there is adequate evidence to generally advocate gait are a likely source of the pattern of weakness typ- a submaximal strengthening program for persons ically seen in myopathies. with slowly progressive NMD. There seems to be no additional benefit to high-resistance, low-repetition There may be increased weakness following training sets, and the risk of actually increasing weak- strengthening exercise in DMD (120). There are other ness becomes greater. Improvement in strength will hopefully translate to more functional issues such as improved endurance and mobility.","Chapter 12 Neuromuscular Diseases 323 Aerobic Exercise in Neuromuscular Disease orthotics, and surgery has recently been comprehen- sively reviewed (130). Contracture is defined as the Aerobic exercise refers to rhythmic, prolonged activity lack of full active of passive range of motion (ROM) due of the level sufficient to provide a beneficial training to joint, muscle, or soft tissue limitation. Contractures stimulus to the cardiopulmonary and muscular systems may be arthrogenic, soft tissue, or myogenic in nature, but below the threshold where anaerobic metabolism of and a combination of intrinsic structural changes of fuels is the primary source of energy. The response of muscle and extrinsic factors leads to myogenic con- normal skeletal muscle to this type of training includes tractures in selected neuromuscular disease condi- increased capillary density in the muscle to improve sub- tions. These factors include the following: degree of strate transfer, increased skeletal muscle mitochondrial fibrosis and fatty tissue infiltration; static positioning size and density, higher concentrations of skeletal mus- and lack of full active and passive range of motion; cle oxidative enzymes, and improvement in utilization imbalance of agonist and antagonist muscle strength of fat as an energy source for muscular activity. Patients across the joint; lack of upright weight bearing and with neuromuscular disease have a diminished capacity static positioning in sitting; compensatory postural for exercise. Children with Duchenne muscular dystro- changes used to biomechanically stabilize joints for phy have been demonstrated to have low cardiovascular upright standing; and functional anatomy of muscles capacity and peripheral oxygen utilization with higher and joints (multijoint muscle groups in which the ori- resting heart rate compared with controls (127). Physical gin and insertion crosses multiple joints). In general, ability and exercise capacity is more likely to be limited dystrophic myopathies have a high degree of fibrosis by muscle strength than by deterioration of cardiorespi- and fatty infiltration, placing these patients at higher ratory function. In a recent study using a home-based risk for contractures. Significant contractures have aerobic walking program, slowly progressive neuromus- been most commonly identified in Duchenne mus- cular disease subjects showed modest improvement in cular dystrophy, Becker muscular dystrophy, Emery- aerobic capacity without evidence of overwork weak- Dreifuss muscular dystrophy, congenital muscular ness or excessive fatigue (128). It is likely that alternative dystrophy, autosomal recessive LGMD, FSHD muscu- exercise approaches, such as aquatic-based therapy, will lar dystrophy, myotonic muscular dystrophy, heredi- need to be utilized in children with more severe neu- tary motor sensory neuropathy, and spinal muscular romuscular diseases who are nonambulatory and have atrophy. less-than-antigravity muscle strength. Contractures and progressive NMD conditions One group recently studied the effect of endur- should be managed with the following concepts ance training on conditioning and strength in adult in mind: Becker muscular dystrophy (BMD). Eleven patients with BMD and seven matched, healthy subjects cycled 1. Prevention of contractures requires early diagno- 50 30-minute sessions at 65% of their maximal oxy- sis and initiation of physical medicine approaches, gen uptake (VO2max) over 12 weeks, and six patients such as passive ROM and splinting wall contrac- continued cycling for 1 year. Endurance training for 12 tures, are still mild. weeks significantly improved VO max by 47 \u00b1 11% and 2. Contractures are inevitable in some NMD condi- 2 tions, such as DMD. maximal workload by 80 \u00b1 19% in patients. This was 3. Advanced contractures become fixed and show lit- significantly higher than in healthy subjects (16 \u00b1 2% tle response to stretching programs. and 17 \u00b1 2%). CK levels did not increase with training. Strength in muscles involved in the cycle exercise (knee 4. A major rationale for controlling contractures of the extension, and dorsi- and plantarflexion) increased sig- lower extremity is to minimize the adverse effect of nificantly by 13% to 40%. Cardiac pump function, mea- contractures on independent ambulation. However, sured by echocardiography, did not change with training. the major cause of wheelchair reliance in NMD is All improvements and safety markers were maintained generally weakness, not contracture formation. after one year of training. Endurance training was dem- onstrated to be a safe method to increase exercise per- 5. Static positioning of both upper and lower extrem- formance and daily function in patients with BMD, and ity joints in patients with weak musculature is the the findings support an active approach to rehabilitation most important cause of contracture formation. of patients with BMD (129). 