title: Clinical significance and neuropathology of primary MADD in C34-T and G468-T mutations of the AMPD1 gene.
abstract: OBJECTIVE
  Primary myoadenylate deaminase deficiency (MADD) is probably the most frequent inborn metabolic myopathy with a prevalence of up to 2%. It is the result of mutations in the AMPDI gene, the most common of which is a C34-T transition in exon 2. The importance of the more rare mutation G468-T in exon 5 is uncertain. Primary objective was to elucidate the clinical significance of the enzyme disorder, which remains unclear since its first description in 1978. We further examined the existence of an association of MADD with other muscle disorders, such as malignant hyperthermia and rhabdomyolysis, as was suspected in earlier studies.
  
  
  METHODS
  In a large collection of 1673 muscle biopsies that had been stored deep frozen we identified 33 cases of primary MADD, 12 of which without any other coinciding muscle diseases, by histochemical, biochemical and molecular genetic examinations. Clinical and laboratory data was collected. By additional examination of randomly chosen blood samples we identified one person carrying the rare compound heterozygosity C34-T/ G468-T, who was examined in clinical respects and a muscle biopsy was taken.
  
  
  RESULTS
  As underlying mutation, the most common transition C34-T/C 143-T was detected in 33 cases. One patient carried the compound heterozygosity C34-T/G468-T. The overall frequency of MADD in the contingent was 1.8%. Only three patients out of 12 with isolated primary MADD suffered from muscle complaints, one of whom did not experience the typical symptoms of exercise related myalgia, muscle cramps and weakness as described by Fishbein. The patient carrying C34-T/G468-T was a fully healthy female. She had never experienced any muscle complaints. Any association with other neuromuscular disorders, if not completely ruled out, was found to be very unlikely.
  
  
  CONCLUSIONS
  The results suggest that MADD itself is unlikely to be solely responsible for the manifestation of muscular symptoms. It is probable that either the loss of a compensation mechanism or coexistent disturbances in muscle metabolism which are unidentified so far are required for the emergence of complaints.
authors.affiliation: Departments of Neuropathology,, University of Leipzig, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fischer
authors.forename: C
authors.initials: C
authors.lastname: Drenckhahn
authors.forename: C
authors.initials: C
authors.lastname: Wolf
authors.forename: K
authors.initials: K
authors.lastname: Eschrich
authors.forename: S
authors.initials: S
authors.lastname: Kellermann
authors.forename: U G
authors.initials: UG
authors.lastname: Froster
authors.forename: R
authors.initials: R
authors.lastname: Schober
mesh_terms: D000659:AMP Deaminase / Q000172:deficiency* / Q000235:genetics*; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000201:enzymology / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*
chemical_list: D000659:AMP Deaminase