Fatty acid oxidation defects (FAODs): FAODs usually present with a history of hypoglycemia or coma after sustained exercise or prolonged fasting (>24 hours), intermittent bouts of weakness, lethargy, ataxia and coma or episodic vomiting. In addition, disorders of lipid metabolism may cause two main clinical syndromes, namely (1) progressive weakness (long- and very long-chain acyl-CoA dehydrogenase (LCAD, VLCAD), and trifunctional enzyme deficiencies) or (2) normal muscle strength between attacks with episodes of acute, recurrent, reversible muscle dysfunction with exercise intolerance, cramps and acute painful rhabdomyolysis or myoglobinuria (with or without myalgia) induced by fever, fasting or prolonged exercise, valproate therapy, cold exposure (carnitine palmitoyltransferase I and II deficiency (CPT I/II) or (3) both (LCAD, VLCAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCAD), and trifunctional enzyme deficiencies). Identification of the specific enzyme requires tissue (muscle, lymphocytes or cultured fibroblasts) analysis.
LCAD may present as a limb-girdle myopathy.
CPT I/II are the commonest FAOD and the most common cause of recurrent myoglobinuria and rhabdomyolysis. CPT is inherited as autosomal recessive trait but occurs most commonly in young adult males. The age of onset in the adult form is typically in the 2nd or 3rd decade of life with episodes of recurrent hospitalizations for rhabdomyolysis with acute renal failure. Rest does not abort the attacks and there is no second-wind phenomenon. Hypoglycemia with minimal-to-absent ketonemia and ketonuria, mild lactic acidosis, hyperammonemia, and reduced plasma carnitine levels. CK levels are normal or mildly elevated (50%) between attacks. During attacks serum CK levels may rise to 100,000 U/L. In contrast to b-oxidation defects, CPT is characterized by the absence of dicarboxylic aciduria (urine analysis (fasting) for organic acids). Iv glucose improves exercise tolerance while oral glucose is not effective. Assays are available for the measurement of CPT I and II in circulating lymphocytes and cultured fibroblasts. The gene has been mapped to chromosome 1p12. McArdle disease needs to be differentiated from CPT I/II deficiency. Treatment consists of frequent meals, low in fat and high in carbohydrates before and during exercise and avoid fasting. An alternate diet involves substitution of medium-chain triglycerides oil for long-chain fat with increased carbohydrate intake.
Respiratory chain defects (RCDS): These can present in adulthood in a variety of ways: 1) myopathy with exercise intolerance followed by fixed weakness and usually associated with lactic acidosis at rest and exaggerated by exercise (NADH-CoQ reductase or complex I deficiency), 2) myopathy with exercise intolerance with premature fatigue and hyperpnea, often followed by fixed weakness (some forms of FSHMD fit into this category) (complex III deficiency), 3) myopathy with exercise intolerance, myoglobinuria, progressive weakness (defects of mitochondrial protein transport), 4) affecting both muscle and brain; myopathy with exercise intolerance, myoglobinuria, progressive weakness, ataxia and seizures, increased serum CK and ragged-red fibers on muscle biopsy (CoQ10 reductase deficiency) 5) mitochondrial encephalopathy (excluding MELAS) (NADH-CoQ reductase or complex I deficiency), 6) various combinations of weakness, short stature, dementia, ataxia, sensorineural deafness, retinitis pigmentosa, sensory neuropathy and pyramidal signs (complex III deficiency).
