Department of Neurology, Boston Children's Hospital, Boston, Massachusetts2F. B. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts3Program in Genomics, Boston Children's Hospital, Boston, Massachusetts4Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts5Dubai Harvard Foundation for Medical Research, Boston, Massachusetts.
Division of Pediatric Neurology, Children's Hospital Los Angeles, Los Angeles, California.
JAMA Ophthalmol. 2013 Dec;131(12):1532-40. doi: 10.1001/jamaophthalmol.2013.4392.
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.
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.
Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed.
Mutations in RYR1.
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.
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.
Ryanodine 受体 1（RYR1）突变可导致完全眼肌麻痹，而无明显相关的骨骼肌病。携带 RYR1 突变的患者发生恶性高热的风险很高。眼科医生应熟悉这些重要的临床关联。
确定 2 个具有非典型 Moebius 综合征或先天性眼外肌纤维化的常染色体隐性遗传家系中先天性上睑下垂、眼肌麻痹、面瘫和轻度肌无力的遗传原因。
设计、地点和参与者：在波士顿儿童医院和 Jules Stein 眼科研究所（Engle 和 Demer 实验室）的研究实验室，对来自 2 个家系的受影响和未受影响的家庭成员进行了临床数据收集，包括病史和家族史。这些患者表现为完全眼肌麻痹、面肌无力和肌病。
对受影响的家庭成员进行了纯合子作图和全外显子组测序，以确定致病突变。回顾病史、体格检查和临床数据。
RYR1 突变。
在一个近亲婚配的家系和一个非近亲婚配的家系中，分别发现了导致 2 个纯合 RYR1 氨基酸替换（E989G 和 R3772W）和 2 个复合杂合 RYR1 替换（H283R 和 R3772W）的错义突变。眼眶磁共振成像显示眼外肌和眶内颅神经明显发育不良。骨骼肌活检显示非特异性肌病改变。临床上，患者的眼肌麻痹和面肌无力远比他们的肌无力和四肢无力更为显著，并伴有未被认识到的恶性高热易感性。
患有严重先天性眼肌麻痹和面瘫的患儿，其骨骼肌肉病较轻，携带编码 Ryanodine 受体 1 的 RYR1 隐性突变，易患恶性高热。虽然眼肌麻痹在 RYR1 相关肌病中很少见，但这些儿童是非典型的，因为他们没有明显的无力、呼吸功能不全或脊柱侧凸。在先天性眼肌麻痹和面瘫的鉴别诊断中应考虑 RYR1 相关肌病，即使没有临床骨骼肌肉病。这些患者也应被认为易患恶性高热，这是一种可避免的危及生命的麻醉并发症，如果术前预测到，可以避免。
