Kraeva N, Heytens L, Jungbluth H, Treves S, Voermans N, Kamsteeg E, Ceuterick-de Groote C, Baets J, Riazi S
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Laboratory of Neurogenetics and Biobank, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; Laboratory of Ultrastructural Neuropathology and Biobank, Institute Born-Bunge (IBB), University of Antwerp, Antwerpen, Belgium; MH Research Unit, University of Antwerp, Antwerpen, Belgium.
Neuromuscul Disord. 2015 Jul;25(7):567-76. doi: 10.1016/j.nmd.2015.04.007. Epub 2015 Apr 27.
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.
恶性高热（MH）是一种潜在致命的药物遗传学肌病，由接触挥发性麻醉剂和/或去极化肌肉松弛剂引发。对MH的易感性主要与1型兰尼碱受体基因（RYR1）的显性突变相关。最近的基因研究表明，RYR1变异是显性和隐性先天性肌病——中央轴空病和多微小轴空病、先天性纤维类型不均、中央核肌病的最常见原因。然而，许多患者的MH状态，尤其是与隐性RYR1相关肌病患者的状态仍不确定。我们报告了在四个无亲缘关系的家庭中发现的一组RYR1变异三联体，即c.4711A>G（p.Ile1571Val）、c.10097G>A（p.Arg3366His）、c.11798A>G（p.Tyr3933Cys），这些家庭分别来自比利时、荷兰和加拿大。表型-基因型相关性分析表明，仅三联体等位基因的存在就赋予了对MH的易感性，并且该等位基因与MH相关的RYR1变异c.14545G>A（p.Val4849Ile）处于复合杂合状态时会导致MH易感性表型以及伴有轴空和杆状体的先天性肌病。我们的研究强调了这样一种观念，即确定单个RYR1变异或变异组合的致病性以及为RYR1相关肌病提供咨询可能需要整合临床、组织病理学、体外挛缩试验、MRI和基因检测结果。
