Brain Advance Access published online on February 2, 2005
Brain, doi:10.1093/brain/awh408
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1 Unidad Experimental, Hospital Donostia, San Sebastián, Basque Country, Spain
* To whom correspondence should be addressed. Summary We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing
Received September 20, 2004
Revised November 16, 2004
Accepted December 21, 2004
Article
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene
2 Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, París, France
3 Unidad de Genética, Hospital Donostia, San Sebastián, Basque Country, Spain
4 Servicio de Neurología, Hospital Donostia, San Sebastián, Basque Country, Spain
5 Service de Neurologie, Hôpital du Haut-Lévèque, Pessac, France
6 Servicio de Neurología, Hospital la Fe, Valencia, Spain
7 Servicio de Neurología, Hospital Universitario 12 de Octubre, Madrid, Spain
8 Servicio de Epidemiología, Hospital Donostia, San Sebastián, Basque Country, Spain
9 Laboratorio di Patologia Neuromuscolare, Istituto Ortopedico Rizzoli, Bologna, Italy
10 Institut de Myologie, Groupe Hospitalier Pitié-Sapêtrière, París, France
11 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany
12 Department of Pediatric Neurology, University Children's Hospital, Göttingen, Germany
13 Service d'Anatomie Pathologique et de Neuropathologie et Laboratoire de Biopathologie, Nerveuse et Musculaire La Timone-IPHM, Marseille, France
A. Sáenz, E-mail: uniexpe2{at}chdo.osakidetza.net
Abstract 
50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG
TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550
A, G222R, IVS6-1GA, A483D, IVS17+1GT, 2069-2070AC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.
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