In 7 cases with RYR1 mutations (6 CCD, one MmD), RyR1 was depleted from the cores; in contrast, the other proteins of the sarcoplasmic reticulum (calsequestrin, SERCA1/2, and triadin) and the T-tubule (dihydropyridine receptor-alpha1subunit) accumulated within or around the lesions, suggesting an original modification of the Ca-release complex protein arrangement.
Initially described in association with malignant hyperthermia, pathogenic variants in RYR1 are typically associated with core pathology in muscle biopsies (central core disease or multiminicore disease) and symptomatic myopathies with symptoms ranging from mild weakness to perinatal lethality.
Malignant hyperthermia (MH), Central Core Disease (CCD), Exertional/environmental Heat Stroke (EHS) and Multiminicore disease (MmD) are inherited disorders of calcium homeostasis in skeletal muscles directly related to mutations of genes coding for proteins of the CRU, primarily ryanodine receptor (RYR1).
Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms.
Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms.
More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and central core disease, and with recessive forms of multi-minicore disease.
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide range of phenotypes, comprising central core disease and distinct subgroups of multi-minicore disease.
Mutations in the skeletal-muscle ryanodine-receptor gene (RYR1) are associated with malignant hyperthermia susceptibility and the congenital myopathies central core disease and multiminicore disease.
Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy.
Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease.
The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background.
We created a mouse model knocked-in for the Q1970fsX16+A4329D RYR1 mutations, which are isogenic with those identified in a severely affected child with MmD.