A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation

Abstract

Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.

Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia

“…The point mutation found in the MH RyR1 horses is at the same codon reported in two of five mutations for exon 46 in humans. 2,3,22,35 In MHS humans, the mutation results in arginine replacement by cysteine or histidine in different families, 3,22 whereas, in our MH RyR1 horses, arginine was replaced by a glycine. Among the known missense mutations in humans, almost half involve an arginine substitution.…”

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

“…CCD has a typical onset in infancy and presents with hypotonia and motor developmental delay. MH can manifest in the absence of any clinical diagnosis of CCD (1,(5)(6)(7)(8) and is one of the main causes of death due to anesthesia affecting humans, dogs, pigs, and horses (9,10). The fulminant MH episode is characterized by muscular rigidity, rhabdomyolysis, rapid increase in body temperature, and signs of generalized metabolic decompensation, which can rapidly lead to death of the patient if unabated (11).…”

Central core disease

“…Malignant hyperthermia, a pharmacogenetic disorder of skeletal muscle characterised by an abnormal response to muscle relaxants such as succinylcholine and volatile anaesthetics, is a frequent complication [23-25]. Malignant hyperthermia is a severe and occasionally fatal reaction characterised by muscular rigidity, rhabdomyolysis, rapid increase in body temperature and signs of generalised metabolic decompensation; survivors may suffer severe renal and neurologic damage.…”

“…Patients with CCD are at risk of malignant hyperthermia, an abnormal response to muscle relaxants such as succinylcholine and volatile anaesthetics [24,25]. The anaesthetist ought to be aware of the diagnosis of CCD and plan the anaesthesia accordingly, avoiding potentially MH-triggering agents.…”