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

• Published in: Neuromuscular disorders : NMD 2011-06, Vol.21 (6), p.420-427
• Main Authors: Dowling, James J, Lillis, Suzanne, Amburgey, Kimberley, Zhou, Haiyan, Al-Sarraj, Safa, Buk, Stefan J.A, Wraige, Elizabeth, Chow, Gabby, Abbs, Stephen, Leber, Steven, Lachlan, Katherine, Baralle, Diana, Taylor, Alexandra, Sewry, Caroline, Muntoni, Francesco, Jungbluth, Heinz
• Format: Article
• Language: English
• Subjects: Adolescent; Biopsy; Central core disease; Child; Congenital myopathies; Female; Humans; King–Denborough syndrome; Male; Malignant Hyperthermia - genetics; Malignant Hyperthermia - pathology; Malignant hyperthermia susceptibility (MHS); Microscopy, Electron; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Mutation, Missense - genetics; Neurology; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Skeletal muscle ryanodine receptor (RYR1) gene
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2011.03.006

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.