Myopathy Due To Myoadenylate Deaminase Deficiency

A number sign (#) is used with this entry because of evidence that myopathy due to myoadenylate deaminase deficiency (MMDD) is caused by homozygous or compound heterozygous mutation in the AMPD1 gene (102770) on chromosome 1p13.

Description

Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (summary by Castro-Gago et al., 2011).

Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).

Clinical Features

Fishbein et al. (1978) reported 5 unrelated Caucasian men with muscle weakness and/or postexertional cramping associated with lack of muscle adenylate deaminase activity and protein levels. Red cell adenylate deaminase (AMPD3; 102772) was normal, suggesting that it is under different genetic control than muscle. This was consistent with evidence that myoadenylate deaminase is antigenically unique to muscle and that the isozyme from red cells has distinctive kinetic properties. Fishbein et al. (1978) suggested that this may be a common form of myopathy of the nonprogressive 'limp infant' and benign congenital hypotonia type.

Sabina et al. (1980) reported a 35-year-old woman who presented with easy fatigability, postexercise myalgia, and delayed recovery of muscle strength. Skeletal muscle biopsy showed less than 1% normal AMPD1 activity and lack of ammonia release in skeletal muscle after ischemic exercise. Further studies demonstrated that depletion and slow repletion of the muscle ATP pool were responsible for the symptoms. The findings suggested that disruption of the purine nucleotide cycle due to myoadenylate deaminase deficiency can result in marked alterations in ATP content of muscle, and that the changes could account for muscle dysfunction.

Shumate et al. (1980) reported an 18-month-old girl referred for delayed motor and speech development. She had always been hypotonic and was unable to stand unsupported. There was no muscle atrophy. Muscle biopsy showed severely decreased adenylate deaminase activity compared to controls.

Morisaki et al. (1992) reported an 18-year-old German woman who first noted calf pain at 4 years of age, usually related to exercise. Her symptoms persisted, and she also had weakness of the upper arms. Morisaki et al. (1992) also reported 10 additional unrelated patients ranging in age from 16 to 68 years, with onset of symptoms between 11 and 55 years. The most common presentation was muscle pain after exercise. Some also reported muscle weakness and/or fatigue; 1 had rhabdomyolysis following a viral infection. Muscle biopsies showed significantly decreased AMPD activity, and immunoblot analysis in some patients showed absence of the AMPD1 protein.

Morisaki et al. (2000) and Abe et al. (2000) reported a 46-year-old Japanese woman who had first noted muscle weakness of the legs at 40 years of age. She had occasional myalgia and cramps in the lower extremities after exercise, as well as muscle atrophy. Serum creatine kinase was slightly elevated. Computed tomography showed a characteristic distribution of skeletal muscle involvement, with proximal and flexor muscles more severely affected than distal and extensor muscles in the leg. In addition, the left sternocleidomastoid muscle showed marked atrophy with an asymptomatic weakness of over 20 years duration, suggesting abnormal development.

Castro-Gago et al. (2011) reported a 6-month-old Spanish girl who presented with weakness and hypotonia from the first month of life. She was conceived by in vitro fertilization with sperm donation. She had severe muscle weakness, hypotonia of the trunk and upper limbs, areflexia, and lacked muscle atrophy. Ocular movements were normal; she also had macrocephaly. EMG showed a myopathic pattern. Skeletal muscle biopsy showed normal levels of all skeletal proteins tested but loss of AMPD1 enzyme activity. Hypotonia persisted, and the child was unable to sit at age 18 months.

Diagnosis

Fishbein et al. (1978) noted that AMPD1 is 10 times higher in skeletal muscle than in any other tissue. Increased plasma ammonia (relative to lactate) after the exercise of sponge-squeezing may be low in this disorder, which could be a useful clinical test.

Valen et al. (1987) found decreased purine release after exercise in MMDD patients compared with that in normal subjects and pointed out that this finding increases the specificity of the forearm ischemic exercise test. Using the standardized ischemic forearm test, Sinkeler et al. (1988) studied 36 relatives of 9 unrelated patients with AMPD1 deficiency. Eight new cases of myoadenylate deaminase deficiency were detected, 5 of which were confirmed histochemically and biochemically. Obligate heterozygotes showed normal ammonia production and AMPD1 staining, but the mean activity of the enzyme was significantly less than in controls. Only 2 of the 8 newly found individuals complained of exertional myalgia.

Inheritance

In the mother of an affected child, Fishbein et al. (1979) observed intermediate values in the ischemic forearm exercise test, suggesting genetic transmission of the deficiency state. Biochemical studies of AMPD1 by Fishbein et al. (1984) demonstrated the existence of a carrier state for the deficiency, indicating an autosomal recessive pattern of transmission for the disorder.

Molecular Genetics

In a German woman and 10 other unrelated individuals with AMPD1 deficiency, Morisaki et al. (1992) identified the same homozygous 34C-T transition in the AMPD1 gene, resulting in a truncated protein (Q12X; 102770.0001). However, this variant was found at high frequency in control populations (see POPULATION GENETICS).

In a Japanese woman with adult-onset AMPD1 deficiency, Morisaki et al. (2000) and Abe et al. (2000) identified compound heterozygous missense mutations in the AMPD1 gene (R388W, 102770.0002 and R425H, 102770.0003).

Genetta et al. (2001) quoted Loh et al. (1999), who purportedly demonstrated a protective effect conferred by 1 AMPD allele on individuals at risk for congestive heart failure; people harboring at least 1 AMPD mutant allele had a significant probability of prolonged survival after the onset of symptoms of congestive heart failure.

In a Spanish infant with hypotonia, Castro-Gago et al. (2011) identified a homozygous Q12X mutation. The unaffected mother was heterozygous for the mutation; paternal DNA was unavailable.

Population Genetics

Fishbein et al. (1978) noted that deficiency of muscle-specific AMPD is apparently a common cause of exercise-induced myopathy and may be the most common cause of metabolic myopathy in humans. Most large screening centers reported that 1 to 2% of all muscle biopsies submitted for pathologic examination are deficient in AMPD enzyme activity.

In an analysis of genomic DNA from 59 Caucasians, 13 African Americans, and 106 Japanese, Morisaki et al. (1992) found that 17% of Caucasians and 23% of African Americans, but no Japanese, carried a Q12X mutant allele of AMPD1 (102770.0001); additionally, 2 Caucasians and 1 African American were found to be homozygous. Morisaki et al. (1992) concluded that the restricted distribution and high frequency of this allele suggested that it arose in a remote ancestor of individuals of western European descent. The frequency of the mutant allele would account for the 2% reported incidence of AMPD deficiency in muscle biopsies, even in the absence of clinical symptoms.