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Original Investigation | Ophthalmic Molecular Genetics

RYR1 Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Sherin Shaaban, MD, PhD1,2,3,4,5; Leigh Ramos-Platt, MD6; Floyd H. Gilles, MD7; Wai-Man Chan, MS1,3,8; Caroline Andrews, MS1,2,8; Umberto De Girolami, MD9,10,11; Joseph Demer, MD, PhD12,13,14,15; Elizabeth C. Engle, MD1,2,3,4,8,16,17,18,19,20
[+] Author Affiliations
1Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts
2F. B. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, Massachusetts
3Program in Genomics, Boston Children’s Hospital, Boston, Massachusetts
4Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Massachusetts
5Dubai Harvard Foundation for Medical Research, Boston, Massachusetts
6Division of Pediatric Neurology, Children’s Hospital Los Angeles, Los Angeles, California
7Division of Pathology (Neuropathology), Children’s Hospital Los Angeles, Los Angeles, California
8Howard Hughes Medical Institute, Chevy Chase, Maryland
9Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts
10Department of Pathology, Harvard Medical School, Boston, Massachusetts
11Division of Neuropathology, Brigham and Women’s Hospital, Boston, Massachusetts
12Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles
13Department of Neurology, Jules Stein Eye Institute, University of California, Los Angeles
14Department of Bioengineering, Jules Stein Eye Institute, University of California, Los Angeles
15Neuroscience Interdepartmental Programs, Jules Stein Eye Institute, University of California, Los Angeles
16Department of Medicine (Genetics), Boston Children’s Hospital, Boston, Massachusetts
17Department of Ophthalmology, Boston Children’s Hospital, Boston, Massachusetts
18Department of Neurology, Harvard Medical School, Boston, Massachusetts
19Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
20Broad Institute of MIT and Harvard, Cambridge, Massachusetts
JAMA Ophthalmol. 2013;131(12):1532-1540. doi:10.1001/jamaophthalmol.2013.4392.
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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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Figure 1.
Pedigree Structures of OH and DR

Schematic of pedigrees OH (A) and DR (B). Genotypes of RYR1 variants c.2966A>G and c.11314C>T in pedigree OH and variants c.848A>G and c.11314C>T in pedigree DR are shown under genotyped family members; black schematic haplotype bars denote wild-type sequence, while red schematic haplotype bars denote mutant sequence. Note that the clinically unaffected parents in pedigree OH each harbor the same 2 RYR1 mutations on 1 allele (red) and have 1 wild-type allele (black). The clinically unaffected parents in pedigree DR each harbor a single, different RYR1 mutation on 1 allele (half red and half black) and have 1 wild-type allele (black). Individual DR I:1 harbors the identical c.11314C>T mutation as 1 of the 2 mutations carried by individuals OH II:4, III:1, and III:2. *Those enrolled in the study. Circles indicate females; filled symbols, affected individuals; and squares, males.

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Figure 2.
Homozygosity Mapping and Mutation Analysis

A, Schematic showing regions of shared homozygosity on chromosome 19 in pedigree OH created by genotypes from individuals III:1, III:2, II:4, IV:1, III:4, and III:6 by dChip software.22 Red or blue denotes homozygous AA or BB, yellow denotes heterozygous AB, and white denotes absent call. The homozygous region shared by the 3 affected children and no parent is bordered by single-nucleotide markers rs725985 and rs883433. B, Sanger sequencing chromatograms from an unrelated control individual (top), unaffected parent (middle), and affected child (bottom) of pedigree OH. The parent is heterozygous and the affected children are homozygous for RYR1 c.2966A>G (left) and RYR1 c.11314C>T (right) nucleotide substitutions. The wild-type and predicted amino acid substitutions are provided below each sequence. Asterisks indicate the bases where the mutation occurred. C, Sanger sequencing chromatograms from an unaffected father (top), unaffected mother (middle), and affected child (bottom) of pedigree DR. The father has a wild-type sequence at RYR1 c.848 and a heterozygous RYR1 11314C>T nucleotide substitution, and the mother has a heterozygous RYR1 848A>G nucleotide substitution and is wild-type at RYR1 c.11314. The affected child is heterozygous at both nucleotides. The wild-type and predicted amino acid substitutions are provided below each sequence. D, Evolutionary conservation of RYR1 glutamic acid 989, histidine 283, and arginine 3772 residues in 8 species. B taurus indicates Bos taurus; G gallus, Gallus gallus; H sapiens, homo sapiens; M musculus, Mus musculus; M nigra, Macaca nigra; O cuniculus, Oryctolagus cuniculus; R norvegicus, Rattus norvegicus; and S scrofa, Sus scrofa.

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Figure 3.
Quasicoronal Magnetic Resonance Imaging of the Right Orbit of Individual DRII:2

Note severe hypoplasia of the lateral (lat) and medial (med) rectus muscles, moderate hypoplasia of the superior (sup) and inferior obliques, and apparent sparing of the inferior rectus. There is central high-intensity material seen within muscles suggestive of fat deposition (red arrowheads). Nerves to the extraocular muscles (EOM) appear hypoplastic, while the optic nerve, superior orbital vein (Sup orb vein), and intracoronal fat appear normal. IO indicates inferior oblique; LLA, lateral levator aponeurosis; n, nerve; obl, oblique; SO, superior oblique; and tndn, tendon.

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Figure 4.
Morphological Findings of Quadriceps Muscle Biopsy Sections From Affected Individual OH IV:1

A, Hematoxylin-eosin stain showing variability of fiber sizes with increased endomysial connective tissue and some internalized nuclei (original magnification ×20). B, Myosin adenosine triphosphatase 9.4 stain demonstrating fibers of variable sizes with small type I (light) and II (dark) fibers (original magnification ×10). C and D, Electron micrographs show focal accumulation of mitochondria accompanied by glycogen and lipid droplets (C) (original magnification ×4000), with some fibers showing an internalized nucleus (D) (original magnification ×2500).

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