Neuromuscular Disorders

Muscular Dystrophies, Metabolic Myopathies, and Mitochondrial Disorders

Muscular dystrophies are a group of neuromuscular disorders characterized by weakness as well as muscle wasting (atrophy) and reduced muscle tone. Patients with certain neuromuscular disorders may also exhibit muscle pain, tenderness, stiffness, cramps, fasciculations, hypotonia, and myoglobinuria. Muscle enzyme levels, EMG, muscle/nerve biopsy, and genetic testing can assist in the diagnosis of these neuromuscular disorders.

• Limb Girdle Muscular Dystrophy and Miyoshi Myopathy³⁶
  LGMD is a heterogenous group of disorders characterized by proximal muscle weakness. Miyoshi myopathy is considered a clinically distinct entity from LGMD, and is characterized by distal muscle weakness. Both disorders are caused by defects in the dysferlin gene, which encodes for the dysferlin protein, and are characterized by autosomal recessive inheritance and creatine kinase in blood at up to 150 times normal levels.
   
• Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder of childhood onset characterized by severe muscle weakness, toe walking, mental retardation, and cardiomyopathy.¹⁸ DMD rapidly progresses, causing the patient usually to be wheelchair-bound by age 12; it often results in death by the late teen years to early twenties.¹⁹ Elevated creatine kinase (CK) levels are present in DMD, while EMG shows myopathic changes.³⁴ A mutation in the dystrophin gene on the X chromosome or less than 3% of the normal amount of dystrophin protein found on muscle biopsy is diagnostic of DMD.¹⁹ DMD may appear clinically similar to other muscular dystrophies.
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• Becker Muscular Dystrophy (BMD) is an X-linked recessive disorder characterized by onset that is later and muscle weakness that is milder than DMD. Cardiomyopathy may also be present in the disease.¹⁸ BMD has a slower progression than DMD, though severely affected patients can be wheelchair-bound by age 16.¹⁹ Elevated CK levels are present in BMD.³⁴ A mutation in the dystrophin gene on the X chromosome detected in a blood sample is diagnostic of BMD.¹⁹ In addition, on muscle biopsy, 3-10% of the normal amount of dystrophin (severe BMD) or 10-20% of the normal amount of dystrophin (mild BMD) is also diagnostic of BMD.¹⁹ BMD may appear clinically similar to other muscular dystrophies.
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• Myotonic Dystrophy (MD) is the most common form of muscular dystrophy in adults, affecting approximately one in 8,000 individuals.³⁷ It is characterized by myotonia, progressive muscle weakness, cardiac arrhythmias, and cataracts.³⁸ Repeat expansions in two genes have been implicated in Myotonic dystrophy: a CTG repeat expansion in the Dystrophia-Myotonica Protein Kinase (DMPK)³⁹ gene causes Myotonic Dystrophy Type 1 (DM1) and a CCTG repeat expansion in the Zinc Finger Protein 9 (ZNF9) gene causes Myotonic Dystrophy Type 2 (DM2).³⁷ Adult onset cases of DM1 and DM2 cannot be reliably differentiated clinically, making genetic confirmation essential. The presence of a severe congenitally affected family member can clinically distinguish DM1 from DM2, as no cases of congenital DM2 have been reported.
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• Fascioscapulohumeral Dystrophy (FSHD) is an autosomal dominant disorder characterized by: asymmetric weakness affecting the face, shoulder girdle, and upper arms; skeletal muscle atrophy; hearing loss; and retinal vascular abnormalities.²⁰ FSHD is slowly progressive with 20% of affected patients eventually requiring the use of a wheelchair and with most patients having a normal life span.²⁰ Elevated CK levels are usually present in FSHD, while EMG shows myopathic potentials.³⁴ Muscle biopsy may show general dystrophic features.³⁴ FSHD results from a deletion of a fragment of DNA located on chromosome 4.²⁰ FSHD may appear clinically similar to other muscular dystrophies.
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• Oculopharyngeal Muscular Dystrophy (OPMD) is an autosomal dominant disorder affecting the muscles of the eyes and the throat. Patients usually present with ptosis or dysphagia in their fifth or sixth decade of life.²² Muscle biopsy may show dystrophic features.³⁴ OPMD is caused by a GCG trinucleotide repeat expansion on the PABP2 gene on chromosome 14.²² OPMD may appear clinically similar to other muscular dystrophies.
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Mitochondrial Encephalomyopathies are a group of multisystemic disorders characterized by molecular defects in mitochondrial DNA (mtDNA). These disorders can have clinical features of weakness, exercise intolerance, hearing loss, seizures, ataxia, short stature, dementia, neuropathy, or strokes.³⁵ These disorders are primarily maternally inherited, though some are sporadic.³²

