Natural history of LGMD2A for delineating outcome measures in clinical trials

Abstract

ObjectiveLimb‐girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium‐dependent cysteine protease of the skeletal muscle.MethodsIn this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14–65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients.ResultsOur study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis.InterpretationAll the generated data will help to determine the endpoints for further clinical studies.

Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21

“…In 1995, CAPN3 recessive mutations were recognized as causative for one of the most common type 2 limb‐girdle muscular dystrophies: LGMD2A . The majority of patients manifested in the first 2 decades of life with proximal lower limb and axial weakness.…”

“…The majority of patients manifested in the first 2 decades of life with proximal lower limb and axial weakness. There was inter‐ and intrafamilial variability, but patients with 2 null mutations demonstrated a more severe phenotype than those carrying at least 1 missense mutation . Creatine kinase (CK) levels were elevated but normalized in severely weak patients.…”

“…There was inter-and intrafamilial variability, but patients with 2 null mutations demonstrated a more severe phenotype than those carrying at least 1 missense mutation. 6 Creatine kinase (CK) levels were elevated but normalized in severely weak patients. The mechanism by which CAPN3 mutations lead to weakness remains undefined but seems related to the perturbation of various homeostatic mechanisms, including calcium dysregulation.…”

“…4,5 A major factor that determines the clinical features of SBMA is the CAG repeat size in the AR gene. 6 Recently, studies on a correlation between the CAG repeat size and electrophysiological motor-and sensory-dominant phenotypes in SBMA have been reported. Suzuki et al reported that compound muscle action potential (CMAP) amplitudes tended to be inversely correlated with the CAG repeat size, whereas sensory nerve action potential (SNAP) amplitudes showed a significant positive correlation with the CAG repeat size.…”

Função e força muscular em pacientes brasileiros com calpainopatia

“…Conforme a progressão da doença pode ser acometida a musculatura distal dos membros, os músculos cardíacos e os respiratórios (Albuquerque, 2013;Richard et al, 2016). AD Com o progresso das pesquisas em avaliação dos distúrbios musculares, esta caracterização clínico-patológica foi contestada, devido à heterogeneidade clínica associada a outras condições, tais como, distúrbios metabólicos e as miopatias congênitas (Fardeau et al, 1996).…”