Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Witting, Nanna; Laforêt, Pascal; Voermans, Nicol C.; Roux-Buisson, Nathalie; Bompaire, Flavie; Rendu, John; Dunø, Morten; Feillet, François; Kamsteeg, Erik‐Jan; Poulsen, Nanna Scharff; Dahlqvist, Julia R.; Romero, Norma B.; Fauré, Julien; Vissing, John; Béhin, Anthony

doi:10.1111/ane.12885

Cited by 29 publications

(23 citation statements)

References 35 publications

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“…Since then, it has been shown in different cohorts of patients with ER that causative mutations or potentially pathogenic variants in RYR1 and CACNA1S account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. [13][14][15] It appears that this genetic predisposition in combination with various stressors (e.g. inhalational anaesthesia, viral infections, environmental heat, strenuous exercise, severe stress and/or drugs) can elicit acute rhabdomyolysis.…”

Section: Discussionmentioning

confidence: 99%

Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation

Heytens

Ridder

Bleecker

et al. 2019

Anaesth Intensive Care

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Some degree of exertional rhabdomyolysis (ER), striated muscle breakdown associated with strenuous exercise, is a well-known phenomenon associated with endurance sports. However in rare cases, severe and/or recurrent ER is a manifestation of an underlying condition, which puts patients at risk for significant morbidity and mortality. Selecting the patients that need a diagnostic work up of an acute rhabdomyolysis episode is an important task. Based on the diagnostic work up of three illustrative patients treated in our hospital, retrospectively using the ‘RHABDO’ screening tool, we discuss the clinical and biochemical clues that should trigger further investigation for an underlying condition. Finally, we describe the most common genetic causes of this clinical syndrome.

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Section: Discussionmentioning

confidence: 99%

Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation

Heytens

Ridder

Bleecker

et al. 2019

Anaesth Intensive Care

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show abstract

“…However, these histopathological features are not unique to RYR1 -RD, and are variable over time. In addition, there is an expanding spectrum of RYR1 -associated clinical phenotypes, including RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, and King-Denborough syndrome [15, 48, 88]. …”

Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9033-2) contains supplementary material, which is available to authorized users.

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“…RYR1 -RM histopathological subtypes reported to date include central core disease (CCD; MIM# 117000), multi-mini core disease (MmD; MIM# 255320), centronuclear myopathy (CNM), congenital fiber-type disproportion (CFTD), and core-rod myopathy (CRM) ( 8 – 12 ). A range of RYR1 -RM clinical phenotypes have also emerged more recently and include RYR1 rhabdomyolysis-myalgia syndrome and atypical periodic paralysis ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings

et al. 2018

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The ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant’s medical records. Alamut Visual Software was used to determine if participant’s variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination.

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Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Abstract: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Cited by 29 publications

References 35 publications

Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation

Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings

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