title: 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.affiliation: Division of Pediatric Neurology, Pediatric Neuromuscular Clinic, 5328 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lillis
authors.forename: Kimberley
authors.initials: K
authors.lastname: Amburgey
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Stefan J A
authors.initials: SJ
authors.lastname: Buk
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.forename: Gabby
authors.initials: G
authors.lastname: Chow
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Steven
authors.initials: S
authors.lastname: Leber
authors.forename: Katherine
authors.initials: K
authors.lastname: Lachlan
authors.forename: Diana
authors.initials: D
authors.lastname: Baralle
authors.forename: Alexandra
authors.initials: A
authors.lastname: Taylor
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000473:pathology*; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel