Myoclonus epilepsy with ragged-red fibers
Jun. 18, 2022
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The author describes the genetic and clinical features of myoadenylate deaminase (mAMPD) deficiency, one of the most common metabolic disorders in the Caucasian population. Although a small percentage of mAMPD-deficient individuals present with exercise-induced cramping and pain, most are asymptomatic. However, genetic and physiological studies show that asymptomatic control subjects display functional abnormalities during aerobic exercise and that the mAMPD-deficient genotype is underrepresented in various groups of elite athletes. Lower anaerobic performance is also observed in elite athletes who participate in sprint/power-oriented sports and carry a mutant mAMPD allele compared to those elite athletes who have two normal mAMPD alleles. In addition, genotype-phenotype correlations indicate that asymptomatic individuals may also be at risk for developing a myopathy triggered by lipid-lowering drug therapy and also that harboring one or more mutant alleles may reduce one's ability to achieve elite athletic status and raise the risk of sports injury. Other correlative studies suggest that an inherited AMPD1 mutation has potential prognostic value for survival, obesity, hyperglycemia, and diabetes in specific subgroups of patients with heart disease, for response to methotrexate treatment in rheumatoid arthritis and juvenile idiopathic arthritis, and for side effects from regadenoson used in myocardial perfusion imaging.
• Myoadenylate deaminase deficiency is an autosomal recessive disorder of skeletal muscle purine metabolism and is most commonly found in Caucasians.
• Although rare alleles have been identified in all examined populations, a prevalent AMPD1 nonsense mutation accounts for the approximate 2% incidence of myoadenylate deaminase deficiency in Caucasians.
• Whereas most individuals with an inherited myoadenylate deaminase deficiency are asymptomatic, physiological studies reveal measurable deficits in performance and cardiorespiratory response to exercise.
• Exertional myalgia is the most common clinical presentation in symptomatic myoadenylate deaminase deficiency, suggesting a contribution of other causative factors in this patient cohort.
• Coincidental inheritance of one or more myoadenylate deaminase mutant alleles can be synergistic in other inherited disorders of skeletal muscle energy metabolism.
• Correlative studies suggest that an inherited AMPD1 mutation has potential prognostic value in specific subgroups of patients with heart disease, for methotrexate treatment in patients with rheumatoid arthritis, and as a genetic determinant of elite exercise performance and risk of sports injury, and risk of side effects from regadenoson, an adenosine analogue currently used in myocardial perfusion imaging.
Myoadenylate deaminase (muscle AMP deaminase) deficiency was first described as a "new disease of muscle" by Fishbein and colleagues in 1978 (19). Five young males, in a series of 250 biopsies, presented with the "chief complaint (often since childhood) of muscle weakness or cramping after exercise. Physical and neurologic examinations were normal except for decreased muscle mass, hypotonia, and weakness in some cases" (19). A relatively noninvasive and simple blood test was also described that is used to initially evaluate suspected cases. This diagnostic test is based on the lack of exertional increase in plasma ammonia in patients, and it exploits the fact that AMP deaminase represents the major ammonia-producing enzymatic activity in muscle. This characteristic had facilitated identification of the enzyme many years earlier.
However, earlier reports had described muscle AMP deaminase deficiency in some patients who had other neuromuscular disorders such as hypokalemic periodic paralysis, Duchenne muscular dystrophy, and inflammatory myopathy (12; 31). The most severe among these patients typically showed not only AMP deaminase deficiency but also decreased values of muscle creatine kinase activity and noncollagen protein (31). Kar and Pearson wrote that "undoubtedly these changes are secondary to the major pathologic alterations that have affected these muscles from a multiplicity of causes." Furthermore, "unlike creatine kinase, AMP deaminase appears to be more sensitive to degeneration of muscle caused by certain diseases." Fishbein, whose patients exhibited normal muscle creatine kinase activities, wrote that "the relation of (these earlier cases) to our series is obscure" (19).
Numerous reports of myoadenylate deaminase deficiency soon followed, approximately half of which were associated with other neuromuscular complications. An inability to ascribe a single clinical picture to myoadenylate deaminase deficiency prompted one group of investigators to proclaim myoadenylate deaminase deficiency as simply "a normal variant rather than a disease state" (64). This viewpoint was subsequently supported by others (30).
In order to explain the clinical heterogeneity, in 1985 Fishbein subdivided myoadenylate deaminase into inherited and acquired forms based on a variety of biochemical and immunological criteria (17). Inherited myoadenylate deaminase deficiency included cases with exertional myalgia but without other known neurologic, pathologic, or biochemical abnormalities. Acquired myoadenylate deaminase deficiency included cases secondary to other neuromuscular disorders. In comparing numerous cases classified according to these criteria, Fishbein showed that muscle biopsies from patients with acquired myoadenylate deaminase deficiency had generally higher residual enzyme activities; these were also more immunoreactive with anti-myoadenylate deaminase antibodies. Consistent with the earlier report by Kar and Pearson, Fishbein also observed in these biopsies less severe decreases of other enzymatic activities (eg, muscle creatine and adenylate kinases). He presumed that these nonspecific changes in muscle enzymatic activities reflected "generalized muscle damage." Careful review of biochemical data from all reported cases support Fishbein's distinction of inherited and acquired forms of myoadenylate deaminase deficiency; however, overlap between the two groups precludes classification based on any one of these criteria alone (57).
Fishbein also suggested that inherited myoadenylate deaminase deficiency was "a complete gene block (transmitted) in an autosomal recessive pattern" (17). Based on the high frequency of the inherited condition (2%), he concluded that "the heterozygous state is common." To explain the apparent vulnerability of AMP deaminase to other muscle pathologies in the acquired forms of myoadenylate deaminase deficiency, Fishbein proposed that "these patients might have been carriers (of the inherited deficiency), whose adenylate deaminase levels have been lowered to the deficient category by the advent of other neuromuscular disease."
Beginning in the late 1980s, efforts to delineate the molecular biology of AMP deaminase expression provided critical evidence in support of Fishbein's hypotheses regarding inherited and acquired forms of myoadenylate deaminase deficiency: the myoadenylate deaminase gene, AMPD1, is located on the short arm of chromosome 1 (60). Different molecular profiles are evident in cases classified as inherited or acquired myoadenylate deaminase deficiency (58). A single mutant AMPD1 allele is responsible for most cases of inherited deficiency (40) and for a subset of acquired deficiency with a coincidental inherited deficiency (72). Subsequently, additional rare mutant alleles have been identified across several ethnic groups (28; 69; 15; 63).
The estimated frequency of the common mutant AMPD1 allele is 11% to 14% in the Caucasian population (40; 27; 43; 49). These incidences not only account for nearly all symptomatic cases of inherited myoadenylate deaminase deficiency but also indicate that 2% of the Caucasian population is homozygous for the common mutant allele. Because 2% of this entire population does not exhibit myopathic symptoms, this identifies a relatively large group of asymptomatic, inherited myoadenylate deaminase deficient individuals. These data also suggest that additional determinants are involved in the clinical manifestations associated with an inherited myoadenylate deaminase deficiency.
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