Clinical manifestations

Presentation and course

Exertional myalgia is the predominant clinical symptom in 93% of reported cases of inherited symptomatic myoadenylate deaminase deficiency (55). The median age at the time of diagnosis is 37 years, with a range from 14 to 76 years. In 79% of patients, onset of symptoms occurs between childhood and the early adult years. In these patients, the disease does not appear to be progressive. In patients with acquired myoadenylate deaminase deficiency, clinical manifestations appear to be dictated by the associated neuromuscular disease and are, therefore, heterogeneous. Prognosis in these patients seems unrelated to their myoadenylate deaminase deficiency, again being related to the associated neuromuscular disorder. However, synergistic effects may be observed in patients with a coincidental inherited deficiency and an associated metabolic disorder (69; 49; 03). Finally, based on the relatively high frequency of the mutant AMPD1 allele in Caucasians, many asymptomatic individuals with inherited myoadenylate deaminase deficiency exist in this population. Individuals with inherited asymptomatic myoadenylate deaminase deficiency may, however, be at risk of developing exertional myalgia.

Although inherited symptomatic myoadenylate deaminase deficiency typically causes only exertional myalgia, other manifestations may occur (57; 43). Myoglobinuria following strenuous exercise has been reported in three patients. Increased serum creatine kinase has been found in 48%. In many patients, however, serum creatine kinase activity was normal at rest and increased into the abnormal range only following exercise. EMG findings may be normal, but minor abnormalities have been described in some patients. Results of muscle biopsy examined by routine histochemical stains and electron microscopy have varied from no pathologic findings to mild abnormalities in distribution of fiber size.

Clinical trials employing patients with inherited symptomatic myoadenylate deaminase deficiency and age- and sex-matched controls indicate that the relative intensity of exertion may dictate dysfunctional manifestations of this disorder. For example, exercise performance is significantly reduced in affected individuals performing moderate-intensity bicycle ergometer testing to fatigue (60) and submaximal isometric contractions (08). Conversely, no differences in performance are observed in ischemic isometric exercise (64) or maximal short-term electrically induced activation (09). One study conducted with asymptomatic subjects indicates similar sprint exercise performances across AMPD1 genotypes (44). However, others have shown that asymptomatic deficient subjects have diminished exercise capacity and cardiorespiratory responses in the sedentary state, limited training response during maximal exercise (47), and faster power decrease, reduced power output, and altered blood flow response during a 30-s Wingate cycling test (12; 42). Although a reduction of peak oxygen consumption is moderate in symptomatic subjects, their greater oxygen cost (ΔV’O2/ΔWork-Rate) slope may reduce exercise tolerance by increasing perceived effort (45). Although there is no evidence for diminished aerobic exercise capacity with the heterozygous genotype (47; 51), augmented hyperemia (24; 48) and decreased tissue damage (48) have been reported in response to forearm ischemia in these individuals compared to normal homozygotes. Moreover, a study of unrelated Caucasian patients with coronary artery disease observed a significantly lower relative increase in peak VO2 after 3 months of training in a cohort comprised of heterozygotes and homozygotes for the common mutant AMPD1 allele compared to individuals homozygous for the normal allele (66).

Prognosis and complications

Inherited symptomatic myoadenylate deaminase deficiency has no consistent complications other than exertional myalgia. Although inherited symptomatic myoadenylate deaminase deficiency is typically associated with exertional myalgia, the reverse is not true; exertional myalgia does not imply inherited myoadenylate deaminase deficiency. Many patients presenting with this relatively common clinical complaint have normal skeletal muscle AMP deaminase activity (36).

Conversely, patients with acquired and coincidental inherited myoadenylate deaminase deficiencies have a wide array of complications that are characteristic of the various associated primary neuromuscular diseases. For example, acquired myoadenylate deaminase deficiency may appear as a secondary phenomenon in advanced stages of many neuromuscular diseases (28), although it is not found in all cases of advanced-stage neuromuscular disease due to the proposed contribution of the mutant AMPD1 allele in the acquired condition (14). Coincidental inherited deficiency may also present with more severe clinical complications when associated with another metabolic defect.

Clinical vignette

Although onset of exertional myalgia may occur at any time during the teenage to middle years, the following case report illustrates a typical example of inherited symptomatic myoadenylate deaminase deficiency.

