title: Phenotype modulators in myophosphorylase deficiency.
abstract: Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p < 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease.
authors.affiliation: E. Medea Scientific Institute, Conegliano Research Centre, Conegliano, Italy. andrea.martinuzzi@cn.lnf.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Elena
authors.initials: E
authors.lastname: Sartori
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.forename: Annachiara
authors.initials: A
authors.lastname: Nascimbeni
authors.forename: Lucia
authors.initials: L
authors.lastname: Valente
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mongini
authors.forename: Paola
authors.initials: P
authors.lastname: Tonin
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertelli
mesh_terms: D000659:AMP Deaminase / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001706:Biopsy; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D024982:Glycogen Phosphorylase, Muscle Form / Q000172:deficiency / Q000235:genetics*; D006012:Glycogen Storage Disease Type V / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D024982:Glycogen Phosphorylase, Muscle Form; D007703:Peptidyl-Dipeptidase A; D000659:AMP Deaminase