Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept

Sheila Riazi, M.Sc., M.D.; Natalia Kraeva, Ph.D.; Philip M. Hopkins, M.D., F.R.C.A.

Disclosures

Anesthesiology. 2018;128(1):168-180. 

In This Article

RYR1-related Disorders

In addition to MH, variants in RYR1 have been previously associated with several other skeletal muscle conditions and congenital myopathies, namely, central core disease, multiminicore disease, congenital myopathy with central or internalized nuclei, and congenital fiber-type disproportion.[14,15,70,71] To this list, King–Denborough syndrome,[72] benign Samaritan congenital myopathy,[73] heat/exercise-induced exertional rhabdomyolysis,[16,74] atypical periodic paralysis,[75] and statin myopathies[76,77] were recently added.

RYR1-related congenital myopathies show both dominant (central core disease) and recessive (multiminicore disease, centronuclear myopathy, and congenital fiber-type disproportion) modes of inheritance. Moreover, some RYR1 variants may act as dominant with regard to the MH phenotype but as recessive with regard to the congenital myopathy phenotype.[78,79]

These myopathies present a challenge for clinical molecular diagnosis due to their strong phenotypic and genetic heterogeneity. A recent study applied an integrated strategy combining whole exome sequencing with clinical and histopathologic investigations to reach an accurate diagnosis for several patients with congenital myopathies. Different sets of recessive RYR1 variants were found in four patients whose phenotypes ranged from a severe lethal neonatal myopathy to a mild adult-onset muscle weakness, underscoring the phenotypic variability of RYR1–related disorders.[80]

Next-generation sequencing panel-based analysis of neonatal hypotonia in a Chinese cohort found several RYR1 variants in this genetically heterogeneous condition, although in the majority of cases these were heterozygous changes involving variants for which a dominant pathogenic effect is not established.[81]

In another study, whole exome sequencing allowed identification of a de novo RYR1 variant in a patient who was originally diagnosed with limb girdle muscular dystrophy on the basis of clinical and histologic presentations: the histologic features were in fact myopathic rather than dystrophic, emphasizing the importance of establishing a genetic diagnosis to exclude an RYR1 etiology.[82]

The spectrum of RYR1-related diseases was expanded further to include a myasthenic-like component of muscle weakness with partial response to pyridostigimine: direct sequencing of the RYR1 gene in this case revealed compound heterozygous RYR1 variants: c.6721C>T (p.Arg2241X) nonsense variant and novel c.8888T>C (p.Leu2963Pro) missense variant.[83]

The role of RyR1 is not limited to skeletal muscle: a mouse model of central core disease, homozygous for a dominant RYR1 variant that causes a loss of function of the RyR1 channel, exhibited embryonic developmental delay and neonatal lethality with multisystem developmental defects, including atrial septal defect: it was hypothesized that RyR1 plays an important role in early cardiac development.[53] In favor of this hypothesis, exome sequencing revealed two rare, potentially deleterious missense RYR1 variants in a patient with atrioventricular septal defect who had no potentially pathogenic variants in other candidate genes.[84]

RYR1 variants have been previously associated with fetal akinesia.[70] Several recent studies used whole exome sequencing to expand the phenotypes associated with recessive RYR1 variants to include arthrogryposis multiplex congenital fetal akinesia,[85,86] and lethal multiple pterygium syndrome.[87] Lethal multiple pterygium syndrome is a fatal disorder associated with prenatal growth failure with pterygium present in multiple areas, akinesia, and severe arthrogryposis. Lethal multiple pterygium syndrome has been associated with variants in genes encoding components of the neuromuscular junction. Identification of RYR1 variants in fetuses affected by lethal multiple pterygium syndrome, together with variants in genes encoding proteins at the neuromuscular junction (CHRNA1, CHRND, CHRNG, and RAPSN), might indicate that lethal multiple pterygium syndrome is caused by defects in the excitation–contraction coupling mechanism.[87] Interestingly, lethal multiple pterygium syndrome in association with MH has been described before.[88]

Whole exome sequencing analysis revealed the first case of severe congenital myopathy with ophthalmoplegia caused by a variant in the CACNA1S gene,[89] pathogenic variants in which have been associated with hypokalemic periodic paralysis type 1.[90,91] The authors hypothesize that the p.Gln1265His variant results in disruption of coupling between dihydropyridine receptor and RyR1, causing CACNA1S-related myopathy. Interestingly, another patient from this study with similar myopathic symptoms was found to carry an in-frame insertion in RYR1.[92] The authors hypothesized that because this variant showed dominant inheritance, it likely had a dominant-negative effect on RyR1 tetramer formation and function.

