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Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

ABSTRACT: The Malignant Hyperthermia Association of the United States and the Department of Anesthesia at the University of Toronto sponsored a Scientific Conference on November 1-2, 2013 in Toronto, ON, Canada. The multidisciplinary group of experts, including clinicians, geneticists, and physiologists involved in research related to malignant hyperthermia (MH), shared new insights into the pathophysiology of diseases linked to the type-1 ryanodine receptor gene (RYR1) as well as the relationship between MH and "awake MH" conditions, such as exertional rhabdomyolysis and exertional heat illness. In addition, the molecular genetics of MH and clinical issues related to the diagnosis and management of disorders linked to RYR1 were presented. The conference also honoured Dr. David H. MacLennan for his contributions to our understanding of the genetics, pathogenesis, and treatment of MH and other RYR1-related myopathies. This report represents a summary of the proceedings of this conference.

SUBMITTER: Riazi S

PROVIDER: S-EPMC4276369 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

Riazi Sheila S Kraeva Natalia N Muldoon Sheila M SM Dowling James J Ho Clara C Petre Maria-Alexandra MA Parness Jerome J Dirksen Robert T RT Rosenberg Henry H

Canadian journal of anaesthesia = Journal canadien d'anesthesie 20140905 11

The Malignant Hyperthermia Association of the United States and the Department of Anesthesia at the University of Toronto sponsored a Scientific Conference on November 1-2, 2013 in Toronto, ON, Canada. The multidisciplinary group of experts, including clinicians, geneticists, and physiologists involved in research related to malignant hyperthermia (MH), shared new insights into the pathophysiology of diseases linked to the type-1 ryanodine receptor gene (RYR1) as well as the relationship between ...[more]

PMID: 25189431

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Project description:Thyroglobulin (Tg) protein is synthesised uniquely by thyroid tissue and is measured as a post-operative differentiated thyroid cancer (DTC) tumour-marker. Tg autoantibodies (TgAb), present in ?20 percent of DTC patients, interfere with Tg immunometric assay (IMA) measurements causing falsely low/undetectable serum Tg values. Tg radioimmunoassay (RIA) methodology appears resistant to such interferences but has limited availability, whereas new Tg mass-spectrometry methods have inferior sensitivity and unproven clinical value. When present, TgAb concentrations respond to changes in thyroid tissue mass. Thus, when Tg IMA measurements are compromised by the presence of TgAb the TgAb trend can serve as a surrogate DTC tumour-marker. Unfortunately, both physiologic and technical factors impact the interpretation of Tg and TgAb used as DTC tumour-markers. Serum Tg Testing Circulating Tg concentrations change in response to thyroid tissue mass, injury (surgery, biopsy or radioiodine) and the degree of TSH stimulation. Technical factors (Tg assay sensitivity, specificity and interferences) additionally impact the clinical utility of Tg testing. Specifically, new 2nd generation Tg IMAs (functional sensitivities ? 0.1 ?g/L) now mostly obviate the need for expensive recombinant human TSH(rhTSH)-stimulated Tg testing. Tg molecular heterogeneity remains responsible for two-fold between-method differences in Tg values that preclude switching methods and TgAb interference remains especially problematic. Serum TgAb Testing Reliable TgAb testing is critical for authenticating that Tg IMA measurements are not compromised by interference. Unfortunately, TgAb methodologies vary widely in sensitivity, specificity and the absolute values they report, necessitating that TgAb concentrations be monitored using the same method. Furthermore, adopting the manufacturer’s TgAb cut-off value to define a ‘detectable’ TgAb results in falsely classifying sera as TgAb-negative, because manufacturers’ cut-offs are set to diagnose thyroid autoimmunity and not to detect TgAb interference.

Project description:BackgroundVariants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility.ObjectiveTo provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients.MethodsWe performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders.ResultsA total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy.ConclusionsPatients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

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Dataset Information

Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

Publications

Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

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