LGMD2A: genotype–phenotype correlations based on a large mutational survey on the calpain 3 gene

Abstract

We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 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 approximately 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, approximately 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, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, 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%.

Natural history of LGMD2A for delineating outcome measures in clinical trials

“…In terms of clinical presentation, our study confirms and further delineates the picture previously reported in several earlier studies 2, 3, 21, 22, 23, 24, 25, 26. Muscle weakness, which is remarkably symmetrical, is predominant in the axial muscles of the trunk and proximal muscles of the lower limb.…”

Limb-girdle muscular dystrophy type 2A in Brazilian children

“…In other studies, including some conducted in Brazil, it was also shown that sarcoglicanopathy is the most common form, particularly when taking into account more severe forms of the disease and forms with earlier onset 13,14 . In a study carried out by a European consortium in 2005 by Saenz et al 15 , which included 484 LGMD patients from different geographic regions, screening for CAPN3 mutations was positive in approximately 50% of cases. In the same study, it was observed that, when specific clinical criteria were used, 80% of cases could be correctly anticipated to have CAPN3 mutations.…”

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

“…Patients with calpainopathy usually present first symptoms around 13 years old, with an onset age range from 1 to 67 years 28 (Table 2). First symptoms may start either in lower or upper limbs.…”

“…First symptoms may start either in lower or upper limbs. In a common presentation, symptoms start almost simultaneously in lower and upper limbs 28 . Muscular weakness usually starts in the lower limbs and, in less than two years, it evolves to the upper limbs 28 .…”