Hipertermia maligna / Malignant hyperthermia

Resumen: La hipertermia maligna es un raro desorden farmacogenético potencialmente mortal, que se presenta como una respuesta hipermetabólica a los anestésicos volátiles y relajantes musculares despolarizantes en individuos susceptibles. Esta susceptibilidad se asocia a mutaciones en tres genes: RYR1, CACNA1S y STAC3. Puede manifestarse con síntomas leves o como una crisis fulminante, con rabdomiólisis severa, fibrilación ventricular e insuficiencia renal y circulatoria aguda, por lo tanto, el pronóstico depende de qué tan pronto se sospeche del diagnóstico y qué tan rápido se inicie el tratamiento. El diagnóstico definitivo se basa en una prueba de sensibilidad en biopsia muscular fresca y en pruebas genéticas. La mejor manera de prevenir un evento es la detección precoz de los pacientes susceptibles así como contar con el equipo para responder ante una crisis en cada centro donde se administren anestésicos volátiles y la capacitación del personal. Esta revisión sintetiza los conceptos actuales clínicos y biomédicos para detección, prevención, diagnóstico y manejo de la hipertermia maligna.

Abstract: Malignant hyperthermia is a rare, life-threatening pharmacogenetic disorder which presents as a hypermetabolic response to volatile anesthetics and depolarizing muscle relaxants in susceptible individuals. This susceptibility is associated with mutations in three genes: RYR1, CACNA1S and STAC3. Can manifest with mild symptoms or as a fulminant crisis, with severe rhabdomyolysis, ventricular fibrillation and acute renal and circulatory failure, therefore the prognosis depends on how soon the diagnosis is suspected and how fast treatment is started. The definitive diagnosis is based on a fresh muscle biopsy sensitivity test and genetic testing. The best way to prevent an event is the early detection of susceptible, as well as have equipment to respond to a crisis in each center where volatile anesthetics are administered and the training of staff. This review synthesizes current clinical and biomedical concepts for detection, prevention, diagnosis and management of malignant hyperthermia.

Enhanced endoplasmic reticulum RyR1 receptor phosphorylation leads to diaphragmatic dysfunction in septic rats / 南方医科大学学报

OBJECTIVE@#To explore the role of endoplasmic reticulum ryanodine receptor 1 (RyR1) expression and phosphorylation in sepsis- induced diaphragm dysfunction.@*METHODS@#Thirty SPF male SD rats were randomized equally into 5 groups, including a sham-operated group, 3 sepsis model groups observed at 6, 12, or 24 h following cecal ligation and perforation (CLP; CLP-6h, CLP-12h, and CLP-24h groups, respectively), and a CLP-24h group with a single intraperitoneal injection of KN- 93 immediately after the operation (CLP-24h+KN-93 group). At the indicated time points, diaphragm samples were collected for measurement of compound muscle action potential (CMAP), fatigue index of the isolated diaphragm and fitted frequencycontraction curves. The protein expression levels of CaMK Ⅱ, RyR1 and P-RyR1 in the diaphragm were detected using Western blotting.@*RESULTS@#In the rat models of sepsis, the amplitude of diaphragm CMAP decreased and its duration increased with time following CLP, and the changes were the most obvious at 24 h and significantly attenuated by KN-93 treatment (P < 0.05). The diaphragm fatigue index increased progressively following CLP (P < 0.05) irrespective of KN- 93 treatment (P>0.05). The frequency-contraction curve of the diaphragm muscle decreased progressively following CLP, and was significantly lower in CLP-24 h group than in CLP-24 h+KN-93 group (P < 0.05). Compared with that in the sham-operated group, RyR1 expression level in the diaphragm was significantly lowered at 24 h (P < 0.05) but not at 6 or 12 following CLP, irrespective of KN-93 treatment; The expression level of P-RyR1 increased gradually with time after CLP, and was significantly lowered by KN-93 treatment at 24 h following CLP (P < 0.05). The expression level of CaMKⅡ increased significantly at 24 h following CLP, and was obviously lowered by KN-93 treatment (P < 0.05).@*CONCLUSION@#Sepsis causes diaphragmatic dysfunction by enhancing CaMK Ⅱ expression and RyR1 receptor phosphorylation in the endoplasmic reticulum of the diaphragm.

Mild Clinical Features and Histopathologically Atypical Cores in Two Korean Families with Central Core Disease Harboring RYR1 Mutations at the C-Terminal Region

BACKGROUND: Central core disease (CCD) is a congenital myopathy characterized by distinctive cores in muscle fibers. Mutations in the gene encoding ryanodine receptor 1 (RYR1) have been identified in most CCD patients. CASE REPORT: Two unrelated patients presented with slowly progressive or nonprogressive proximal muscle weakness since childhood. Their family history revealed some members with the same clinical problem. Histological analysis of muscle biopsy samples revealed numerous peripheral cores in the muscle fibers. RYR1 sequence analysis disclosed a novel mutation in exon 101 (c.14590T>C) and confirmed a previously reported mutation in exon 102 (c.14678G>A). CONCLUSIONS: We report herein two families with CCD in whom missense mutations at the C-terminal of RYR1 were identified. Although it has been accepted that such mutations are usually associated with a severe clinical phenotype and clearly demarcated central cores, our patients exhibited a mild clinical phenotype without facial muscle involvement and skeletal deformities, and atypical cores in their muscle biopsy specimens.

Progress on genotypic and phenotypic features of central core disease / 国际儿科学杂志

Central core disease (CCD) is a dominantly inherited congenital myopathy,manifesting as static or slowly progressive weakness ofproximal muscles.Histological characteristics on muscle biopsy are the well defined areas devoid of oxidative enzyme stains.Ryanodine receptor 1 gene mutations are associated with CCD.Great progress has been made in recent years about the RYR1 gene mutaion and the clinical feature of CCD.Genotypic and Phenotypic variations of RYR1 related CCD are reviewed.