A 20-year-old woman developed increasing difficulty with muscle fatigue on heavy exercise. This had previously not been a problem, and she had participated in varsity-level tennis and basketball at college. The neurologic exam was entirely normal, creatine kinase was normal repeatedly, and muscle biopsy revealed normal histochemistry with the exception of the absent AMPDA. The patient's mother had no specific complaints referable to muscle, and her muscle biopsy was normal (63).

Genetic testing will also be included in more case studies to confirm a compete AMPD1 deficiency, either homozygous for the common mutant allele or, less frequently, a compound heterozygote with a minor variant.

Biological basis

Etiology and pathogenesis

Myoadenylate deaminase produces ammonia (NH3) and inosine monophosphate (IMP) from adenosine monophosphate (AMP). This enzyme reaction is a component of the purine nucleotide cycle (PNC), which is thought to play an important role in skeletal muscle function for several reasons (31). Activities of the three PNC enzymes, including adenylosuccinate synthetase and adenylosuccinate lyase that re-synthesize AMP from IMP, are several-fold greater in skeletal muscle than in other tissues, and myoadenylate deaminase activity is approximately 100 times greater than that of the other two enzymes. During exercise, NH3 production and IMP content of skeletal muscle increase in proportion to the work performed by the muscle, indicating increased myoadenylate deaminase activity under these conditions. Activation of myoadenylate deaminase and increased flux through the PNC during exercise lead to an increase in energy production through the generation of intermediates for the citric acid cycle from amino acids and through stimulation of glycolysis. Thus, one might anticipate that deficiency of myoadenylate deaminase activity and disruption of the PNC would lead to skeletal muscle dysfunction.

Most individuals with inherited myoadenylate deaminase deficiency are homozygous for a single mutant allele of the AMPD1 gene, which includes a C->T transition at nucleotide +34. This creates a nonsense codon, Q12X, in the myoadenylate deaminase mRNA that would be predicted to produce a severely truncated polypeptide devoid of enzymatic activity. Acquired myoadenylate deaminase deficiency is recognized in patients exhibiting advanced stages of other neuromuscular disorders who are also carriers of an AMPD1 mutant allele. In these individuals, pathologic change associated with unrelated neuromuscular disorders lowers AMP deaminase activities into the deficient range. This scenario has been documented in two unrelated cases of myotonic dystrophy and a single case of Sjögren syndrome (54) and described in an acquired myoadenylate deaminase deficiency with Type II muscle fiber atrophy (34); it also has been referred to in a number of other cases with severe neuromuscular disease (15). However, a coincidental inheritance of the homozygous mutant genotype has been reported in 10 individuals with a variety of other neuromuscular disorders (71). A coincidental inheritance of myoadenylate deaminase deficiency has also been documented in six patients with inherited defects in either the myophosphorylase (69; 49; 50; 35) or phosphofructokinase (03) genes. Notably, five of these six subjects exhibited clinical features that were more severe than expected for either condition alone. The emergence of coexisting, multiple neuromuscular disorders in patients exhibiting complex phenotypes has been editorialized with special reference to myoadenylate deaminase deficiency (72). In addition, individuals have been identified who present with clinical symptoms consistent with abnormal energy metabolism due to partial defects in multiple pathways, including myoadenylate deaminase, a condition termed “synergistic heterozygosity” (74). Finally, heterozygosity at the AMPD1 locus may contribute to the clinical variability of other inherited disorders, such as reduced submaximal aerobic capacity in females with McArdle disease (52).

Typically, pathogenesis and pathophysiology of acquired myoadenylate deaminase deficiency are characteristic of the associated neuromuscular disorder; however, synergistic effects have been noted in patients with a coincidental inherited deficiency and a second inherited metabolic disorder.