6. Passive stretching for control of lower limb con- Management of Limb tractures is most successful in ambulatory patients Contractures and Deformity with early mild joint contractures. The management of limb contractures in progressive 7. Upper extremity contractures may not negatively neuromuscular disease and the role of stretching, affect the function if they are mild. 8. Joint range of motion should be monitored regularly by physical therapists and occupational therapists using objective goniometric measurement.","324 Pediatric Rehabilitation Principle therapy modalities must be regu- Bracing\/Orthotic Management and larly carried out to prevent or delay the develop- ment of lower extremity contractures for those at Orthopaedic Surgical Management of risk for musculoskeletal deformity. These include: regularly prescribed periods of daily standing and Limb Deformity walking if the patient is functionally capable of being upright; passive stretching of muscles and Management in Neuromuscular Diseases joints with a daily home program; positioning of With Proximal Weakness the leg to promote extension and oppose joint flex- ion when the patient is non-weight bearing through The prototypical disorder in which bracing and sur- the lower extremities; and splinting, which is a gical management of contractures for prolonged useful measure for the prevention or delay of ankle ambulation has been applied is Duchenne muscular contracture. dystrophy. In this population, wheelchair reliance is imminent when knee extension strength becomes less In the upper extremity, elbow flexion contractures than antigravity and time to ambulate 30 feet is greater in dystrophic myopathies may occur soon after transi- than 12 seconds (9). A number of principles should be tion to the wheelchair, secondary to static positioning emphasized for these populations. First, with an appro- of the arms and elbow flexion on the armrests of the priate and aggressive home-based therapy program, wheelchair (9). Other associated deformities in DMD equinovarus contractures generally are absent or very and other dystrophic myopathies include forearm mild in DMD at the time walking ability ceases (9). In pronator tightness and wrist flexion-ulnar deviation addition, hip and knee flexion contractures are also in the later stages of the disease. The regular palm- absent or extremely mild in ambulatory DMD patients down position of the hand increases the occurrence at the time of transition to wheelchair. The wide-based of forearm pronator contracture. Mild elbow flexion Trendelenburg\u2019s gait exhibited by these patients with contractures of \u2264 to 15 degrees are of no functional gluteus medius weakness places the hip in an abducted consequence to the patient using crutches or a wheel- position, leading to iliotibial band contractures. The chair. Contractures of the elbows over 30 degrees late phase of ambulation often is associated with more can interfere with the use of crutches in ambulatory marked joint contractures involving the iliotibial bands patients with NMD. Severe elbow flexion contrac- and heel cords because DMD patients spend more time tures of >60\u00ba are associated with decreased distal sitting and less time standing. The release of contrac- upper extremity function and produce difficulty when tures at both the heel cord and iliotibial band gener- dressing. ally is necessary to obtain successful knee ankle foot orthotic (KAFO) bracing (131\u2013134). Other authors have Passive stretching of the elbow flexors may be reported bracing of DMD patients without surgical combined with passive stretching into forearm supi- release of the iliotibial bands (135,136). Hip and knee nation to help prevent contractures. Prophylactic flexion contractures generally are not severe enough occupational therapy management of the wrist and to interfere with bracing at the time of transition to hand is recommended in NMD to slow the devel- wheelchair (9). The iliotibial band contractures may opment of contractures and to maintain fine motor be released with a low Young fasciotomy and a high skills. Daily passive stretching of the wrist flexors Ober fasciotomy. and intrinsic and extrinsic muscles of the hand and wrist are recommended, as are active range-of-mo- The ankle deformity may be corrected by either a tion exercises for the wrist and long finger flexors. tendo-Achilles lengthening (TAL) or a TAL combined Nighttime resting