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.
Article: Pediatric Ambulatory Anesthesia[Show abstract] [Hide abstract]
ABSTRACT: Pediatric patients often undergo anesthesia for ambulatory procedures. This article discusses several common preoperative dilemmas, including whether to postpone anesthesia when a child has an upper respiratory infection, whether to test young women for pregnancy, which children require overnight admission for apnea monitoring, and the effectiveness of nonpharmacological techniques for reducing anxiety. Medication issues covered include the risks of anesthetic agents in children with undiagnosed weakness, the use of remifentanil for tracheal intubation, and perioperative dosing of rectal acetaminophen. The relative merits of caudal and dorsal penile nerve block for pain after circumcision are also discussed.Anesthesiology Clinics 06/2014;
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ABSTRACT: Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes. However the relationship between each congenital myopathy, defined on histological grounds, and the genetic cause is complex. Many of the congenital myopathies are due to mutations in more than one gene, and mutations in the same gene can cause different muscle pathologies. The International Standard of Care Committee for Congenital Myopathies performed a literature review and consulted a group of experts in the field to develop a summary of 1. the key features common to all forms of congenital myopathy and 2. the specific features that help to discriminate between the different genetic subtypes. The consensus statement was refined by two rounds of on-line survey, and a three-day workshop. This consensus statement provides guidelines to the physician assessing the infant or child with hypotonia and weakness. We summarise the clinical features that are most suggestive of a congenital myopathy, the major differential diagnoses and the features on clinical examination, investigations, muscle pathology and muscle imaging that are suggestive of a specific genetic diagnosis to assist in prioritisation of genetic testing of known genes. As next generation sequencing becomes increasingly used as a diagnostic tool in clinical practice, these guidelines will assist in determining which sequence variations are likely to be pathogenic.Neuromuscular Disorders 01/2013; · 3.46 Impact Factor
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ABSTRACT: The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.Journal of the American Society for Experimental NeuroTherapeutics 08/2014; · 5.38 Impact Factor