Inherited myoadenylate deaminase deficiency is transmitted as an autosomal recessive trait. However, the existence of symptomatic and asymptomatic cases demonstrates variable penetrance of the exertional myalgia associated with this genetic disorder. The AMPD1 gene, which produces transcripts encoding myoadenylate deaminase, is composed of 16 exons and is located on the short arm of chromosome 1 in the region p21-p23 (58). Exon 2, a miniexon composed of only 12 nucleotide base pairs, is subject to an alternative splicing event that removes it from 0.6% to 2% of mature AMPD1 transcripts (38). The identified common mutant AMPD1 allele contains C->T transitions at nucleotides +34 (codon 12 in exon 2) and +143 (codon 48 in exon 3) (37). The latter transition is reported to be functionally silent, whereas the former results in a nonsense codon near the 5'-end of the myoadenylate deaminase open reading frame. Therefore, the mRNA produced from the mutant AMPD1 allele would be predicted to encode a severely truncated myoadenylate deaminase polypeptide. Due to its location in exon 2, the functionally significant transition at nucleotide +34 would be removed from 0.6% to 2% of mature AMPD1 transcripts. Rare mutant alleles have been identified as compound heterozygous genotypes with the common nonsense mutation (23; 65). Whether homozygous or compound heterozygous for the common mutant AMPD1 allele, individuals with an inherited deficiency would be predicted to produce small amounts of catalytically active myoadenylate deaminase owing to alternative splicing of exon 2.

Other isoenzymes of AMP deaminase are present in all human tissues and cells, including skeletal muscle (46; 70). Isoforms L and E are encoded by transcripts produced from the AMPD2 and AMPD3 genes, respectively (32; 33). Isoform E accounts for most of the residual AMP deaminase activity present in muscle extracts from individuals with inherited myoadenylate deaminase deficiency (20). Furthermore, across all tissues and cell types examined, AMPD3 mRNAs are most abundant in skeletal muscle where their production appears regulated by protein/E-box interactions (32). Immunocytochemical analysis has demonstrated differential expression of AMP deaminase isoenzymes in fiber types: myoadenylate deaminase, or isoform M, is expressed predominantly in Type II fibers, and isoform E in Type I fibers (70).

The functional significance of alternative AMPD1 transcript and multiple AMP deaminase isoenzyme expression in skeletal muscle is unknown but does offer testable hypotheses to explain symptomatic and asymptomatic forms of inherited myoadenylate deaminase deficiency. These include variable expression of AMPD1 exon 2- (38) and AMPD3 (57; 43) transcripts. Partial defects in other energy-generating pathways may also contribute to the clinical variability of inherited myoadenylate deaminase deficiency.

Acquired myoadenylate deaminase deficiency also has a genetic component (14) involving a mutant AMPD1 allele in the heterozygous state. In these individuals, inherently able to produce only half of the normal amount of myoadenylate deaminase, other unrelated neuromuscular diseases lower AMP deaminase activity into the deficient range. This profile has been documented in two unrelated cases of myotonic dystrophy and a single case of Sjögren syndrome (54), described in an acquired myoadenylate deaminase deficiency secondary to Type II muscle fiber atrophy (34), and referred to in a number of other cases of severe neuromuscular disease (15). The high prevalence of the mutant AMPD1 allele in numerous sample populations supports this hypothesis, as does the inverse correlation between the relative degree of pathology in several neuromuscular disease states and AMP deaminase activity or AMPD1 transcript abundance (28; 40; 59). However, other cases of acquired myoadenylate deaminase deficiency, initially classified on the basis of clinical presentation, are likely to be homozygous for the mutant allele (ie, a coincidental inherited deficiency). This profile has been reported in 10 patients with acquired myoadenylate deficiency (71). Furthermore, five patients with combined McArdle disease and myoadenylate deaminase deficiency were found to be homozygous for mutant alleles in both the myophosphorylase and AMPD1 genes (69; 49; 50; 35), and a sixth individual was identified with combined inherited defects in muscle phosphofructokinase and AMP deaminase (03).

The myoadenylate deaminase enzyme exhibits a mutually dependent stability relationship with skeletal muscle histidine-proline-rich-glycoprotein (HPRG). Although the clinical significance of this association is unknown, HPRG levels are dramatically reduced in the inherited forms of myoadenylate deaminase deficiency (54).

