title: Analysis of spectrum and frequencies of mutations in McArdle disease. Identification of 13 novel mutations.
abstract: BACKGROUND
  McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and many rare mutations in the myophosphorylase gene.
  
  
  OBJECTIVE
  To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease, to discuss diagnostic implications, and to analyse genotype-phenotype relationship.
  
  
  METHODS
  Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35), UK (n = 13), and several other countries (n = 8) was performed using direct sequencing.
  
  
  RESULTS
  Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected 26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T, IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed by R94W and G686R representing a frequency of 4% each.
  
  
  CONCLUSIONS
  The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no genotype-phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular testing can avoid muscle biopsy.
authors.affiliation: Klinik und Poliklinik für Neurologie, Martin-Luther Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle/Saale, Germany. marcus.deschauer@medizin.uni-halle.de
authors.forename: M
authors.initials: M
authors.lastname: Deschauer
authors.forename: A
authors.initials: A
authors.lastname: Morgenroth
authors.forename: P R
authors.initials: PR
authors.lastname: Joshi
authors.forename: D
authors.initials: D
authors.lastname: Gläser
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: J
authors.initials: J
authors.lastname: Aasly
authors.forename: H
authors.initials: H
authors.lastname: Schreiber
authors.forename: M
authors.initials: M
authors.lastname: Knape
authors.forename: S
authors.initials: S
authors.lastname: Zierz
authors.forename: M
authors.initials: M
authors.lastname: Vorgerd
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005060:Europe; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D024982:Glycogen Phosphorylase, Muscle Form / Q000235:genetics*; D006012:Glycogen Storage Disease Type V / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D024982:Glycogen Phosphorylase, Muscle Form