splints, which promote wrist exten- with a surgical transfer of the posterior tibialis muscle sion, metacarpophalangeal extension, and proximal tendon to the dorsum of the foot. The posterior tibialis interphalangeal flexion, are recommended. Daytime tendon transfer corrects the equinovarus deformity positioning should emphasize wrist and finger exten- but prolongs the time in a cast and recovery time, and sion, but any splinting should not compromise sensa- it increases the risks of prolonged sitting. tion or function. Orthopedic surgical release of these contractures Shoulder contractures are less problematic in allows the DMD patient to be braced in lightweight patients with profound proximal muscle weakness. polypropylene KAFOs with the sole and ankle set at Combined shoulder internal rotation, adduction con- 90 degrees, drop-lock knee joints, and ischial weight- tracture, and elbow flexion deformity may interfere bearing polypropylene upper thigh component. DMD with self-feeding. Severe shoulder internal rotation patients who are braced may or may not require a deformities may complicate dressing, produce pain walker for additional support. At times, DMD patients on passive range of motion, and cause pain during who have had excellent home stretching programs sleep. can be placed immediately into KAFO bracing without surgical tenotomies.","Chapter 12 Neuromuscular Diseases 325 While DMD subjects are still ambulating indepen- with forefoot initial contact to maintain a knee exten- dently without orthotics, they often use their ankle sion moment in the setting of quadriceps weakness. equinus posturing from the gastrocnemius-soleus Heel cord contractures may need to be surgically group to create a knee extension moment at foot con- lengthened to allow for AFO or KAFO bracing. Cavus tact, thus stabilizing the knee when the quadriceps feet are common in peripheral neuropathies. Intrinsic muscle is weak. Several authors have cautioned against muscle weakness of the foot results in hyperextension isolated heel cord tenotomies while DMD patients are at the metatarsophalangeal joints and flexion at the still ambulating independently. Overcorrection of the interphalangeal joints with resultant claw toe defor- heel cord contracture in a DMD patient may result in mities. This constellation of deformities may cause immediate loss of the ability to walk without bracing difficulty in walking, lack of balance and painful cal- unless the quadriceps are grade 4 or better (131). losities. Treatment of the cavus foot depends on the patient\u2019s age, flexibility of the foot, bony deformity, The duration of ambulation in DMD has been and muscle imbalance. A supple foot can be managed successfully prolonged by prompt surgery and brac- nonoperatively by serial casting in a walking cast, fol- ing, immediately implemented following loss of lowed by an AFO with a solid ankle in neutral posi- independent ambulation. Generally, the gains in add- tion and a lateral heel wedge if significant hindfoot itional walking time have been variable, but generally varus exists. Fixed soft tissue or bony deformity may reported between two and three years. require orthopedic surgery to produce a plantigrade foot. In skeletally immature children, triple arthrod- Long-term benefits of prolonged walking include esis is contraindicated. Triple arthrodesis should only decreased severity of heel cord and knee flexion con- be considered as a salvage procedure for severe heel tractures at age 16 (137). This may ultimately improve varus and severe midfoot deformity, with the goal shoe wear tolerance and foot positioning on the wheel- being achievement of hindfoot stability in a skeletally chair leg rests. Prolonged ambulation by lower extrem- mature patient. ity bracing in DMD has never been documented to be an independent factor in the prevention of scoliosis. Management of Spinal Deformity Disadvantages of braced ambulation center around the excessive energy cost of braced ambulation and safety Severe spinal deformity and progressive NMD lead concerns in the event of falls. DMD subjects with to multiple problems, including poor sitting balance, KAFO bracing usually need gait training by physical difficulty with upright seating and positioning, pain, therapy, and they need to be taught fall techniques. difficulty in parental or attendant care, and poten- tial exacerbation of underlying restrictive respiratory Weakness is the major cause of loss of ambulation compromise (Fig. 12.18). Severe scoliosis and pelvic in DMD, not contracture formation. Thus, the primary obliquity can, in some instances, completely preclude indication of orthopedic surgical tenotomies and pos- upright sitting in a wheelchair. The management of spi- terior tibialis tendon transfers likely is the provision nal deformity and progressive neuromuscular disease of optimal alignment for KAFO bracing. Little evi- has recently been reviewed (17). Populations at risk dence supports the efficacy