An unusual ryanodine receptor 1 (RYR1) phenotype

Abstract

ObjectiveTo identify the genetic defect causing a distal calf myopathy with cores.MethodsFamilies with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.ResultsA novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.ConclusionsOur findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

“…80,81 SUNFISH studying SMA types 2 and 3 (ongoing trial finishing in 2023) also showed improvement of motor function in treated patients, particularly in younger patients. [82][83][84] JEWELFISH, a Phase II open label trial (finishing in December 2024), is currently investigating the safety and tolerability of risdiplam in SMA patients ages 6 months-60 years who have previously been treated with nusinersen or onasemnogene abeparvovec. 85 RAINBOWFISH (finishing in October 2025) is assessing risdiplam safety and efficacy in presymptomatic newborns and infants up to 6 weeks old.…”

Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature

“…The wide range of phenotypes associated with RYR1 variants, the large size of RYR1, and complex histopathological overlap across different CMs due to variants in other genes encoding sarcolemmal and sarcotubular proteins [29] present challenges in confirmatory diagnosis. RYR1-RM-affected individuals show a consistent pattern of relative sparing of rectus femoris, adductor longus, hamstring muscles, the medial head of the gastrocnemius (except in calf-predominant myopathy) [106], and muscles of the anterior compartment of leg [107]. In 2004, Jungbluth and colleagues used magnetic resonance imaging (MRI) to classify distinct patterns of selective muscle fatty infiltration using in congenital myopathies associated with RYR1 causative variations [107].…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…Moreover, RYR1 mutations are a well-known cause of dominant malignant hyperthermia (MH) susceptibility [38], and of exercise-induced rhabdomyolysis [39]. Recently, a calf-predominant myopathy with core pathology was associated with dominantly inherited RYR1 mutations [14].…”

“…When interpreting variants in large genes, a 'deep phenotyping' is crucial to identify a correlation between the observed phenotype and the known geneassociated clinical presentations [51]. The recent large HTS-based studies are further expanding the already broad range of clinical phenotypes associated to the genes discussed in this review [13,14,19]. Traditionally, the diagnosis of skeletal muscle disorders benefits from a careful evaluation of clinical signs and symptoms, of creatine kinase level, of histopathological findings on a muscle biopsy and of electromyography records.…”

“…analysis of large genes. The use of HTS has also resulted into a growing number of variants identified in these genes and in an increased diagnostic yield [7][8][9], expanding the spectrum of diseases associated with large-genes [10][11][12][13][14].…”