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

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.

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

“…A continuum between the histopathological appearance of CCD and MmD related to RYR1 mutations has been suggested, 11,15 with evolution over time, as observed on consecutive muscle biopsies of the same patient. 7,28 The histological features found in this study are similar to those described in the literature (see Table 2). The scarcity of clinical findings contrasted with the marked morphological changes, namely type 1 fiber predominance, central nuclei, variability in fiber size, and cores and multiminicores on SDH and NADH staining.…”

“…However, there have been reports of at least 18 families with compound heterozygosity, as proven by haplotyping and/or segregation analysis. 4,7,30,[33][34][35][36] Nevertheless, the majority of the previously reported RYR1 recessive cases had a neonatal or childhood onset. Our report adds some more complexity to this picture and widens the phenotypic variability.…”

“…Histologically, type I and type II muscle fibers are characterized by multiple cores that do not extend along the entire length of the myofiber and short areas of sarcomeric disorganization lacking mitochondria. 1 MmD was initially associated with recessive mutations in the selenoprotein N1 gene (SEPN1), 3 but there have been increasing reports of recessive mutations in the RYR1 gene being related to this entity, 1,[4][5][6][7] and in some cases also with enhanced susceptibility to MH. [8][9][10][11] The onset of MmD is usually in infancy or childhood with hypotonia or proximal weakness, and only a limited number of cases have been reported with onset in adult life.…”

The Genetics of Malignant Hyperthermia

“…Nemaline rods have been found in some CCD patients [53], although nemaline rod myopathy has been described as a disease entity of the muscle cytoskeletion different from CCD. There are other examples of clinical overlap between these myopathies, associated with variants of RYR1 [54,55].…”

Multi-minicore disease revisited

“…Recently, studies provided evidence for genetic heterogeneity of MmD [8][9][10][11] . Mutation in the skeletal muscle ryanodine receptor (RYR-1) gene (locus 19q13) 8,9,11 , well recognized in CCD, has been found in cases of MmD, thus linking the two diseases at least at the genetic level. On the other hand, classical cases of MmD harbor a mutation in the selenoprotein N (SE-PN-1) gene (locus 1p36) 10 , which may also be found in congenital muscular dystrophy with rigid spine syndrome.…”