Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21

Abstract

Introduction: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation.

Methods: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals.

Results: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced.

Discussion: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018.

Keywords: CAPN3; autosomal dominant myopathy; axial myopathy; limb-girdle muscular dystrophy.

FIGURE 1

Pedigrees of family 1 (A), family 2 (B), and family 3 (C). Asterisks denote individuals carrying the CAPN3 mutation. Gray color indicates symptomatic individuals or subjects with elevated CK for whom a neurological evaluation was not available.

FIGURE 2

Clinical, radiological, muscle histological, and Western blot findings. Photographs depicting (A) abdominal wall muscle weakness and (B) asymmetric scapular winging for proband (V-6) in family 2. (C) Axial computed tomography image of the abdomen showing oblique muscle atrophy (red arrow) for this proband. (D) Axial T2 lumbar spine MRI highlights marked atrophy and fatty replacement of the posterior paraspinal musculature (asterisks) for this proband. (E) Triceps muscle biopsy shows small clusters of necrotic fibers (asterisk indicates a necrotic fiber) in subject IV-13 of family 1 (hematoxylin–eosin stain). (F) Control muscle (lane C) was compared with the muscle biopsy from subject IV-13 of family 1 (lane 1) and proband muscle biopsies from families 2 and 3 (lanes 2, and 3). Although dysferlin appears normal in size and amount for each affected subject, full-length (94-kd) calpain-3 and calpain-3 degradation products are greatly reduced in each subject.