King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Abstract

King-Denborough syndrome (KDS), first described in 1973, is a rare condition characterised by the triad of dysmorphic features, myopathy, and malignant hyperthermia susceptibility (MHS). Autosomal dominant inheritance with variable expressivity has been reported in several cases. Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been implicated in a wide range of myopathies such as central core disease (CCD), the malignant hyperthermia (MH) susceptibility trait and one isolated patient with KDS. Here we report clinical, pathologic and genetic features of four unrelated patients with KDS. Patients had a relatively uniform clinical presentation but muscle biopsy findings were highly variable. Heterozygous missense mutations in RYR1 were uncovered in three out of four families, of which one mutation was novel and two have previously been reported in MH. Further RyR1 protein expression studies performed in two families showed marked reduction of the RyR1 protein, indicating the presence of allelic RYR1 mutations not detectable on routine sequencing and potentially explaining marked intrafamilial variability. Our findings support the hypothesis that RYR1 mutations are associated with King-Denborough syndrome but that further genetic heterogeneity is likely.

• Authors: James J Dowling, Suzanne Lillis, Kimberley Amburgey, Haiyan Zhou, Safa Al-Sarraj, Stefan J A Buk, Elizabeth Wraige, Gabby Chow, Stephen Abbs, Steven Leber, Katherine Lachlan, Diana Baralle, Alexandra Taylor, Caroline Sewry, Francesco Muntoni, Heinz Jungbluth
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 21 Issue 6 Pg. 420-7 (Jun 2011) ISSN: 1873-2364 [Electronic] England
• PMID: 21514828 (Publication Type: Case Reports, Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Ryanodine Receptor Calcium Release Channel

Topics

• Adolescent
• Biopsy
• Child
• Female
• Humans
• Male
• Malignant Hyperthermia (genetics, pathology)
• Microscopy, Electron
• Muscle, Skeletal (metabolism, pathology)
• Mutation, Missense (genetics)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)