Journal of Neurology

, 254:797 | Cite as

Analysis of spectrum and frequencies of mutations in McArdle disease

Identification of 13 novel mutations
  • M. Deschauer
  • A. Morgenroth
  • P. R. Joshi
  • D. Gläser
  • P. F. Chinnery
  • J. Aasly
  • H. Schreiber
  • M. Knape
  • S. Zierz
  • M. Vorgerd



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.


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.


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.


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.


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.

Key words

genetic testing McArdle disease mutations myophosphorylase deficiency 


  1. 1.
    Bartram C, Edwards RH, Clague J, Beynon RJ (1993) McArdle’s disease: A nonsense mutation in exon 1 of the muscle glycogen phosphorylase gene explains some but not all cases. Hum Mol Genet 2:1291–1293CrossRefPubMedGoogle Scholar
  2. 2.
    Deschauer M, Opalka JR, Lindner A, Zierz S (2001) A novel nonsense mutation (R269X) in the myophosphorylase gene in a patient with McArdle disease. Mol Genet Metab 74:489–491CrossRefPubMedGoogle Scholar
  3. 3.
    Deschauer M, Hertel K, Zierz S (2003) Two novel mutations in the myophosphorylase gene in a patient with McArdle disease. Muscle Nerve 27:105–107CrossRefPubMedGoogle Scholar
  4. 4.
    DiMauro S, Andreu AL, Bruno C, Hadjigeorgiou GM. (2002) Myophsophorylase deficiency (glycogenosis type V; McArdle disease). Curr Mol Med 2:189–196CrossRefGoogle Scholar
  5. 5.
    Hudson JW, Golding GB, Crerar MM (1993) Evolution of allosteric control in glycogen phosphorylase. J Mol Biol 234:700–721CrossRefPubMedGoogle Scholar
  6. 6.
    Isackson PJ, Tarnopolsky M, Vladutiu GD (2005) A novel mutation in the PYGM gene in a family with pseudodominant transmission of McARdle disease. Mol Genet Metab 85:239–242CrossRefPubMedGoogle Scholar
  7. 7.
    Kubisch C, Wicklein EM, Jentsch TJ (1998) Molecular diagnosis of McArdle disease: revised genomic structure of the myophosphorylase gene and identification of a novel mutation. Hum Mutat 12:27–32CrossRefPubMedGoogle Scholar
  8. 8.
    Martin MA, Rubio JC, Buchbinder J, Fernandez-Hojas R, del Hoyo P, Teijeira S, Gamez J, Navarro C, Fernandez JM, Cabello A, Campos Y, Cervera C, Culebras JM, Andreu AL, Fletterick R, Arenas J (2001) Molecular heterogeneity of myophosphorylase deficiency (McArdle’s disease): a genotype-phenotype correlation study. Ann Neurol 50:574–581CrossRefPubMedGoogle Scholar
  9. 9.
    Martin MA, Rubio JC, Wevers RA, van Engelen BGM, Steenbergen GCH, van Diggelen OP, De Visser M, De Die-Smulders C, Blazquez A, Andreu AL, Arenas J (2003) Molecular analysis of myophosphorylase deficiency in Dutch patients with McArdle’s disease. Ann Hum Genet 68:17–22CrossRefGoogle Scholar
  10. 10.
    Martinuzzi A, Tsujino S, Vergani L, Schievano G, Cadaldini M, Bartoloni L, Fanin M, Siciliano G, Shanske S, DiMauro S, Angelici C (1996) Molecular characterization of myophosphorylase deficiency in a group of patients from Northern Italy. J Neurol Sci 137:14–19CrossRefPubMedGoogle Scholar
  11. 11.
    Quintans B, Sanchez-Andrade A, Teijeira S, Fernandez-Hojas R, Rivas E, Lopez MJ, Navarro C (2004) A new rare mutation (691del.CC/ins.AAA) in exon 17 of the PYGM gene causing McArdle disease. Arch Neurol 61:1108–1110CrossRefPubMedGoogle Scholar
  12. 12.
    Sprang S, Fletterick RJ (1979) The structure of glycogen phosphorylase alpha at 2.5 A resolution. J Mol Biol 131:523–551CrossRefPubMedGoogle Scholar
  13. 13.
    Sugie H, Sugie Y, Ito M, Fukada T, Nonaka I, Igarashi Y (1995) Genetic analysis of Japanese patients with myophosphorylase deficiency (McArdle’s disease): single-codon deletion in exon 17 is the predominant mutation. Clin Chim Acta 236:81–86CrossRefPubMedGoogle Scholar
  14. 14.
    Tsujino S, Shanske S, DiMauro S (1993) Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle disease). N Engl J Med 329:241–245CrossRefPubMedGoogle Scholar
  15. 15.
    Tsujino S, Shanske S, Martinuzzi A, Heiman-Patterson T, DiMauro S (1995) Two novel missense mutations (E654K, L396P) in Caucasian patients with myo-phosphorylase deficiency (McArdle’s disease). Hum Mutat 6:276–277CrossRefPubMedGoogle Scholar
  16. 16.
    Vorgerd M, Kubisch C, Burwinkel B, Reichmann H, Mortier W, Tettenborn B, Pongratz D, Lindemuth R, Tegenthoff M, Malin J-P, Kilimann MW (1998) Mutation analysis in myophosphorylase deficiency (McArdle’s disease). Ann Neurol 43:326–331CrossRefPubMedGoogle Scholar
  17. 17.
    Wolfe GI, Baker NS, Haller RG, Burns DK, Barohn RJ (2000) McArdle’s disease presenting with asymmetric, late-onset arm weakness. Muscle Nerve 23:641–645CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2007

Authors and Affiliations

  • M. Deschauer
    • 1
    • 2
  • A. Morgenroth
    • 3
  • P. R. Joshi
    • 2
  • D. Gläser
    • 4
  • P. F. Chinnery
    • 5
  • J. Aasly
    • 6
  • H. Schreiber
    • 7
  • M. Knape
    • 2
  • S. Zierz
    • 2
  • M. Vorgerd
    • 3
  1. 1.Klinik und Poliklinik für NeurologieMartin-Luther Universität Halle-WittenbergHalle/SaaleGermany
  2. 2.Klinik und Poliklinik für NeurologieMartin-Luther Universität Halle-WittenbergHalle/SaaleGermany
  3. 3.Klinik und Poliklinik für NeurologieRuhr-Universität Bochum, Kliniken BergmannsheilBochumGermany
  4. 4.Gregor Mendel LaboratoriesCentre for Human GeneticsNeu-UlmGermany
  5. 5.Dept. of NeuroscienceUniversity of Newcastle upon TyneNewcastle upon TyneUK
  6. 6.Dept. of NeurologyUniversity TrondheimTrondheimNorway
  7. 7.Klinik und Poliklinik für NeurologieUniversität UlmUlmGermany

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