Whole exome sequencing of patients presenting with severe congenital ophthalmoplegia and facial weakness in association with malignant hyperthermia revealed the presence of missense variants resulting in two homozygous RYR1 amino acid substitutions and two compound heterozygous RYR1 substitutions in a consanguineous and a nonconsanguineous pedigree, respectively.[93] Whereas ophthalmoplegia may occur in RYR1-related myopathies, these children were atypical because they lacked significant muscle weakness, respiratory insufficiency, or scoliosis. The common RYR1 variant in these cases, p.R3772Q, was previously reported to be associated with MH susceptibility in the heterozygous state and MH susceptibility with myopathy in the homozygous state.[79]

Another interesting case is of congenital ptosis, scoliosis, and MH susceptibility in siblings who are homozygous for the MH-pathogenic RYR1 variant, p.T2206M.[93] This variant in heterozygous carriers was previously reported in association with mild clinical and histopathologic features.[94] The last two studies emphasize the notion that RYR1-associated myopathies should be included in the differential diagnosis of congenital ptosis with scoliosis and of congenital ophthalmoplegia and facial weakness without scoliosis, especially because a risk of MH can be high in these patients.

This wide spectrum of clinicopathologic conditions reflects the distinct effects of different RYR1 variants on skeletal muscle Ca2+ homeostasis and excitation–contraction coupling.[95] Functional studies showed that different central core disease variants exhibited varying degrees of excitation–contraction uncoupling with impaired Ca2+ release. Certain dominant variants displayed dual functional characteristics accounting for both MH (hypersensitivity to voltage activation and to agonists) and myopathy (reduced sarcoplasmic reticulum Ca2+ content and voltage-gated Ca2+ release) phenotypes.[96] Additionally, some recessive RYR1 variants led to a reduction in RyR1 protein levels.[2,32]

Complexity of functional effects of RYR1 variants together with clinical overlap between different RYR1-related myopathies complicates MH susceptibility counseling in patients with RYR1-related myopathies. Certainly, patients with myopathies carrying MH–associated RYR1 variants, as well as potentially pathogenic variants of unknown significance, should avoid triggering anesthetics. However, patients carrying uncoupling, loss-of-function RYR1 variants may be considered as being at a low risk of developing MH. Counseling in RYR1-related myopathic patients as for MH susceptibility requires a combined approach, integrating clinical, histopathologic, in vitro contracture testing, magnetic resonance imaging, and genetic findings.[3]

RYR1 in Nonskeletal Muscle Cells

Lopez et al.[13] reported that some MH–susceptible patients, carrying specific gain-of-function RYR1 variants, give a history of mild bleeding abnormalities. They demonstrated that RyR1Y522S mice carrying the MH gain-of-function variant had abnormalities of vascular smooth muscle cell Ca2+ homeostasis consistent with a bleeding phenotype.[13] Indeed, although RyR1 is predominantly found in skeletal muscle, it is also present at lower levels in immune and smooth muscle cells. The study found that primary vascular smooth muscle cells from RyR1Y522S mice had an increased frequency of Ca2+ spark events and were significantly more hyperpolarized than those from wild-type mice. In contrast to skeletal muscle cells where gain-of-function RYR1 variants led to an increased sensitivity to activating stimuli and to sustained muscle contractions, primary vascular smooth muscle cells from RyR1Y522S mice showed a decreased Ca2+ influx through the dihydropyridine receptor and smooth muscle relaxation, causing prolonged rather than shorter bleeding times. Administration of the specific RyR1 antagonist dantrolene, which is clinically approved for the treatment of MH reactions, reversed the bleeding phenotype by decreasing spark activity in murine vascular smooth muscle cells. Thus, this study suggested that RYR1 variants may be responsible for certain cases of mild bleeding abnormalities. If the clinical findings of Lopez et al.[13] of prolonged bleeding in MH patients carrying RYR1 variants are confirmed, their animal studies offer a pathologic mechanism and indicate a potential therapeutic use of dantrolene for such cases.

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