Abstract |
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene ( RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.
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Authors | N Kraeva, L Heytens, H Jungbluth, S Treves, N Voermans, E Kamsteeg, C Ceuterick-de Groote, J Baets, S Riazi |
Journal | Neuromuscular disorders : NMD
(Neuromuscul Disord)
Vol. 25
Issue 7
Pg. 567-76
(Jul 2015)
ISSN: 1873-2364 [Electronic] England |
PMID | 25958340
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier B.V. All rights reserved. |
Chemical References |
- Ryanodine Receptor Calcium Release Channel
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Topics |
- Adult
- Child
- Child, Preschool
- Family
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genetic Variation
- Heterozygote
- Humans
- Leg
(pathology)
- Male
- Malignant Hyperthermia
(genetics, metabolism, pathology)
- Middle Aged
- Muscle, Skeletal
(metabolism, pathology)
- Myopathy, Central Core
(genetics, metabolism, pathology)
- Phenotype
- Ryanodine Receptor Calcium Release Channel
(genetics, metabolism)
- White People
(genetics)
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