of early prophylactic lower for scoliosis include DMD, autosomal-recessive LGMD, extremity surgery in DMD for independently produc- congenital muscular dystrophy, FSHD muscular dys- ing prolonged ambulation (9,131,138). trophy, congenital myotonic muscular dystrophy, spi- nal muscular atrophy II and III, and Friedreich\u2019s ataxia. In general, with the increased utilization of corti- While previous estimates of incidence of severe scoli- costeroids in DMD, there has been a trend over the past osis in DMD approached 80% to 90%, recent evidence two decades towards reduced use of lower extremity suggests that corticosterorids (specifically deflazacort) surgery and long leg bracing to prolong ambulation. may significantly decrease the incidence of severe pro- gressive scoliosis in DMD (22). Management of NMD Patients With Distal Lower Extremity Weakness Close clinical monitoring is essential for children with NMD at risk for scoliosis. Curves may progress Ankle dorsiflexors are often clinically weaker than rapidly during the adolescent growth spurt, and chil- ankle plantar flexors in neuromuscular disease because dren need to be monitored every three to four months of selective involvement of the peroneal nerve in many during this time, with clinical assessment and spine neopathies and isolated anterior and lateral compart- radiographs if indicated. In addition, patients who are ment weakness in several myopathic conditions such likely to require surgical arthrodesis at some point as FSHD, scapuloperoneal distribution LGMD, DMD, should be monitored with pulmonary function tests and Emery-Dreifuss muscular dystrophy. Ankle foot every six months. A forced vital capacity falling below orthotics (AFOs) often are used for patients with distal weakness. AFOs are generally contraindicated in situ- ations where NMD patients utilize equinus posturing","326 Pediatric Rehabilitation arthrodesis because of continued spinal growth, which decreases in rate after age 11 to 12. If a younger child has a severe progressive curve and severely compro- mised pulmonary function, a posterior fusion may be considered, with acceptance of the fact that some rota- tional \u201ccrank shaft deformity\u201d will ensue. Spinal arthrodesis is the only effective treatment for scoliosis in DMD, autosomal-recessive LGMD, congeni- tal muscular dystrophy, congenital myotonic muscular dystrophy SMA, and Friedreich\u2019s ataxia. The decision to pursue posterior spinal instrumentation involves a consideration of the severity of the restrictive lung disease, severity of the cardiomyopathy, severity and flexibility of the spinal deformity, and likelihood that the spinal deformity will continue to progress. Surgical spinal arthrodesis should be deferred to a later date in marginally ambulatory patients with LGMD, congen- ital muscular dystrophy, FSHD, and spinal muscular atrophy type III, as these individuals may use signifi- cant lumbar lordosis during gait to compensate for hip extensor weakness. Figure 12.18 Scoliosis in Duchenne muscular dystrophy Provision of Functional Mobility compromising long-term comfortable supported sitting in a power wheelchair. Generally, antigravity quadriceps are required for com- munity ambulation in childhood neuromuscular dis- 30% to 40% of predicted does not contraindicate sur- ease. Short-distance ambulation may be achieved by gery (28), but is associated with increased periop- some patients with more severe weakness using KAFO erative morbidity and likely the need for prolonged bracing, with or without a walker. Such orthotic inter- noninvasive ventilatory support during the postopera- vention is often provided to children with SMA type III, tive recovery period (27). Thus, there is often a critical severe childhood autosomal recessive muscular dystro- window of time where the spinal deformity is evident phy (SCARMD), congenital muscular dystrophy, DMD, and likely to continue to progress and the restrictive and Becker muscular dystrophy during adulthood. lung disease is not of a severity that would contra- Children with DMD SMA type II, congenital muscular indicate surgery or be associated with perioperative dystrophy, congenital myopathies, some myasthenic complications. syndromes, and more severe hereditary motor sen- sory neuropathies utilize power mobility devices for The management of spinal deformity with orthot- functional mobility. Generally, children can be taught ics is ineffective in DMD and does not change the nat- to safely operate a power wheelchair when they are ural history of the curve. Spinal orthoses are often at the developmental age of approximately 2 years reported to be uncomfortable and poorly tolerated by (139,140). The initial power wheelchair prescription DMD patients. Furthermore, vital capacity potentially needs to consider the natural history of the neuromus- can be lowered with constrictive orthoses. On the other cular disease condition over the following five years, hand, in neuromuscular