Multiminicore Disease in a Family Susceptible to Malignant Hyperthermia

Guis, Sandrine; Figarella‐Branger, Dominique; Monnier, Nicole; Bendahan, David; Kozak‐Ribbens, G.; Mattei, Jean‐Pierre; Lunardi, Joël; Cozzone, Patrick J.; Pellissier, Jean‐François

doi:10.1001/archneur.61.1.106

Cited by 67 publications

(6 citation statements)

References 33 publications

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“…28 On the other hand, as in our report, it appears that when malignant hyperthermia-causing RYR1 mutations are associated with a second RYR1 mutation, the resulting phenotype can be more extensive. 37, 40, 43 Given these observations, the combination of the homozygous R3772W substitution with the novel homozygous E989G substitution in pedigree OH, or the combination of the heterozygous R3772W substitution with the heterozygous H283R substitution in pedigree DR, could explain the more extensive phenotypes seen in our patients. Moreover, the parents and other family members who harbor heterozygous mutations may, themselves, be at risk of malignant hyperthermia.…”

Section: Discussionmentioning

confidence: 71%

“…It is interesting that a similar observation was noted for the R3772Q substitution at the same residue: the heterozygous R3772Q substitution was reported to cause malignant hyperthermia, 38 while the homozygous or compound heterozygous R3772Q substitution was found to cause a more severe phenotype including ptosis, facial weakness, non-specific myopathy, and/or malignant hyperthermia. 37, 39, 40 …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Shaaban¹,

Ramos‐Platt²,

Gilles³

et al. 2013

JAMA Ophthalmol

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IMPORTANCE Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk of developing malignant hyperthermia. Ophthalmologists should be familiar with these important clinical associations.OBJECTIVE To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis, and mild hypotonia segregating in 2 pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles. DESIGN, SETTING, AND PARTICIPANTS Clinical data including medical and family histories were collected at research laboratories at Boston Children's Hospital and Jules Stein Eye Institute (Engle and Demer labs) for affected and unaffected family members from 2 pedigrees in which patients presented with total ophthalmoplegia, facial weakness, and myopathy.INTERVENTION Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed. MAIN OUTCOME AND MEASURE Mutations in RYR1.RESULTS Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a nonconsanguineous pedigree, respectively. Orbital magnetic resonance imaging revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsy specimens revealed nonspecific myopathic changes. Clinically, the patients' ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness and were accompanied by an unrecognized susceptibility to malignant hyperthermia.CONCLUSIONS AND RELEVANCE Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis. RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated presurgically.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Shaaban¹,

Ramos‐Platt²,

Gilles³

et al. 2013

JAMA Ophthalmol

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“…8026C > T (p.Arg2676Trp) (on two alleles)11YesNoPathogenicLikely pathogenicGillard [33]; Girard [34] for first mutationGuis (2004) [35] for second mutationc.2488C > T (p.Arg830Trp)c.10219G > A (p.Ala3407Thr) (on two alleles)11NoNoVUSVUSSnoeck [21]Molenaar [36]c.4178A > G (p.Lys1393Arg)c.14210G > A (p.Arg4737Gln) (on two alleles)11NoVUSLikely pathogenicDlamini [5]Monnier [37]; Gomez [38]c.4711A > G (p.Ile1571Val)c.10097G > A (p.Arg3366His)c.11798A > G (p.Tyr3933Cys) (on one allele)22NoVUSVUSVUSTammaro [39]; Kraeva [28]Duarte [40]; Kraeva [28]Gillies [41]; Kraeva [28]c.6385G > A (p.Asp2129Asn)11NoVUSDlamini [5]c.6502G > A (p.Val2168Met)11YesPathogenicManning [42]; Girard [34]c.6617C > T (p.Thr2206Met)11YesPathogenicManning [42]; Murayama [43]c.6838G > A (p.Val2280Ile)11NoLikely benignGalli [44]c.7025A > G (p.Asn2...…”

Section: Resultsmentioning

confidence: 99%

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

et al. 2019

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ObjectiveThe histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases.MethodsWe performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987–2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible.ResultsThrough the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants.ConclusionsPatients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.Electronic supplementary materialThe online version of this article (10.1007/s00415-019-09209-z) contains supplementary material, which is available to authorized users.

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“…Identifying MH susceptibility is very important for both MH probands and their relatives in preparing for future medical care. In particular, several hereditary myopathies that can predispose to MH susceptibility include central core disease, [4] multiminicore disease, [5] and King–Denborough syndrome [10] . Other myopathies associated with MH-like hypermetabolic reaction (anesthesia-induced rhabdomyolysis; AIR), which is not genuine MH, include DM1 and Duchenne and Becker muscular dystrophy [3,7] .…”

Section: Discussionmentioning

confidence: 99%

“…Several neuromuscular diseases strongly associated with MH susceptibility include central core disease, multiminicore myopathy, congenital myopathy with cores and rods, and centronuclear myopathy, all of which are linked to mutations in ryanodine receptor 1 (RYR1). [2][3][4][5] Myotonic dystrophy type I (dystrophia myotonia type 1, DM1; Steinert disease) is a slowly progressive hereditary muscular disorder characterized by weakness and wasting of involved muscles, usually of the cranial musculature including facial, sternocleidomastoid (SCM), and distal limb muscles. Several studies suggest that the risk of MH is not high in DM1 patients, although the evidence is limited to only a few case reports.…”

Section: Introductionmentioning

confidence: 99%

A case report of malignant hyperthermia in a patient with myotonic dystrophy type I

et al. 2021

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Rationale: Several hereditary myopathies that can predispose to malignant hyperthermia (MH) are reported. However, the risk of MH in myotonic dystrophy type I (DM1) has been suggested equal to general population, although the evidence is limited to only a few case reports. Patient concerns: We encountered a rare case of MH during anesthesia induction with sevoflurane in a male adolescent with previously undiagnosed DM1. Diagnoses: After the event, genetic testing revealed the presence of a previously unknown heterozygous missense mutation in ryanodine receptor 1 ( RYR1 ) associated with MH (c.6898T > C; p.ser2300Pro). Concomitantly, the patient was diagnosed with DM1 with abnormal cytosine-thymine-guanine triplet expansion in the DMPK gene. Interventions: Dantrolene was administered to treat the hypermetabolic manifestations in 20 minutes after the identification of MH. Outcomes: The patient was successfully treated and discharged without any complications. Laboratory abnormalities were recovered to baseline at postoperative 4 days. Lessons: The authors suggest that possible MH susceptibility in DM1 patients may be refocused. Genetic testing can be a screening tool for MH susceptibility in these population, prior to receiving general anesthesia.

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Multiminicore Disease in a Family Susceptible to Malignant Hyperthermia

Cited by 67 publications

References 33 publications

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

A case report of malignant hyperthermia in a patient with myotonic dystrophy type I

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