Myoadenylate deaminase is the muscle-specific isoenzyme of AMP deaminase (EC 18.104.22.168). Deficiency of myoadenylate deaminase is heterogeneous in etiology and results in derangement of purine nucleotide catabolism and interconversion. While demonstrated in approximately 2 percent of muscle biopsy specimens submitted for pathologic examination for a wide array of indications, there is a similar incidence of myoadenylate deaminase deficiency in the normal Caucasian population, indicating that most individuals with this disorder are asymptomatic.
Three distinct forms of symptomatic myoadenylate deaminase deficiency have been identified. Inherited (primary) deficiency is associated with exercise-related cramps and myalgias. Coincidental inherited deficiency is associated with a wide array of other neuromuscular or rheumatologic disorders. Acquired (secondary) deficiency is found in heterozygotes for the inherited disorder who become deficient due to pathological changes associated with a variety of etiologies.
Myoadenylate deaminase deficiency is transmitted as an autosomal recessive trait. A common AMPD1 (myoadenylate deaminase) mutant allele (c.34C>T) that results in a Q12X nonsense producing a severely truncated myoadenylate deaminase peptide. The AMPD1 c.34C>T allele is responsible for most cases of myoadenylate deaminase deficiency in Caucasians, although several rare mutations have been identified in this, and other, populations.
Despite the relatively low incidence of clinical complications associated with inherited deficiency of muscle AMP deaminase, AMPD1 c.34C>T allele frequencies are high, for example, 0.10 to 0.14 in several Caucasian sample populations.
Acquired deficiency of myoadenylate deaminase may result from a limitation in AMPD1 transcript availability, perhaps as a consequence of pathologic abnormalities caused by the associated disease in heterozygous individuals. Genetic testing is required in order to distinguish these latter individuals from those who have a coincidental inherited myoadenylate deaminase deficiency.
In most patients with associated disorders, it is difficult to determine the contribution, if any, of the myoadenylate deaminase deficiency to the clinical phenotype. However, inheritance of one or more AMPD1 (myoadenylate deaminase) mutant alleles can be synergistic with a second metabolic myopathy.
AMPD1 mutant allele heterozygotes may have improved clinical outcome should they develop heart disease, or in response to methotrexate therapy for rheumatoid arthritis.
Whether symptomatic or asymptomatic, when individuals with myoadenylate deaminase deficiency exercise, their skeletal muscle does not accumulate NH3 and IMP, as occurs in normal subjects.
Inhertited deficiency of myoadenylate deaminase impacts on exercise performance and blood flow response to exercise in otherwise healthy individuals. Thus, this enzyme and the purine nucleotide cycle, of which it is one component, play important roles in skeletal muscle metabolism and function during exercise.
Although similar functional abnormalities might be expected in all individuals with myoadenylate deaminase deficiency, a relative larger asymptomatic cohort strongly argues that AMPD1 mutations are not solely responsible for exercise-induced clinical manifestations (typically aches, cramps and pain) in symptomatic patients.