diseases with spinal defor- as some children will subsequently develop the need mity beginning in the first decade of life, such as SMA, for a power recline system and the chair needs to be congenital muscular dystrophy, congenital myotonic able to accommodate such a recline or be retrofit. In muscular dystrophy, some congenital myopathies, and more severe disability, the power wheelchair electron- congenital myasthenic syndromes, spinal bracing is ics should be sufficiently sophisticated to incorporate generally used to improve sitting balance in patients alternative drive control systems, environmental con- who are unable to walk. In addition, spinal orthotics trol adaptations, and possibly communication systems are employed in these younger patients in an attempt to in patients who are unable to vocalize. halt curve progression until children are 10 to 11 years of age, when a single posterior spinal arthrodesis pro- Pulmonary Management cedure is sufficient. Children younger than the age of 10 generally require both anterior and posterior spinal Pulmonary complications are recognized as the lead- ing cause of mortality in childhood neuromuscular","Chapter 12 Neuromuscular Diseases 327 disease. Respiratory insufficiency in neuromuscular at the time they require institution of mechanical disease results from a number of factors, including: ventilatory support. Hahn and colleagues (144) have respiratory muscle weakness and fatigue, alteration reported the predicted value of maximal static airway of respiratory system mechanics, and impairment of pressures in predicting impending respiratory fail- a central control of respiration. Progressive muscle ure. Splaingard (145) reviewed a series of 40 patients weakness and fatigue lead to restrictive lung disease with a diverse group of neuromuscular disease condi- and ultimately to hypoventilation, hypercarbia, and tions. They noted that all their patients who required respiratory failure. Increased inelastic load on respi- mechanical ventilation had a vital capacity of \u226425%, ratory muscles occurs because of chest wall stiffness, with at least one of the following associated findings: airway secretions, and ineffective cough mecha- PaCO2 >than 55 mmHg, recurrent atelectasis or pneu- nism. This may result in atelectasis and increased monia, moderate dyspnea at rest, or congestive heart airway resistance, and kyphoscoliosis can further failure. alter respiratory mechanics. Defects in central con- trol of respiration may be secondary to hypoxemia Noninvasive forms of both positive and negative and hypercarbia, associated with severe restrictive pressure ventilation are being increasingly applied lung disease. Significant nocturnal decreases in par- to children with neuromuscular diseases. Initially, tial pressure of oxygen, as well as elevations in arte- patients may require ventilatory support for only part rial partial pressure of carbon dioxide, occur in more of the day. Noninvasive nocturnal ventilation has severe restrictive lung disease. Hypercapnia or hypox- become a widely accepted clinical practice, providing emia occurring at night may have a role in reducing ventilatory assistance for patients while sleeping and daytime central respiratory drive. A chronic increase allowing them to breathe on their own during the day. in the bicarbonate pool may blunt the stimulus to Intermittent ventilation may ameliorate symptoms of breathe, generated by respiratory acidosis and per- respiratory failure, reduce hypercarbia, increase oxy- petuating the hypercapnic state. Expiratory muscle genation (even during periods off the ventilator), and weakness may produce ineffective cough, problems prolong survival in patients with neuromuscular dis- with clearance of secretions, and predisposition to ease. The long-term use of noninvasive ventilation pulmonary infections. (Fig. 12.19) may be associated with fewer complica- tions than ventilation via a tracheostomy; however, Respiratory failure may present acutely or insidi- bulbar muscle function should be adequate for safe ously. Respiratory difficulties in the delivery room or swallowing (117). Ventilatory support has allowed pro- early infancy may be seen in acute infantile type I longed survival and acceptable quality of life in SMA I, SMA, myotubular myopathy, congenital hypomyeli- SMA II, and DMD (143,146,147,148). nating neuropathy, congenital infantile myasthenia, congenital myotonic muscular dystrophy, transitory Improved pulmonary toilet and clearance of secre- neonatal myasthenia, and severe neurogenic arthro- tions can be achieved with assisted cough; deep breath- gryposis. In most other childhood neuromuscular ing; and setup spirometry, percussion, and postural diseases, the respiratory insufficiency develops more insidiously unless an acute decompensation occurs Figure 12.19 Noninvasive ventilatory support using bilevel from an event such as an aspiration episode or acute positive airway pressure and nasal pillows mask