In addition to its role as an underlying genetic defect associated with metabolic myopathy, the mutant AMPD1 allele has also been extensively examined in patients with cardiovascular diseases. A meta-analysis of eight studies meeting rigorous inclusion and exclusion criteria indicated that the T allele of AMPD1 gene C34T polymorphism correlated with elevated left ventricular ejection fraction (LVEF), reduced left ventricular dilation (LVEDD) and decreased systolic blood pressure, which play protective roles in cardiovascular disease patients, but had no effects on total survival rate and cardiac survival rate for heart failure (11). Furthermore, decreased pulse wave velocity and lower levels of serum ICAM-1a in subjects harboring one or more mutant AMPD1 allele in a high-risk population of coronary artery disease subjects suggest positive effects on aortic stiffness and inflammatory status (67). Additionally, reduced frequency of obesity in coronary artery disease, and reduced hyperglycemia and diabetes in coronary artery disease and heart failure, has been positively associated with the mutant AMPD1 allele (61). Furthermore, accumulating evidence on the association between gene polymorphisms and methotrexate treatment in rheumatoid arthritis predicts a positive response in affected individuals harboring the C->T transition at nucleotide +34 in the AMPD1 gene (06). Moreover, a clinical pharmacogenetics model for predicting response to methotrexate that includes four clinical variables and four SNPs (one of which is the C-> T transition at nucleotide +34 in the AMPD1 gene) shows a good benefit-cost relationship for informing methotrexate (MTX) prescription (30). Conversely, this gene polymorphism has been associated with adverse gastrointestinal effects in juvenile idiopathic arthritis (01).

Epidemiology

Myoadenylate deaminase deficiency is noted histochemically in approximately 2% of muscle biopsies submitted for evaluation, making it the most common of the known enzymopathies of muscle. More than 200 cases have been reported in the literature, approximately half of which present with exertional myalgia (ie, inherited myoadenylate deaminase deficiency) (55). The remainder are secondary to other neuromuscular diseases and would be classified either as acquired or coincidental inherited myoadenylate deaminase deficiency. The identification of a common mutant AMPD1 allele led to a preliminary estimation of its frequency in various populations (37). Using a relatively simple polymerase chain reaction-based diagnostic test, mutant allele frequencies of 12% and 19% were found initially in 59 Caucasians and 13 African Americans, respectively; all of the 106 Japanese subjects surveyed were homozygous for the normal allele. Mutant allele frequencies of 11% to 14% were subsequently found in larger population samples of Caucasians (22; 41; 47), whereas a much lower prevalence (0.5%) was observed in 273 African Americans (47) and in a cohort of greater than 200 suspected myopathic individuals from the Indian subcontinent (05). The relatively high mutant allele frequency in the Caucasian population is sufficient to account for the reported 2% incidence of myoadenylate deaminase deficiency in muscle biopsies. Clearly, 2% of all Caucasians do not have symptoms severe enough to require medical attention; however, these data identify individuals who may be at risk of developing exertional myalgia. Notably, significantly different mutant allele frequencies have been found in the following sample population studies: higher in 320 German myopathic patients compared to a group of 290 subjects without muscle symptoms (22). In addition, a 2006 study identified asymptomatic, inherited myoadenylate deaminase deficiency as a genetic risk factor in individuals who develop pain, weakness, and other symptoms of muscle dysfunction while on lipid-lowering (statin) drug therapy (73).

Research starting in the late 1990s has investigated DNA polymorphisms associated with sports-related characteristics, culminating to date with meta-analyses that indicate that the normal C allele of the AMPD1 gene C34T polymorphism is related to enhanced athletic performance. For example, among 41 of the 114 reported genetic markers associated with elite athlete status, the C allele of the AMPD1 gene C34T polymorphism is positively associated with endurance and power (62). A second meta-analysis evaluated the relationship between four genetic markers reportedly associated with power athlete status, and three of these, including the C allele of the AMPD1 gene C34T polymorphism, are significantly more prevalent in power athletes (27). A third meta-analysis examined DNA polymorphisms associated with athlete status, physical performance, and injury risk in soccer players (39). Among six genetic markers associated with physical performance, the C allele of the AMPD1 gene C34T polymorphism in combination with three other “favorable” genetic markers correlates with greater agility (change of direction). Moreover, the C allele of the AMPD1 gene C34T polymorphism is the only genetic variant to date that appears to influence acceleration and speed in this athletic cohort.

Prevention

No specific methods of prevention are known. Because inherited myoadenylate deaminase deficiency can result in exertional myalgia, those individuals who are homozygous for the mutant AMPD1 allele without clinical complications would appear to be at risk. However, no information is available regarding the prevalence of sudden onset of clinical symptoms in these individuals, nor have risk factors been identified.

