The Clinical, Histological, and Genetic Spectrum of RYR1 Variants—A Multi-Center Israeli Cohort Study

TL;DR

This study explores the range of symptoms and genetic changes in RYR1 gene among Israeli patients, showing how different gene regions affect disease severity.

Contribution

The study expands the known clinical and histological spectrum of RYR1-related disorders and identifies a link between Bsol domain variants and disease severity.

Findings

RYR1 variants are associated with diverse clinical features, including perinatal weakness and respiratory issues.

Variants in the Bsol domain correlate with more severe disease outcomes.

Muscle biopsies showed varied histological features like fiber-size variation and fibrosis.

Abstract

Background: Variants in the ryanodine receptor 1 (RYR1) gene have been linked to a range of disorders, from congenital myopathy to adult-onset manifestations, with phenotypes varying from mild to severe. Methods: A retrospective review was conducted on an Israeli cohort of 36 individuals with RYR1 variants, identified through genetic testing as part of a national collaboration among multiple pediatric and adult neuromuscular clinics. Clinical features, molecular data, laboratory results, electromyographic findings, and muscle histology were analyzed. Each variant was classified according to its respective domain within the RYR1 gene. Results: Thirty-six cases were included in the analysis; 31 were from 11 unrelated families, and 5 were sporadic. Nine individuals were asymptomatic with normal CK levels. Most of the 27 affected patients presented with variable degrees of perinatal weakness, often accompanied by respiratory impairment or arthrogryposis. Weakness was predominantly proximal, with clinical courses that included deterioration, improvement, or stabilization. Three cases of King–Denborough syndrome were identified. Additional presentations included malignant hyperthermia and, in isolated cases, periodic paralysis. Muscle biopsies demonstrated considerable histologic heterogeneity, including fiber-size variation, internal nuclei, multiminicores, and fibrosis or dystrophic features. The pathogenic RYR1 variants included five compound-heterozygous genotypes, two homozygous variants, and two heterozygous variants. There was a positive correlation between variants located in the Bsol domain and disease severity. Conclusions: This cohort confirms and expands the clinical and histological diversity associated with RYR1 variants in Israel. Variants in the Bsol domain appear to be indicative of disease severity.

Figures