interface onset of weakness, as seen in Guillain-Barr\u00e9 syn- in young adult with Duchenne muscular dystrophy. drome, botulism, and myasthenic syndromes. Signs and symptoms of significant respiratory difficulties may include subcostal retractions, accessory respi- ratory muscle recruitment, nasal flaring, exertional dyspnea or dyspnea at rest, orthopnea, generalized fatigue, and paradoxic breathing patterns. A history of nightmares, morning headaches, and daytime drows- iness may indicate nocturnal hypoventilation with sleep-disordered breathing. Pulmonary function tests have been used to help in the decision-making process regarding the institution of mechanical ventilation. In a study of 53 patients with proximal myopathy, hyper- capnia occurred when the maximal inspiratory pres- sure was less than 30% of predicted and when vital capacity was less than 55% of predicted (141). Other authors (142,143) have noted lower values for vital capacity measurements in their patients with DMD","328 Pediatric Rehabilitation drainage, and, in more severe cases, the additional use of interpulmonary percussive ventilation (IPV), given two to three times daily. Nutritional Management Figure 12.20 Severe weight loss in young adult with Duchenne muscular dystrophy. Management of Swallowing Problems Branched-Chain Ketoacid Supplementation Involvement of palatal and pharyngeal muscles may produce dysphagia. Patients at particular risk include Based on the observations that muscle protein degra- those of SMA, myasthenia gravis, congenital myas- dation is accelerated in DMD and administration of thenic syndromes, and congenital myopathies, such branched-chain ketoacids reduces protein breakdown as myotubular myopathy, oculopharyngeal muscular in fasting obese subjects, Stewart and colleagues (152) dystrophy, late-stage Duchenne muscular dystrophy, conducted a trial of branched-chain ketoacid supple- and late-stage SCARMD. The presence of dysphagia mentation. The ketoacids of the branched-chain amino in patients with neuromuscular disease has been acids leucine, valine, and isoleucine were administered documented by others (51,149). The function of the orally as ornithine salts at a dosage of 0.45 gm\/kg body swallowing mechanism is best evaluated with a fluo- weight\/day for four days in nine boys with DMD, aged roscopic video dynamic swallowing evaluation. DMD 5\u20139 years. An equivalent amount of protein was removed patients have a high prevalence of dysphagia dur- from the diet during this time. A small but significant ing the late stages of the disease (51). DMD patients reduction in muscle protein degradation was observed may also rarely develop acute gastric dilatation sec- as a result of the treatment, and no negative effects were ondary to gastric paresis (150). Bulbar dysfunction noted. The results warrant further investigation regard- and\/or respiratory distress may affect feeding in ing the effects of longer-term branched-chain ketoacid SMA patients. In SMA I, therapeutic modifications supplementation on muscle protein degradation. may include use of a premature baby nipple with a large opening, use of proper head and jaw position, Weight Reduction along with a semireclined trunk position and use of frequent small feedings to minimize fatigue. These DMD patients typically gain excessive weight between larger bolus feeds may distend the stomach and 9\u201313 years of age, subsequent to the onset of wheelchair encroach on the diaphragm, thus affecting respira- tory status. Improved nourishment in SMA leads to a feeling of well-being and therefore a better quality of life. Poor nutritional status, labored feeding, and\/or symptoms of dysphagia are indications for initiation of supplemental enteral feedings via nasogastric tube or gastrostomy. Gastroesophageal reflux with risk of aspiration may be an indication for placement of a gastrojejunostomy tube. Energy and Protein Supplementation Severe deficits in energy and protein intake have been documented in DMD (49,50) during the sec- ond decade. Substantial weight loss has been docu- mented in DMD to occur between the ages of 17 and 21 (Fig. 12.20). Protein and calorie needs in DMD may be approximately 160% of that required for able-bodied adolescents. Beneficial effects in weight gain, anthro- pometric measurements, and nitrogen balance were documented for DMD patients aged 10\u201320 years, subsequent to a three-month nutritional supplemen- tation, which consisted of an additional 1,000 kcals and 37.2 grams of protein (151). The positive effects on metabolism observed in this study warrant further investigation.","Chapter 12 Neuromuscular Diseases 329 reliance. This is likely due to a reduction in total daily with cardiac signs or symptoms nr screening ECG, energy expenditure with increased sedentary exis- echocardiography, or for those with Holter recording tence. Edwards and colleagues (153) demonstrated abnormalities suggestive of cardiac disease. Late-stage that weight