Chronic progressive external ophthalmoplegia (CPEO): The age of onset is usually during the 2nd and 3rd decades of life. Pure CPEO presents with ptosis (often asymmetrical, weak opening and closure) and ophthalmoplegia (multidirectional limitation of eye movements affecting upward gaze maximally). Very often diplopia is absent or transient. The term CPEO plus is used when additional clinical features are present: such as retinitis pigmentosa, weakness and wasting of other muscles in 25% of cases (facial, sternocleidomastoideus, deltoids and/or peronei) and never precede the ophthalmolgical features, dysphagia, fatigue or exercise intolerance. Encephalopathic features may also occur with CPEO (dementia, seizures, myoclonus and stroke-like episodes. Seizures are however much less frequent than in other mitochondrial disorders. The disease leads to complete ophthalmoplegia with the eyes in central position. While blood mitochondrial DNA is usually normal, DNA extracted from muscle biopsy is always diagnostic and reveals single mitochondrial deletions in 70% of patients (sporadic cases). Other patients show maternal pattern of inheritance with mitochondrial DNA mutations (e.g. A3243G) or autosomal dominant or recessive patterns. Disability is mild except when coexisting CNS disease is present. Histological examination of muscle reveals ragged red fibers and a mosaic pattern of cytochrome c oxidase (COX) negative fibers. This OXPHOS mtDNA defect is often mistaken for MG, DM1 (myotonia, cataract, endocrine disturbances), FSHMD, KSS (abnormal growth and mentation, heart block, abnormal CSF) or OPMD.
Myophosphorylase deficiency type V or McArdle disease (MPD5): This autosomal recessive (chromosome 11q13) glycogen storage disease is one of the most common muscle glycogenoses and typically presents in adolescence or its late-onset form (up to the 8th decade) with exercise intolerance, severe myalgia, myoglobinuria (25%), and cramps in exercising muscle due to contractures, relieved by rest. Often a “second wind” phenomenon (improvement after rest) is found. In addition, fixed, asymmetric proximal limb and bulbar weakness can be found particularly at an advanced age. The resting serum CK levels are usually increased. EMG confirms the myopathic process, the forearm ischemic exercise test is positive (no increase in serum lactate) in complete myophosphorylase deficiency and muscle biopsy (residual myophosphorylase activity less than 12 mmol/min/g) is diagnostic. Analysis of the patient’s DNA from leucocytes can be used for diagnosis. Oral fructose and high protein diet may sometimes be helpful. This form is indistinguishable from phosphofructokinase deficiency type VII or Tarui disease (PFKD) which is characterized by lifelong intolerance to vigorous exercise, often accompanied by cramps and nausea that are relieved by rest. Hemolytic anemia is suggestive (PFKD in RBC)
Phosphorylase b kinase deficiency (PBKD): Muscle-specific phosphorylase b kinase deficiency is an unusual autosomal recessive glycogen storage disorder (chromosome 16q12-13 or 7p12). The majority of patients are male with an age at diagnosis between 15 - 46 years. Clinical features include exercise intolerance, cramps, stiffness, myalgia (with myoglobinuria) and progressive, predominantly distal muscle weakness with atrophy. Serum CK levels may be increased. A forearm ischemic exercise test may show increased lactate production. The demonstration of reduced muscle, erythrocyte or liver phosphorylase b kinase activity by biochemical assay confirms the diagnosis.
Other adult exercise intolerance, cramp and myoglobinuria disorders: phosphoglycerate kinase deficiency (chromosome Xq13), phosphoglycerate mutase deficiency (mainly black Americans, chromosome 7) and lactate dehydrogenase deficiency (chromosome 11).
Debrancher enzyme deficiency type III or Forbes-Cori disease (DED3): The clinical appearance of this autosomal recessive (chromosome 1p21) myopathy is highly variable. In the adult forms (starting in the 3rd and 4th decade) we differentiate several phenotypes: (1) muscular symptoms in adult years while the liver symptoms start in childhood, (2) muscle weakness starting in adult years long after liver symptoms in childhood have remitted, (3) only muscular symptoms as adults without any sign or history of liver dysfunction since childhood. Rapid fatigue and aching of muscles is a common presentation, occurring at exertion and beginning at an early age. The myopathy can also have different forms: (1) adult onset distal myopathy (distal leg weakness and intrinsic hand muscles); (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance is uncommon. Rarely, a mild polyneuropathy may be observed. The clinical course is complicated by advanced liver dysfunction and by severe cardiomyopathy. All patients have raised CK concentrations (up to 800 U/l), myogenic and neurogenic (denervation) features with pseudomytonic discharges on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. Leucocyte glycogen debrancher enzyme assay provides the diagnosis.