G.P.4.15 CAPN3 mutations in patients with idiopathic eosinophilic myositis: A predystrophic stage of LGMD2A?

Abstract

Objective and Background: Mutations in the gene encoding calpain-3 (CAPN3) cause autosomal-recessive limb girdle muscular dystrophy type 2A (LGMD2A). In six children, we recently identified CAPN3 mutations as a genetic cause of idiopathic eosinophilic myositis (EM), a rare pathological entity characterised by eosinophilic infiltration of skeletal muscles. Here, we further evaluated the hypothesis of EM being a possible histopathological pre-dystrophic developmental stage of LGMD2A. Methods: We screened CAPN3 for mutations using DHPLC and direct sequencing, in five unrelated patients (four children and one young adult), recruited on the basis of EM diagnosed after histological examination of muscle biopsy samples, without any identified aetiological factor. In addition, information on the presence of eosinophils was retrospectively assessed in 17 genetically confirmed LGMD2A patients and inflammatory changes by analysing haematoxylin-eosin stained cryosections from muscle samples (mean age of biopsy 28 years). Results: Two disease-causing CAPN3 mutations were identified in the five patients affected with idiopathic EM. In one additional patient, only one disease-causing CAPN3 mutation was identified. Additionally, we found a sparse presence of eosinophils in muscle biopsies from 5/17 patients with inflammatory (n = 3 mild focal, n = 2 moderate focal) and myopathic changes (n = 2 mild, n = 2 moderate, n = 1 severe). Conclusion: Our findings confirm mutations in CAPN3 as a genetic cause of eosinophilic myositis. The presence of eosinophils has been discussed before as a component of muscular dystrophy (Cai et al. 2000). The presence of marked eosinophilic infiltrates in EM patients, together with the findings of our retrospective analysis of biopsies from LGMD2A patients might suggest the following possibilities (1) EM associated with CAPN3 mutations could be a distinct phenotype, (2) eosinophilic infiltration might represent an early or transient developmental stage in the inflammation associated with primary calpainopathy.