Differential diagnosis

Confusing conditions

Most patients with metabolic myopathies other than a myoadenylate deaminase deficiency typically complain of exercise intolerance or muscle pain and cramps with exercise. Consequently, these disorders should be considered in those individuals with a suspected or confirmed myoadenylate deaminase deficiency. Most commonly, these include derangements of glycogen metabolism, lipid metabolism, and mitochondrial disorders.

Diagnostic workup

An ischemic forearm protocol that measures exertional increases in plasma ammonia and lactate offers a relatively noninvasive and simple test for diagnosing suspected myoadenylate deaminase deficiency (16). Based on the risk of rhabdomyolysis associated with glycogenosis under ischemic conditions, a nonischemic test was developed, which is now more commonly used with similar diagnostic accuracy (26). In both tests, because AMP deaminase is the major ammonia-producing enzyme in muscle, a flat ammonia profile indicates a deficiency. However, care must be taken to ensure that enough work is performed by the subject in order to prevent a false-negative result. A flat ammonia response accompanied by a rise in plasma lactate of 2.5 to 4 mM (approximately 20 to 35 mg/dL) is sufficient to ensure a reliable diagnosis (14; 07).

Although myoadenylate deaminase deficiency was historically confirmed in muscle biopsy by histochemical stain (18) or by direct enzymatic assay (13), the availability of reliable genetic tests that simply require a blood sample precludes the need for a muscle biopsy to confirm an AMPD1 deficiency. The mutant AMPD1 allele can be readily confirmed by a polymerase chain reaction-based test using genomic DNA isolated from whole blood (37). Nucleotide +34 is at the 3'-boundary of exon 2 in the AMPD1 gene, and a C->T transition at this position destroys a Mae II restriction endonuclease site in the mutant allele. Alternative polymerase chain reaction-based and allele-specific oligomer polymerase chain reaction-based assays are also available for diagnosing the mutant AMPD1 allele (21; 17; 41). Gene panels including AMPD1 have been developed using next-generation sequencing (eg, National Library of Medicine GTR Test ID: GTR000502959.3). Although biochemical and immunological criteria have been described that may be used to distinguish inherited and acquired forms of the disease (14), genetic tests currently provide the most reliable method by which to establish that a myoadenylate deaminase deficiency is inherited. Furthermore, due to the high frequency of the mutant AMPD1 allele in the Caucasian population, many cases of acquired myoadenylate deaminase deficiency are also suspected of harboring this defect on one or both homologues of chromosome 1. Once AMPD1 mutation is established by genetic testing, it is important to also consider other contributing causes, genetic or acquired, in symptomatic individuals.

Management

No reliable therapies are currently available for inherited symptomatic myoadenylate deaminase deficiency. Oral ribose administered at the beginning of exercise has been reported to prevent or decrease symptoms in one patient with an inherited deficiency (75) but has been unsuccessful in others (29). Xylitol can be metabolically converted to ribose, and oral administration has been reported as beneficial to one patient (04). In lieu of specific therapies, many patients modify their lifestyle to avoid strenuous physical activity. However, the majority of individuals with inherited myoadenylate deaminase deficiency are asymptomatic, and successful treatment of the exertional myalgia in symptomatic individuals may ultimately be achieved through a better understanding of the biochemical and molecular distinction between these two groups of myoadenylate deaminase deficient individuals.

Special considerations

Pregnancy

Normal pregnancy and spontaneous delivery have been reported in a single case exhibiting clinical features of an inherited myoadenylate deaminase deficiency (no genotype given) with no postpartum deterioration of the condition (02).

Anesthesia

Evidence has been presented suggesting that patients with inherited symptomatic myoadenylate deaminase deficiency (and possibly individuals heterozygous for the mutant AMPD1 allele) may be at increased risk for malignant hyperthermia while under halothane-succinylcholine anesthesia (14).

Genotype–drug interaction

In addition to being a potential risk factor for statin-induced myopathy, a study has also associated the mutant AMPD1 allele with a higher rate and higher likelihood for the occurrence of side effects of regadenoson, an adenosine analogue and selective A2A adenosine receptor agonist used in myocardial perfusion imaging (53).