METABOLIC MYOPATHIES
Inborn errors of glycogen metabolism and fatty acid metabolism may result in neuromuscular disorders. The major clinical presentations include fixed and progressive weakness or exercise intolerance, cramps and myalgias, and myoglobinuria.
Fixed and progressive weakness may be caused by glycogenoses (acid maltase deficiency or “Pompe disease,” debrancher deficiency, brancher deficiency, and aldolase A deficiency), or disorders of lipid metabolism (primary systemic carnitine deficiency, primary myopathic carnitine deficiency, secondary carnitine deficiency, short-chain acyocoenzyme A synthetase defiency [SCAD], medium-chain acylocoenzyme A synthetase dehydrogenase deficiency [MCAD], etc.).
Exercise intolerance, cramps/myalgias, and myoglobinuria may be caused by glycogenoses (myo- phosphorlase deficiency or “McArdle's disease,” phosphorylase kinase defiency, phosphofructokinase [PFK] deficiency, phosphoglycerate mutase deficiency [PGAM], etc.); disorders of lipid metabolism (carnitine palmitoyltranferase II deficiency [CPT II], VLCAD deficiency, and TP deficiency, etc.); and respiratory chain defects (coenzyme Q10 deficiency, complex I deficiency, complex III deficiency, and complex IV deficiency). While an exhaustive review of metabolic myopathies is not presented here, two prototypical metabolic myo- pathies—McArdle's disease and Pompe's disease— deserve mention.
Myophosphorylase Deficiency
The most common glycogen storage disease is myo- phosphorylas deficiency, also known as McArdle's disease or glycogenosis type 5. The autosomal-recessive disorder has been linked to chromosome 11q13, and more than 65 different disease-causing mutations have been identified. Initial onset of symptoms often occurs during childhood and consists of poor endurance, fatigue, and exercise-induced cramps and myalgia that mainly affects active muscle groups.
Myoglobinuria may also be absent during childhood, with prevalence of fixed muscle weakness increasing as patient ages. Symptoms can be precipitated by activities such as lifting heavy weights or climbing long flights of stairs. The “second wind phenomenon” is characteristic of this disorder. With the onset of myalgia, patients who rest briefly are then able to continue their physical activity with few or no symptoms. The normal function of muscle myophosphorylase is to catalyze the removal of 1,4-glycosyl residues from glycogen to produce glucose-1-phosphate. Its absence leads to decreased metabolic substrate for glycolysis to produce adenosine triphosphate. CK is persistently elevated between episodes of myoglobinuria. EMG is normal when patients are asymptomatic, but can show myotonic discharges and fibrillation potentials during an acute attack. Nonischemic forearm exercise testing shows only an increase in ammonia and stable levels of lactic acid and pyruvate. Diagnosisis made by demonstrating absence of myophosphorylase on muscle biopsy or by genetic mutation analysis. Possible treatments include high protein diet, pyridoxine, and creatine monohydrate.Acid Maltase Deficiency
Acid maltase deficiency, also referred to as glycogenosis type 2 or Pompe's disease, is caused by a deficiency of acid α-1,4-glucosidase (GAA). Inheritance is autosomal recessive, with linkage to chromosome 17q23. Disease incidence is 1 in 40,000 to 50,000 live births. The level of residual enzyme activity correlates with the severity of disease. Those with infantile onset (birth to 1 year) show Progressive fixed proximal weakness is more common, and patients may develop decreased muscle bulk. Premature fatigue, exercise intolerance, myalgia, and recurrent myoglobinuria can be symptoms of mitochondrial disorders. Serum lactate and pyruvate often are elevated at rest, and these levels may increase significantly after moderate exercise. Sensorineural hearing loss is frequently associated with mitochondrial encephalomyopathies.
The hearing loss may be asymmetric and fluctuating in severity. Maternally inherited deafness and diabetes (DAD) is another phenotypic combination in patients with mitochondrial DNA mutations. Dementia can be a prominent feature in mitochondrial cytopathy.The diagnostic workup of a mitochondrial disorder often includes a complete blood count, serum electrolytes (including calcium and phosphate), liver function tests, blood urea nitrogen, creatinine, blood lactate and pyruvate, ECG, lumbar puncture for CSF protein, glucose, lactate, pyruvate, EMG and nerve conduction study, brain imaging with MRI, and muscle biopsy for histology and electron microscopy. Histochemical stains for mitochondrial enzymes (SDH, NADH-TR, and COX) may be obtained, and the activities of mitochondrial respiratory chain enzymes can be measured in muscle tissue. The identification of numerous mitochondrial DNA (mtDNA) mutations, including duplications, deletions, multiple deletions, and more than 100 pathgenic point mutations, provides specific genetic diagnoses.
