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.
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ABSTRACT: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. © 2014 American Academy of Neurology.Neurology 11/2014; 84(1). DOI:10.1212/WNL.0000000000001110 · 8.30 Impact Factor
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ABSTRACT: Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity. In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM. FOR PROVISIONAL PDF: http://www.ojrd.com/content/10/1/51/abstractOrphanet Journal of Rare Diseases 05/2015; 10(1). DOI:10.1186/s13023-015-0264-3 · 3.96 Impact Factor
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; DOI:10.1016/j.anclin.2014.02.002