Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies

Abstract

Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential.

Congenital myopathies

“…We identified consistent genotype-phenotype correlations of relevance to clinical practice. At the severe end of the spectrum, dramatic neonatal onset with bulbar and respiratory complications was observed in all patients with MTM1 mutation, 18 but also in several patients with ACTA1 mutation, 35,36 a few RYR1 cases, mainly with recessive inheritance, 17,37 and some patients with KLHL40 mutation. 38 Despite severe neonatal onset in some cases, all patients with RYR1 mutation survived, in keeping with only a few lethal cases previously reported in the literature.…”

“…[1][2][3][13][14][15]19 Neonatal presentation was more frequently preceded by pregnancy complications, including polyhydramnios and preterm deliveries, compared with a previous study in which only a few neonates were included. 30 Although lethal outcome for a few specific conditions has been reported, 15,17,19,26,27 the relative mortality rate of different CM subgroups has not been investigated. In our cohort, 12% of patients died, predominantly within the first year of life.…”

“…4 The natural history of specific subgroups has been described in only a few cohorts, not all of which had been fully genetically characterized. 5,[13][14][15][16][17][18][19] Herein, we report the clinical course of 125 patients with CM, reviewed at a single neuromuscular center. Furthermore, genotypephenotype correlations in a subgroup of 99 genetically characterized cases are illustrated.…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…The first 4000 amino acids make up the large cytoplasmic domain that contains binding sites for various modulators, while the last 1000 amino acids constitute the carboxy terminal pore-forming domain [21,22]. Dominant and recessive mutations in RYR1, the gene encoding the RyR1, are associated with a range of early-onset neuromuscular disorders including the core myopathies central core disease (CCD) and multi-minicore disease (MmD), congenital fiber type disproportion, (CFTD) centronuclear myopathy (CNM), exertional rhabdomyolysis/myalgia as well as the pharmacogenetic disorder malignant hyperthermia (MH) [23][24][25][26].…”

“…Since this initial discovery in the early 90s, more than 200 mutations have been identified in patients with a variety of inherited myopathies including MHS, exertional rhabdomyolysis/myalgia and a range of congenital myopathies including CCD, as well as subgroups of MmD, CNM and CFTD [23][24][25][26]. Because of the sheer size of the RYR1 gene which spans 106 exons and >15 kb DNA, initial mutation searches were confined to hotspot domains originally implicated in autosomal dominant MHS and CCD.…”