AMPD1 – Adenosine Monophosphate Deaminase Deficiency

Adenosine monophosphate deaminase deficiency is an autosomal recessive metabolic myopathy characterized by exercise-induced muscle pain, cramps, myoglobinuria, and elevated creatine kinase activity. Patients often present in childhood or adulthood with exertional intolerance, episodic rhabdomyolysis, and progressive weakness (PMID:8335021). Biochemical and histochemical assays reveal absent myoadenylate deaminase activity in skeletal muscle fibers, while ischaemic forearm tests show no ammonia elevation despite lactate increase. Clinical severity ranges from asymptomatic carriers to congenital hypotonia in infants (PMID:21343608; PMID:10996775).

Genetic analyses confirm autosomal recessive inheritance with biallelic pathogenic variants in AMPD1. The founder nonsense mutation c.34C>T (p.Gln12Ter) in exon 2 accounts for homozygous deficiency in multiple cohorts, including 26 of 27 Spanish cases and a hypotonic infant (PMID:19353846; PMID:21343608). Novel missense variants c.1162C>T (p.Arg388Trp) and c.1274G>A (p.Arg425His) cause compound heterozygosity with progressive muscle weakness (PMID:10996775). A deep intronic deletion c.35-7_35-4del disrupts splicing leading to multiple aberrant transcripts and residual activity in two affected brothers (PMID:16040263). Rare alleles such as c.468G>T (p.Gln156His) further diversify the spectrum and contribute to symptomatic deficiency in compound heterozygotes (PMID:12117480).

Population studies report a c.34C>T carrier frequency of ~12% in Caucasians and near absence in East Asians, correlating with the 2% incidence of histochemical MAD deficiency in muscle biopsies (PMID:1631143). In a series of 27 Spanish patients, 70% showed elevated serum CK and consistent exercise intolerance, supporting high penetrance of homozygous c.34C>T (PMID:19353846).

Functional assays demonstrate tissue-specific alternative splicing of exon 2 that produces a functional AMPD1 peptide, explaining asymptomatic homozygotes via phenotypic rescue (PMID:8486786). Expression models confirm that loss of AMPD1 activity perturbs purine nucleotide metabolism in muscle, leading to clinical manifestations. Rescue experiments with spliced transcripts restore enzyme function in vitro, consistent with haploinsufficiency as the primary mechanism.

No studies have refuted the causative role of biallelic AMPD1 variants in this metabolic myopathy. Variable clinical expressivity is explained by differential splicing efficiency rather than alternative phenotypes.

Overall, AMPD1 has a Strong gene–disease association for adenosine monophosphate deaminase deficiency based on >30 unrelated probands, multiple families with confirmed AR inheritance, and concordant functional data across models. Key take-home: comprehensive AMPD1 molecular testing including founder and splice-site mutations reliably confirms diagnosis in patients with exercise-induced metabolic myopathy.

References

• European journal of pediatrics • 1993 • Myoadenylate deaminase deficiency with severe rhabdomyolysis PMID:8335021
• Neuromuscular disorders : NMD • 2000 • Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient PMID:10996775
• Molecular genetics and metabolism • 2005 • Myoadenylate deaminase deficiency caused by alternative splicing due to a novel intronic mutation in the AMPD1 gene PMID:16040263
• Journal of child neurology • 2011 • Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant PMID:21343608
• Clinical neuropathology • 2009 • Myoadenylate deaminase deficiency: clinico-pathological and molecular study of a series of 27 Spanish cases PMID:19353846
• The Journal of clinical investigation • 1993 • Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect PMID:8486786
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Molecular basis of AMP deaminase deficiency in skeletal muscle PMID:1631143
• Neuromuscular disorders : NMD • 2002 • A G468-T AMPD1 mutant allele contributes to the high incidence of myoadenylate deaminase deficiency in the Caucasian population PMID:12117480

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