• Kearns-Sayre Syndrome (KSS)
  Progressive external ophthalmoplegia (PEO) is a maternally inherited, pediatric disorder characterized by progressive external ophthalmoplegia, atypical pigmentary retinal degeneration, cardiac conduction block, dementia, ataxia, and short stature.²⁶ Muscle biopsy typically demonstrates ragged red fibers.²⁶ Most typical cases show a single, large deletion in mtDNA as diagnostic of KSS/CEO.²⁶
   
• Myoclonus epilepsy with ragged red fibers (MERRF) is a maternally inherited disorder characterized by myoclonus, ataxia, lactic acidosis, weakness, seizures, progressive dementia, and hearing loss.²⁶ Muscle biopsy typically demonstrates ragged red fibers.²⁶ Distinct mtDNA point mutations (involving nucleotide position A8344G, T8356C, G8363A or A8296G) are diagnostic of MERRF syndrome.²⁶
   
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a maternally inherited disorder characterized by short stature, recurrent strokes, lactic acidosis, and progressive mental deterioration.²⁶ Muscle biopsy typically demonstrates ragged red fibers.²⁶ Distinct mtDNA point mutations (involving nucleotide position A3243G, A3271G, C3256T, A3252G, C3271T or T3291C) are diagnostic of MELAS syndrome.²⁶
   
• Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP): see Hereditary Movement Disorders
   
• Leber hereditary optic neuropathy (LHON): see Hereditary Movement Disorders
   

Metabolic muscle disorders result from abnormalities of enzymes in the biochemical pathways related to energy production. These enzyme levels are crucial to the cellular respiratory pathways and metabolism of various energy source substrates.

• Mitochondrial Enzyme Deficiency Myopathies are a group of maternally inherited, multisystemic disorders affecting the brain and the muscle.³² They are characterized by deafness, ataxia, involuntary movements, pigmentary retinopathy, lactic acidosis, cardiomyopathy, and neuropathy.^26,35 Weakness associated with exercise intolerance may also be present.²⁹ Defects in various mitochondrial enzymes are diagnostic of the disorder.
   
• Glycogen Storage Disorders are a group of autosomal recessive conditions affecting adults and children characterized by a range of clinical features: chronic, progressive weakness with atrophy, cardiomegaly, hepatomegaly, macroglossia, and respiratory dysfunction.³⁰ Elevated CK levels may also be found in some patients.³⁰
   
• Lipid Storage Disorders are metabolic disorders which can have clinical features of muscle weakness and pain, myoglobinuria, and exercise intolerance.³¹ Reports suggest that lipid storage disorders are inherited in an autosomal recessive pattern.³¹ Carnitine deficiency is a typical finding in lipid storage disorders presenting with proximal muscle weakness, cardiomyopathy and in some cases encephalopathy.³¹ Abnormal accumulations of lipid droplets are found in muscle biopsy of affected patients.³¹
   
• Myoglobinuria is a metabolic condition seen in the glycogen storage and lipid storage disorders characterized by the presence of myoglobin protein in the urine often accompanied by transient muscle weakness, pain, and sometimes swelling of the affected muscle, usually after exercise.²¹ It primarily affects adults causing them to excrete amber-colored urine, especially after prolonged exercise or fasting.²⁹

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