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Original Investigation
Ophthalmic Molecular Genetics
December 2013

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

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
Abstract

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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