Treatment is symptomatic for seizures (with avoidance of valproic acid, which is contraindicated because of depletion of carnitine and direct inhibitory effects on the mitochondrial respiratory chain). Electrolyte disturbances related to hypoparathyroidism and diabetes mellitus are corrected. Thyroid replacement alleviates hypothyroidism, Cardiac pacemaker placement prolongs life in Kearns-Sayre syndrome (KSS) with conduction defects. Impairments in the oxidative phosphorylation pathway may generate increased amounts of free radicals; therefore, antioxidants are prescribed, which include β-carotene, vitamin C, vitamin E, and CoQ10. CoQ10 shuttles electrons from complex I and II to complex III and may stabilize the oxidative phopho- rylation enzyme complexes within the inner mitochondrial memebrane. The dose for CoQ10 in adults is 50 to 100 mg, three times per day. L-xarnitine is also recommended.
Dicholroacetate increases the pyruvate dehydrogenase complex and reduces lactate. Aerobic training is recommended for some conditions.More common mitochondrial disorders presenting in childhood are discussed in the following sections.
Kearns-Sayre Syndrome
These patients show progressive external ophthalmoplegia, retinitis pigmentosa on fundoscopic examination, and complete heart block. Onset is usually before 20 years of age. Cerebellar findings may be present on physical examination, and patients may show limb weakness, hearing loss, diabetes mellitus, hypoparathyroidism, irregular menses, and growth hormone deficiency. Dementia may be progressive. CSF protein is frequently greater than 100 mg/dL.
Myoclonus Epilepsy With Ragged-Red Fibers
This clinical syndrome is defined by the presence of myoclonus, generalized seizures, ataxia, and ragged red fibers on muscle biopsy. Symptoms usually begin in childhood. Other common clinical manifestations include hearing loss, dementia, exercise intolerance, and lactic acidosis. Multiple lipomatosis is common. Multiple members of a pedigree usually show the full syndrome.
Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike Episodes
This clinical syndrome is characterized by strokelike 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 both as manifestations of the respiratory chain defects. Other frequent clinical features include normal early development, myogenic limb weakness, ataxia, myoclonus, migrainelike headaches, recurrent nausea and vomiting, and hearing loss. The abrupt-onset strokes often affect the occipital cortex, but may involve other regions of the brain. These patients often describe an antecedent history of migraine headaches that often occur prior to the strokelike event. Patients may experience improvement over weeks to months, but events virtually always recur.
The lesions do not conform to territories of large vessels, a finding that favors the term strokelike episodes. Dementia may occur and be progressive. There is infrequent occurrence of the full syndrome in more than one member of a pedigree. Based on the hypothesis that MELAS is caused by impaired vasodilation in an intracerebral artery, investigators have evaluated the effects of administering L-arginine, a nitric oxide precursor to patients acutely with the first signs of strokelike episodes. Oral L-arginine administration within 30 minutes of a stroke was shown to significantly decrease frequency and severity of strokelike episodes (85).Neuropathy Ataxia and Retinis Pigmentos
This disorder consists of the variable combinations of proximal neurogenic limb weakness, sensory neuropathy, ataxia, pigmentary retinopathy, developmental delay, dementia, and seizures. The onset occurs in teens and young adults, and the course is gradually progressive.
Mitochondrial Neurogastrointestinal Encephalomyopathy
This syndrome is clinically recognized by the unusual combination of six features: PEO, severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, diffuse leukoencephalopathy on MR imaging, and evidence of mitochondrial dysfunction (histologic, biochemical, or genetic). The peripheral neuropathy and the prominent gastrointestinal dysmotility are defining features. Lactic acidosis at rest is present in two-thirds of patients. Both axonal and demyelination polyneuropathy is frequent. Muscle biopsy reveals ragged red fibers (RRFs) and neurogenic changes.