Contribución a la caracterización clínica y genética de la enfermedad de McArdle

Abstract

INTRODUCTION. McArdle's Disease (Glycogenosis Type V) is a metabolic myopathy caused by a deficiency of myophosphorylase. This enzyme initiates glycogen breakdown, catalysing glycogen phosphorylitic cleavage to glucose-1-phosphate at a-1,4-glucosydic linkages. McArdle's patients typically present exercise intolerance, premature fatigue, myalgia and cramps. Approximately half present recurrent myoglobinuria. Other clinical presentations have been reported.
The myophosphorylase gene has been cloned, sequenced and assigned to chromosome 11q13. Molecular genetic studies have so far identified 32 different mutations. The most common defect is a nonsense mutation (R49X) in exon-1. Private ethnically-related mutations are being increasingly described, especially in Mediterranean countries.
OBJECTIVES: (1) identify the molecular defect in a 21-family series with McArdle's patients, according to clinical and histological criteria, (2) establish the pathogenicity of these mutations and study the prevalence of R49X and other mutations, (3) describe the clinical findings concerning those affected, (4) establish whether there is a genotype-phenotype correlation.
PATIENTS AND METHODS: we studied 35 McArdle's patients (20 male, 15 female), from 21 non-related families. Patients were evaluated by interviews, physical examination, biochemical analysis, neurophysiological study, ischemic forearm test, muscle biopsy (in one individual from each family) and genetic studies, including myophosphorylase gene sequencing. Data were analysed using standard statistical methods.
RESULTS: The mean age was 42.7 years old (range 18-85). Mean clinical onset age was 13.3 years old (range 3-51). Mean age of clinical diagnosis was 36.2 years old (range 16-76). Almost 43% of patients presented with myoglobinuria, and 9 patients (25.7%) had over 5 episodes. Mean "second wind" duration was 5.9 minutes. Mean resistance in the forearm ischemic exercise test was 41.6 seconds. Employment was impossible for 14.2% of patients, who were registered as disabled. Mean CK at rest was 1914 UI/L. Nine patients showed uric concentration of over 7.0 mg/dl. The lactate curve in forearm ischemic exercise tests was flat in all patients. In our patients, the classic phenotype was most frequent (74.3%). Five others (14.2%) presented an adult onset form. Two had thoracic pain, one had acute abdominal pain and another had renal failure. Six families showed a pseudo-dominant inheritance pattern.
Consanguinity was present in 4 families. Seven families had common ancestry, as they all originated in small population centres. We identified 10 different mutations in the 35 patients. Three had been described (R49X, G204S and W797R). We found seven novel mutations - 5 missense (R93W, L115P, R489W, A669V, and N684Y), one nonsense (Y573X) and a splice junction (K608K). The molecular defect was identified in 62 alleles. We found R49X in 30 alleles (42.85%), W797R in 14 (20%), G204S in 7 (10%). L115P, R489W, Y573X, and K608K in 2 each (2.85%), and N684Y, A669V and R93W in 1 each (1.42%). The molecular defect in 8 alleles has yet to be identified, but it is neither R49X, G204S nor W797R. No clinical genotype-phenotype correlation was found in the series.
CONCLUSIONS: Forearm ischemic exercise test is the first choice test when investigating suspected McArdle's patients. R49X prevalence was 42.85%, similar to the French and German series, and slightly less than those in the UK and the USA. The suggested north-south gradient should be therefore analysed with caution. We identified seven novel mutations. These results confirm this disease's allelic heterogeneity in Spain. Muscle biopsy is an important diagnostic test, especially in Spanish patients, due to the likelihood of private mutations. A clear phenotype-genotype correlation was not found. Most late-onset patients in fact have benign forms starting early in life, which become clinically evident with age. Delay in diagnosing these individuals, who are frequently labelled as psychosomatic, suggests the need for awareness-raising programmes among healthcare professionals, especially those involved in primary care.

Date of Award	13 Dec 2002
Original language	Spanish
Supervisor	Antonio L. Andreu Periz (Director) & Carlos Cervera Radigales (Director)