Genetics: Dystrophin gene mutation, Xp21.2 (X-linked recessive). Epid: Incidence: 1 in 3,500 male births. Prevalence: 1 in 18,000 males. Female carriers may have mild sx because of lyonization (skewed X-inactivation).

Si/Sx: Usually nl at birth or mildly weak/hypotonic. Gait affected between 2 and 6 yo (wide based, waddling, toe walking, difficulty running/jumping). Then develop arm/
torso weakness. Usually wheelchair bound by 12 yo. Exam: Calf pseudohypertrophy, Gower sign when arising from floor, symmetric weakness, diminished DTRs (though ankle jerks may remain, even late in disease), Achilles/hamstring contractures, kyphoscoliosis. Cardiac muscle is involved, leading to cardiomyopathy, EKG abnormalities, sinus tachycardia. Many pts have cognitive impairment. Pts develop respiratory decline leading to death, usually in early 20 s.

Dx: Genetic testing. CK (50-100× nl or greater). EMG: ↑ spontaneous activity; may have myopathic changes. Muscle MRI: Fatty replacement. Muscle biopsy: Reduced/absent dystrophin on immunohistochemistry & Western blot.

Rx: Corticosteroids (stabilizes/improves strength & can delay wheelchair dependence), annual PFTs, regular echocardiography/EKGs, cardiology follow-up.

Genetics: Dystrophin gene mutation, Xp21.2 (X-linked recessive).

Epid: Incidence: 5 in 100,000 male births.

Si/Sx: Similar to Duchenne, but milder phenotype, presents later. Pts ambulatory past 15 yr of age, but ˜50% lose ambulation by 4th decade.

Dx: Genetic testing. CK (20-200× nl). Muscle biopsy: Reduced/absent dystrophin on immunohistochemistry & Western blot.

Rx: Monitor respiratory & cardiac function.

Large, clinically heterogenous group of disorders; AD or AR inheritance. AD: LGMD 1, subtypes A-H incl myotilin, lamin A/C, caveolin-3 forms. AR: LGMD 2, subtypes A-S incl calpain-3, dysferlin, sarcoglycans, telethonin, TRIM 32, fukutin-related protein (FKRP), titin forms.

Si/Sx: Predominantly limb-girdle weakness, though additional muscle groups are involved to varying extents.

Dx: Targeted genetic testing based upon inheritance pattern & clinical phenotype (e.g., presence/absence of facial weakness, scapular winging, calf atrophy, contractures, early cardiac/respiratory involvement).

Myotonia: Delayed relaxation of a muscle, usually worse w/cold or stress. Seen commonly in facial & hand muscles. May be elicited by percussion (e.g., thenar eminence, extensor digitorum communis) or strong contraction (e.g., grip myotonia, eyelid myotonia). Often described by pts as muscle “stiffness.”

Genetics: AD, caused by unstable trinucleotide repeat on DPMK gene (19q13.2). Up to 27 repeats nl, but pts w/DM1 can have 50-4,000 repeats w/↑ repeats correlating w/worse disease severity. # of repeats often increases in successive generations, causing earlier/more severe presentation (anticipation).

Epid: Incidence of 13.5/100,000 live births & prevalence of 3-5/100,000.

Si/Sx: Can present at any age (incl severe congenital form). Pts develop distal then proximal limb weakness, neck flexor weakness, facial weakness/atrophy leading to characteristic “hatchet face” appearance, may develop bulbar weakness as well. Often have frontal balding. Clinical myotonia on exam (percussion, grip, eyelid). Multisystem involvement: Cardiac (conduction defects), GI (reduced gastrointestinal motility w/pseudoobstruction), respiratory (alveolar hypoventilation, sleep apnea), ophtho (cataracts), endocrine (testicular atrophy, insulin resistance), neurobehavioral (cognitive/mood issues).

Dx: Genetic testing; EMG w/electrical myotonia (“dive bomber” sound), ↑ spontaneous activity, myopathic motor unit potentials.

Rx: Mexiletine or phenytoin for disabling myotonia; annual EKGs; ophthalmological exams; consider sleep study to eval for sleep apnea; genetic counseling if planning to have children.

Dystrophia myotonica 2 (DM2): Also known as “proximal myotonic myopathy” (PROMM), resembles DM1 (myotonia, weakness, cataracts, cardiac issues), but often presents between 20 and 60 yo.

Genetics: AD, caused by unstable CCTG repeat expansion on chromosome 3q21. More prevalent in northern European families.

Si/Sx: Slowly progressive proximal & distal weakness that may fluctuate over time. Myotonia, which often manifests as muscle stiffness/pain w/“warm-up” phenomenon (improves w/repeated contractions).

Dx: Genetic testing, myotonia on EMG.