reduction through a medically supervised DMD, BMD, and Emery-Dreifuss muscular dystrophy decrease in energy intake could be achieved success- patients should be followed by a cardiologist on a reg- fully in DMD without compromising skeletal mus- ular basis. Appropriate management of cardiac com- cle mass. Obesity has also been observed in SMA III plications in childhood neuromuscular disease will patients and has been attributed to a relatively seden- hopefully increase life expectancy. tary lifestyle. Increased adiposity has been documented in adults with slowly progressive neuromuscular dis- Pharmacologic Intervention eases (154). Approaches to weight reduction in slowly progressive neuromuscular disease patients has been The rehabilitation specialist may become involved previously reviewed (155). in the prescription of pharmacologic agents, which affect the pathophysiology of various neuromuscular Management of Cardiac Complications diseases. Evaluation of therapeutic efficacy for phar- macologic agents requires careful objective measure- Early treatment with ACE inhibitors is probably war- ment of strength, with quantitative measurements, ranted in DMD when the measured ejection fraction functional status using timed motor testing and the falls below 55% (36,37). The benefits of earlier protec- six-minute walk test, pulmonary function parameters, tive treatment with either ACE inhibitors or ARBs is cardiac parameters, and patient-reported quality of life under investigation. Digitalis has been demonstrated measures. to be effective in decreasing morbidity from heart fail- ure, but not mortality, and probably is also indicated Corticosteroids such as prednisone and deflazacort for the treatment of heart failure observed in DMD may have an effect on the inflammatory component of patients with cardiomyopathy. Beta blockers may also the dystrophic myopathy and other disease pathways have a role in DMD. Treatment with coenzyme Q10 in DMD, slow the progression of the strength loss, pro- remains controversial. Cor pulmonale, confirmed on long ambulation by two years, reduce the occurrence echocardiography, may benefit from continuous sup- of scoliosis, and slow the loss of pulmonary function plemental oxygen. Patients with known arrhythmias (11\u201313,22\u201324,156). Alternative pulsed-dosing regimens, who are at risk for fatal tachyarrhythmias may ben- such as high-dose weekend administration (5 mg\/kg\/ efit from antiarrhythmic medication. DMD patients day on both Saturday and Sunday) may decrease the with mitral valve prolapse and mitral regurgitation side effects of weight gain and growth retardation should be given antibiotic prophylaxis for dental with similar clinical efficacy. Deflazacort is an alter- and surgical procedures in accordance with current nate corticosteroid with a potentially better side effect guidelines. profile and equal efficacy to prednisone in DMD. The management of the cardiomyopathy, seen in The identification of specific genes and the pro- Becker muscular dystrophy, is similar to that seen in tein products implicated in the pathogenesis of var- DMD; however, in cases of severe end-stage cardiomy- ious neuromuscular diseases provides hope that opathy, cardiac transplantation should be considered. meaningful therapeutic interventions that target the defective genes will alter the natural history of many Cardiac conduction abnormalities observed in of these neuromuscular diseases. It is likely that tra- myotonic muscular dystrophy may ultimately require ditional rehabilitation approaches will need to be used implantation of cardiac pacemakers. In rare instances adjunctively with newer pharmacologic interventions, with cardiomyopathy, treatment may consist of ACE molecular genetic-based therapies, and possibly gene inhibitors, digitalis, and diuretics, based on proven therapy in the management of these conditions. efficacy in cardiomyopathies of other etiologies. REFERENCES Emery-Dreifuss muscular dystrophy patients with symptomatic bradycardia or heart block should 1. Hogrel JY, Lafor\u00eat P, Ben Yaou R, Chevrot M, Eymard B, undergo implantation of a permanent cardiac pace- Lomb\u00e8s A. A non-ischemic forearm exercise test for the maker. Atrial standstill, atrial fibrillation, and atrial screening of patients with exercise intolerance. Neurology. flutter are all disorders in which blood can pool in 2001;56(12):1733\u20138. the atria, leading to thrombus formation and possible embolic events, including stroke. Anticoagulation with 2. Kazemi-Esfarjani P, Skomorowska E, Jensen TD, Haller RG, warfarin to an international normalized ratio (INR) Vissing J. A nonischemic forearm exercise test for McArdle of 2\u20133 has demonstrated a reduction in the incidence disease. Ann Neurol. 2002;52(2):153\u20139. of stroke in patients with atrial fibrillation. Prompt referral to a cardiologist should be made for children 3. Dubowitz V. Muscle Disorders in Childhood 2nd ed. London: W.B. Saunders, 1995."]