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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
Author(s) -
Ferreiro Ana,
Monnier Nicole,
Romero Norma B.,
Leroy JeanPaul,
Bönnemann Carsten,
Haenggeli CharlesAntoine,
Straub Volker,
Voss Wolfgang D.,
Nivoche Yves,
Jungbluth Heinz,
Lemainque Arnaud,
Voit Thomas,
Lunardi Joël,
Fardeau Michel,
Guicheney Pascale
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10231
Subject(s) - central core disease , congenital myopathy , missense mutation , genetics , locus (genetics) , biology , compound heterozygosity , myopathy , phenotype , medicine , gene , ryr1 , ryanodine receptor , muscle biopsy , biopsy , intracellular
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.