Clinical utility gene card for: Central core disease

Lillis, Suzanne; Abbs, Stephen; Mueller, C.W.; Muntoni, Francesco; Jungbluth, Heinz

doi:10.1038/ejhg.2011.179

Cited by 5 publications

(7 citation statements)

References 36 publications

(22 reference statements)

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“…Central core disease is characterized by oxidative histological staining that reveals centralized absence of mitochondria and non-stained areas named “cores,” which are evident on muscle biopsy and can span the length of an entire muscle fiber ( 15 ). Genetically, CCD often occurs due to dominant or de novo RYR1 variants although recessive cases have been reported ( 16 , 17 ). Furthermore, CCD is considered allelic to malignant hyperthermia (MH) susceptibility (MIM# 145600), a potentially fatal pharmacogenetic condition which typically manifests following exposure of predisposed individuals to certain volatile anesthetics and muscle relaxants, including halothane and succinylcholine, respectively.…”

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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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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“…Biopsy findings typically revealed predominance of type I fibers in all patients; of these, 5 patients (including patient 6) had exclusively type I fibers. This result suggests that the exclusive presence or predominance of type I fibers is a characteristic pathologic finding in CCD patients and is closely associated with a C‐terminal RYR1 mutation . Skeletal muscle fiber type formation is thought to be regulated by neural control and the following intracellular signal transduction, including Ca 2+ release that leads to transcriptional activation of fiber‐type–specific genes .…”

Section: Discussionmentioning

confidence: 99%

“…To date, 3 genes have been associated with core myopathies (including CCD and multi‐minicore disease): selenoprotein N1 ( SEPN1 ; 1p35, OMIM # 606210); myosin heavy chain 7 ( MYH7 ; 14q11.2, OMIM # 160760); and ryanodine receptor 1 ( RYR1 ; 19q13.1, OMIM # 180901) . Mutations in RYR1 are associated with > 90% of cases of CCD and malignant hyperthermia susceptibility (MH; MIM # 145600) .…”

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confidence: 99%

Next generation sequencing reveals ryanodine receptor 1 mutations in a Chinese central core disease cohort

Zhao

et al. 2016

Muscle and Nerve

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“…MH susceptibility (MHS) is usually associated with mutations in RYR1 , which encodes the Ca 2+ release channel of the sarcoplasmic reticulum (SR). 4 , 5 Mutations in the CACNA1S 4 and Stac3 genes 6 , 7 are also associated with MHS. 8 , 9 , 10 …”

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confidence: 99%

Abnormal calcium signalling and the caffeine–halothane contracture test

Figueroa

Kraeva

Manno

et al. 2019

British Journal of Anaesthesia

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BackgroundThe variable clinical presentation of malignant hyperthermia (MH), a disorder of calcium signalling, hinders its diagnosis and management. Diagnosis relies on the caffeine–halothane contracture test, measuring contraction forces upon exposure of muscle to caffeine or halothane (FC and FH, respectively). Patients with above-threshold FC or FH are diagnosed as MH susceptible. Many patients test positive to halothane only (termed ‘HH’). Our objective was to determine the characteristics of these HH patients, including their clinical symptoms and features of cytosolic Ca2+ signalling related to excitation–contraction coupling in myotubes.MethodsAfter institutional ethics committee approval, recruited patients undergoing contracture testing at Toronto's MH centre were assigned to three groups: HH, doubly positive (HS), and negative patients (HN). A clinical index was assembled from musculoskeletal symptoms and signs. An analogous calcium index summarised four measures in cultured myotubes: resting [Ca2+]cytosol, frequency of spontaneous cytosolic Ca2+ events, Ca2+ waves, and cell-wide Ca2+ spikes after electrical stimulation.ResultsThe highest values of both indexes were found in the HH group; the differences in calcium index between HH and the other groups were statistically significant. The principal component analysis confirmed the unique cell-level features of the HH group, and identified elevated resting [Ca2+]cytosol and spontaneous event frequency as the defining HH characteristics.ConclusionsThese findings suggest that HH pathogenesis stems from excess Ca2+ leak through sarcoplasmic reticulum channels. This identifies HH as a separate diagnostic group and opens their condition to treatment based on understanding of pathophysiological mechanisms.

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Clinical utility gene card for: Central core disease

Cited by 5 publications

References 36 publications

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

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

Next generation sequencing reveals ryanodine receptor 1 mutations in a Chinese central core disease cohort

Abnormal calcium signalling and the caffeine–halothane contracture test

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