Article

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

Division of Pediatric Neurology, Pediatric Neuromuscular Clinic, 5328 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, USA.
Neuromuscular Disorders (Impact Factor: 2.64). 06/2011; 21(6):420-7. DOI: 10.1016/j.nmd.2011.03.006
Source: PubMed

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.

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    • "The genetic basis of this disorder is not entirely clear; MH is one of the characteristic features of the syndrome. De novo dominant mutations and recessive mutations in the RYR1 gene have been reported in some but not all patients[D'Arcy et al., 2008;Dowling et al., 2011], therefore suggesting further genetic heterogeneity. Comparing the overall severity between patients with recessive and dominant inheritance in both groups, there is marked variability . "
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    ABSTRACT: The core myopathies, Central Core Disease and Multiminicore Disease, are heterogeneous congenital myopathies with the common defining histopathological feature of focally reduced oxidative enzyme activity (central cores, multiminicores). Mutations in the gene encoding for the skeletal muscle ryanodine (RyR1) receptor are the most common cause. Mutations in the selenoprotein N (SEPN1) gene cause a less common variant. Pathogenic mechanisms underlying dominant RYR1 mutations have been extensively characterized, whereas those associated with recessive RYR1 and SEPN1 mutations are emerging. Identifying a specific genetic defect from the histopathological diagnosis of a core myopathy is complex and ought to be informed by a combined appraisal of histopathological, clinical, and, increasingly, muscle magnetic resonance imaging data. The present review aims at giving an overview of the main genetic and clinicopathological findings, with a major emphasis on features likely to inform the diagnostic process, as well as current treatments and perspectives for future research.
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