Facioscapulohumeral (FSH) dystrophy: AD, sx typically manifest between 3 and 45 yr of age, though can be later. Variable penetrance, even in members of the same family. Exam: Facial weakness, scapular winging, proximal arm weakness that spares forearms (“Popeye” arms), inverted axillary folds. Weakness may be asymmetric. Dx: Genetic testing (there are two genetically distinct subtypes).

Scapuloperoneal muscular dystrophy: P/w foot drop (often asymmetric) followed by scapular winging w/in first 2 decades of life. Rx: Supportive—AFOs for foot drop, consider surgery to stabilize scapula.

Emery-Dreifuss muscular dystrophy: X-linked or AD. Pts p/w early contractures (elbows, ankles, neck) & slowly progressive weakness, as well as cardiac conduction defects. May require prophylactic pacemaker or intracardiac defibrillator. Rx: Annual EKGs, PT to reduce contractures. Dx: Genetic testing (emerin mutations are most common form of X-linked cases, while most dominant cases are caused by mutations in lamin A/C).

Oculopharyngeal muscular dystrophy (OPMD): Usually AD, more commonly seen in pts of French-Canadian descent. P/w slowly progressive ptosis (often asymmetric) in 4th-6th decade, accompanied by restricted EOMs, pharyngeal weakness w/dysphagia, & proximal limb weakness. Pts may require surgery to help w/ptosis, cricopharyngeal myotomy for dysphagia. Dx: Genetic testing.

Genetics: Mutation in ryanodine receptor gene (chromosome 19), AD > AR.

Si/Sx: Proximal & mild facial weakness beginning in infancy/early childhood, contractures, kyphoscoliosis, pes cavus, cardiac abnormalities.

Dx: Genetic testing; biopsy w/round areas of clearing (“cores”) in type I fibers on NADH-TR staining.

Rx: Pts at risk for malignant hyperthermia & should avoid certain anesthetics (e.g., halothane), neuromuscular blocking agents (e.g., succinylcholine). Monitor cardiac function (EKG, TTE).

Genetics: X-linked myotubularin gene mutations account for 90% of cases, have a more severe phenotype. AD dynamin mutations are milder.

Si/Sx: X-linked: severe neonatal hypotonia, progressive weakness of limb girdle & neck muscles, facial weakness, dysarthria, ptosis, EOM weakness. Children w/AD mutation may be nl or mildly hypotonic at birth, have a slower progression.

Dx: Genetic testing; muscle biopsy w/myonuclei in the center of fibers.

Rx: Supportive; early initiation of tube feeding, mechanical ventilation if needed. Prognosis is often poor for X-linked mutation, w/death in infancy. Milder cases present in childhood or adulthood, progress more slowly.

Genetics: At least three different genetic defects (tropomyosin 3, &agr;-actin, selenoprotein N).

Si/Sx: Static limb-girdle weakness associated w/myopathic facies, dolichocephaly, high-arched palate, occasional scoliosis. May occur in isolation or as a component of another disease (e.g., Krabbe, congenital myotonic dystrophy). Most cases static, but some have progressive weakness & respiratory insufficiency.

Dx: Genetic testing; muscle biopsy w/disproportionate ratio of type I to type II myofibers, type I fibers are smaller than usual & type II are nl to enlarged.

Rx: Supportive: PT/OT; tube feeding, mechanical ventilation if needed.

Genetics: Five associated genes (AD & AR) w/variable penetrance, code for thin filament-associated proteins (nebulin, &agr;-actin, troponin, &agr;-tropomyosin, &bgr;-tropomyosin).

Si/Sx: Most commonly presents in infancy/early childhood w/generalized hypotonia, static/slowly progressive weakness (incl facial weakness, ptosis), dysmorphic facies.
Can also see severe infantile form (often fatal in 1st yr) or adult-onset form w/mild proximal & distal weakness, at times associated w/cardiomyopathy.

Dx: Muscle biopsy w/nemaline rods (best seen on trichrome stain, EM); genetic testing.

Rx: Supportive (PT, bracing). In severe infantile form, aggressive early rx of respiratory & feeding difficulties.

Genetics: AR: Mutations in ryanodine receptor (RYR1) & selenoprotein N genes.

Si/Sx: Hypotonia, proximal > distal weakness (occasionally hand muscles involved). May p/w facial weakness, ptosis, ophthalmoparesis. Skeletal abnormalities (kyphoscoliosis, club feet, high-arched palate) often present. Contractures of neck extensors/trunk cause rigidity of spine. Cardiomyopathy & respiratory weakness may develop.

Dx: Muscle biopsy: NADH stain w/multiple small “cores” (areas w/no oxidative enzyme activity). CK usually nl or mildly elevated.