GENETICS

Mutations in RYR1 occur in at least 50% of susceptible subjects and almost all families with central core disease (CCD). More than 30 missense mutations^[24] and one deletion^[25] have been associated with a positive contracture test (CHCT or IVCT) result or clinical MH, or both. Genetic heterogeneity in MH is documented by five other loci (17q21-24, 1q32, 3q13, 7q21-24, and 5 p), designated as malignant hyperthermia susceptibility (MHS) 2 through 6, respectively. The only known gene other than RYR1 is the one coding for the α_1S -subunit of DHPR, CACNL1A3, in MHS3. Two causative mutations in this gene are linked to less than 1% of MHS families worldwide.^[26] For practical purposes, the RYR1 gene remains the target for genetic analysis.

Distribution of RYR1 Mutations

Multiple mutations that segregate with MHS are dispersed throughout the RYR1 gene, and many silent polymorphisms are present in the coding region.^[27] Some of these have been found in patients with CCD, and in others, the RYR1 mutation is associated with CCD and MH phenotypes ( Fig. 29-3 ). All reported mutations lead to an amino acid change or, in one case, a deletion, and all are putatively functional.^{[24] [25]} Until recently, it was thought that most RYR1 mutations were clustered between amino acid residues 35 and 614 (MH/CCD region 1) and amino acid residues 2163 and 2458 (MH/CCD region 2) in the myoplasmic foot region of the protein, but a third hotspot is in the carboxyl-terminal transmembrane loop of the receptor, where MHS/CCD region 3 mutations may cluster.^[28] The first mutation found in this region (Ile4898Thr) was identified in a large Mexican family with a severe and highly penetrant form of CCD, but no evidence of clinical MH was found despite exposure of 18 members to triggering anesthetics. Subsequently, 14 more mutations associated with CCD have been identified in this region, but many are private, found only in the index case and his or her family. However, mutations causing MH exist in this region. In one large Maori family, the mutation Thr4826Ile was found in five probands who experienced clinical episodes of MH and in 130 members diagnosed by IVCT.^[29]

Regional differences in the frequencies of common MHS mutations are observed across Europe. The G341R mutation ( Table 29-1 ) is present in about 6% of Irish, English, and French families but is rare in Northern Europe. The Arg614Cys mutation is more common in German families but less frequent in other European families. G2434R, the most prevalent mutation in the United Kingdom, accounting for 17.5% of MHS families, has a low frequency in continental Europe.^[26] Frequencies of RYR1 gene mutations detected in North Americans vary significantly from those found in Europe.^[25] The Arg614Cys and Val2168Met mutations, common in Germany and

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Figure 29-3 Ryanodine receptor 1 gene (RYR1) structure and mutational hot spots. Amino- and carboxyl-terminal domains are indicated as NH₂ and COOH, respectively. Myoplasmic and transmembrane domains are shown at the bottom and arrows indicate dihydropyridine receptor (DHPR) and calmodulin binding sites. Red boxes indicate mutational hot spots with amino acid numbers below. The ovals above represent mutations associated with malignant hyperthermia (gray), central core disease (black), or both (red). (Courtesy of N. Sambuughin, Barrow Neurological Institute, Phoenix, AZ.)

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