A recessive form of central core disease, transiently presenting as multi‐minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene

TLDR

Multi‑minicore disease is an autosomal recessive congenital myopathy marked by multiple short core lesions in both muscle fiber types, yet its boundaries remain unclear due to nonspecific lesions and heterogeneous clinical presentation. The authors sought to identify the genetic cause by performing a genome‑wide screen in a consanguineous Algerian family with three affected infants. Linkage analysis mapped the disease to chromosome 19q13, a locus then excluded in 16 other multi‑minicore families with a classical phenotype. The linkage analysis yielded a maximum LOD score of 5.19 at D19S570, and a novel homozygous P3527S missense mutation in RYR1 was identified; adult biopsies of the affected patients revealed classic central core disease with rods, establishing this 19q13‑linked group as the first recessively inherited central core disease variant that transiently presents as multi‑minicore disease.

Abstract

Abstract Multi‐minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short‐length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi‐minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome‐wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi‐minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency (“classical” phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi‐minicore disease.