Central core disease due to recessive mutations in <i>RYR1</i> gene: Is it more common than described?

Kossugue, Patrícia M.; Paim, Júlia Filardi; Navarro, Monica M.; Silva, Helga Cristina Almeida da; Pavanello, Rita de Cássia M.; Gurgel-Giannetti, Juliana; Zatz, Mayana; Vainzof, Mariz

doi:10.1002/mus.20715

Cited by 48 publications

(20 citation statements)

References 21 publications

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“…Although the patient's father is an asymptomatic carrier of the same mutation, we cannot completely exclude its pathologic role, because high inter-and intra-familiar phenotype variability, ranging from asymptomatic to severely affected individuals, has been described with other mutations in this disease. 13 Epigenetic allele silencing of the RYR1 gene due to imprinting could also provide an explanation for our case.…”

Section: Discussionmentioning

confidence: 76%

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Rocha

Taipa

Pires

et al. 2014

Pediatric Neurology

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BACKGROUND: Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized. PATIENTS: Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic. CONCLUSIONS: These patients illustrate early-onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate.

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Section: Discussionmentioning

confidence: 76%

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Rocha

Taipa

Pires

et al. 2014

Pediatric Neurology

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“…In the past, MH was believed as being exclusive to Caucasians, which has proven to be incorrect with the description of MH episode in BLACKS, Orientals, and Indians [15][16][17] . In Brazil, the initial impression that the MH genetic trait would be concentrated in European descendants in the south has also been disproved by genetic studies, such as the description of a patient from Minas Gerais who was compound heterozygous (i.e., an individual with two different mutations in their ryanodine receptor, each inherited from one of the non-consanguineous parents) 18 . This fi nding from the work of Kossugue et al 18 conforms the estimated frequency of the ryanodine gene mutation in ryanodine carriers, which could reach up to 1:2000 19 .…”

Section: Discussionmentioning

confidence: 99%

“…In Brazil, the initial impression that the MH genetic trait would be concentrated in European descendants in the south has also been disproved by genetic studies, such as the description of a patient from Minas Gerais who was compound heterozygous (i.e., an individual with two different mutations in their ryanodine receptor, each inherited from one of the non-consanguineous parents) 18 . This fi nding from the work of Kossugue et al 18 conforms the estimated frequency of the ryanodine gene mutation in ryanodine carriers, which could reach up to 1:2000 19 . This prevalence would be much higher than the estimated rate for MH episode -explained by the fact that many mutation carriers are never anesthetized with triggering drugs and, even if exposed, they may not develop a MH episode, as occurred in patient 2 of this report 20 .…”

Section: Discussionmentioning

confidence: 99%

Hipertermia maligna no Brasil: análise da atividade do hotline em 2009

Silva¹,

Almeida²,

Brandão³

et al. 2013

Rev. Bras. Anestesiol.

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Background and objectives: Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in São Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009. Methods: Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009. Results: Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In fi ve episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isofl urane; 3, sevofl urane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the fi ve MH episodes were tachycardia

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“…Thus far, more than 200 sequence variants have been identified in the RYR1 gene [Anderson et al, 2008;von der Hagen et al, 2008;Monnier et al, 2008;Sato et al, 2008;Kossugue et al, 2007;Lyfenko et al, 2007;Rossi et al, 2007;Zhou et al, 2007Zhou et al, , 2006Robinson et al, 2006;Wu et al, 2006]. Identification of novel RYR1 variants and their functional characterization help shed light on the molecular bases of the distinct pathophysiological characteristics of each disorderP P(drug-dependent hyperactivity in MH versus muscle weakness and core development in CCD and minicores in MmDP P [Treves et al, 2008]), and are an aid to the diagnosis of MH.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes

et al. 2009

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Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi-minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4-chloro-mcresol (4-CmC) and the rate of extracellular acidification was recorded. We demonstrate that the increased acidification rate of lymphoblastoid cells in response to 4-CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N-terminal and in the central region of the protein (p.Arg530His, p.Arg2163Pro, p.Asn2342Ser, p.Glu2371Gly and p.Arg2454His) displayed higher activity compared with controls; this could account for the MH-susceptible phenotype. Cell lines harboring RYR1P Cys4664Arg P were significantly less activated by 4-CmC. This result indicates that the p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease-causing alterations and the acidification rate measurements as a means to monitor CaP 2+ P-induced metabolic changes in cells harboring mutant RYR1 channels.

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Central core disease due to recessive mutations in RYR1 gene: Is it more common than described?

Cited by 48 publications

References 21 publications

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Hipertermia maligna no Brasil: análise da atividade do hotline em 2009

Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes

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