Molecular genetic analysis of McArdle's disease in Spanish patients

Andreu, Antoni L.; Bruno, Claudio; Gamez, Josep; Shanske, Sara; Cervera, Carlos; Navarro, Carmen; Arbós, M.A.; Tamburino, Lucia; Schwartz, Simó; DiMauro, Salvatore

doi:10.1212/wnl.51.1.260

Cited by 24 publications

(8 citation statements)

References 3 publications

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“…Five had compound heterozygotes for the R49X and G204S mutations, 12 for the R49X mutation and an unidentified mutant allele, and 1 for the G204S mutation and an unidentified mutant allele. Three homozygous patients with the R49X mutation (Patients 10, 13, and 19) were reported in the paper by Andreu and colleagues 26. Thirteen patients harbored neither mutation in their alleles.…”

Section: Resultsmentioning

confidence: 97%

“…This mutation was distinctly less common in Mediterranean populations. Approximately 50% of Italian and Spanish patients had the R49X mutation, accounting for 32% of mutant alleles (9 of 28 alleles and 12 of 38 alleles, respectively) 26, 27. These results led some authors to suggest a North‐South gradient for the R49X mutation across Europe.…”

Section: Discussionmentioning

confidence: 99%

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Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

Martín

Rubio

Buchbinder

et al. 2001

Annals of Neurology

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We report on 54 Spanish patients with McArdle's disease from 40 unrelated families. Molecular analysis revealed that the most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent and found in 14.8% of patients and 9% of mutant alleles. The W797R mutation was observed in 16.5% of patients, accounting for 13.7% of mutant alleles. Moreover, 78% of mutant alleles among Spanish patients can be identified by using polymerase chain reaction-restriction fragment length polymorphism analysis for the R49X, G204S, and W797R mutations, which makes noninvasive diagnosis possible through molecular genetic analysis of blood DNA. Six novel mutations were found. Three were missense mutations, E348K, R601W, and A703V; two nonsense mutations, E124X and Q754X; and one single base pair deletion, 533 delA. No clear genotype-phenotype correlation emerges from our study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen bonding networks, introducing severe incompatible partnering that is caused by poor packing or electrostatic repulsions.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

Martín

Rubio

Buchbinder

et al. 2001

Annals of Neurology

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“…For example, the Arg49Stop mutation has never been found in Japan, and its frequency in Europe seems to decline from north to south, with 81% alleles in the U.K 11,. 56% in Germany,162 and 32% in Italy89 and Spain 7…”

Section: Glycogenoses Causing Exercise Intolerance Cramps and Myoglmentioning

confidence: 99%

Muscle glycogenoses

2001

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There are 11 hereditary disorders of glycogen metabolism affecting muscle alone or together with other tissues, and they cause two main clinical syndromes: episodic, recurrent exercise intolerance with cramps, myalgia, and myoglobinuria; or fixed, often progressive weakness. Great strides have been made in our understanding of the molecular bases of these disorders, all of which show remarkable genetic heterogeneity. In contrast, the pathophysiological mechanisms underlying acute muscle breakdown and chronic weakness remain unclear. Although glycogen storage diseases have been studied for decades, new biochemical defects are still being discovered, especially in the glycolytic pathway. In addition, the pathogenesis of polyglucosan deposition is being clarified both in traditional glycogenoses and in disorders such as Lafora's disease. In some conditions, combined dietary and exercise regimens may be of help, and gene therapy, including recombinant enzyme replacement, is being actively pursued.

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“…Molecular heterogeneity has been demonstrated by the identification of various different mutations in the coding regions or splice sites of the gene , Bartram et al 1993, Bruno et al 1999a, Bruno et al 1999b, Bruno et al 2006, Deschauer et al 2003, Fernandez-Cadenas et al 2003, Martin et al 2001a, Martin et al 2001b, Quintans et al 2004, Tsujino et al 1994a, Tsujino et al 1993, Tsujino et al 1994b, Vorgerd et al 1998. The most common among European and American patients is a nonsense mutation at codon 50 in exon 1 (p.R50X) (Andreu et al 1998, Bartram et al 1993, Bruno et al 2006, el-Schahawi et al 1996, Martin et al 2001a, Martinuzzi et al 1996, Tsujino et al 1993, Tsujino et al 1995, Vorgerd et al 1998. In this article, we present molecular studies in 55 Spanish patients with McArdle disease, and describe nine novel mutations in the PYGM gene.…”

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confidence: 99%