MitoLab Team, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France.
Unit of Molecular Neurogenetics, Istituto di Ricovero e Cura a Carattere Scientifico, Foundation of the Carlo Besta Neurological Institute, Milan, Italy.
JAMA Neurol. 2018 Jan 1;75(1):105-113. doi: 10.1001/jamaneurol.2017.2065.
Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies.
To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase.
DESIGN, SETTING, AND PARTICIPANTS: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016.
Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies.
Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation.
A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.
孤立症状或复杂综合征的神经紊乱在遗传性线粒体疾病中相对常见。已经表明，隐性 RTN4IP1 基因突变可导致孤立和综合征性视神经病变。
定义与编码线粒体醌氧化还原酶的 RTN4IP1 基因突变相关的临床表型谱。
设计、地点和参与者：本研究纳入了 11 个家庭的 12 名患有严重中枢神经系统疾病和视神经萎缩的个体。在昂热医院（法国）、米兰神经病学研究所（意大利）、巴黎想象研究所（法国）、慕尼黑赫尔姆霍茨中心（德国）和北京基因组研究所（中国）进行了靶向和全外显子组测序，以阐明患者的分子诊断。研究了每位患者的神经学、眼科、磁共振成像和生化特征。这项研究于 2014 年 5 月 1 日至 2016 年 6 月 30 日进行。
鉴定出 RTN4IP1 的隐性突变。临床表现范围从孤立性视神经萎缩到严重的脑病。
研究中的 12 名个体中，有 6 名（50%）为男性，6 名（50%）为女性。他们的年龄从 5 个月到 32 岁不等。在 11 个家庭中，有 6 个（其中 5 个是近亲结婚）有成员表现出孤立性视神经萎缩，其已报道的 p.Arg103His 或新的 p.Ile362Phe、p.Met43Ile 和 p.Tyr51Cys 氨基酸变化。另外 5 个家庭有成员表现出严重的神经系统综合征，具有共同的核心症状，包括视神经萎缩、癫痫发作、智力障碍、生长迟缓以及乳酸水平升高。受影响者的其他临床特征包括耳聋、大脑磁共振图像异常、喘鸣和异常脑电图模式，所有这些最终导致 3 岁前死亡。在这些患者中，发现了新的和非常罕见的纯合和复合杂合突变，导致蛋白质缺失和复合物 I 解体，以及线粒体网络轻度碎片化。
从孤立性视神经萎缩到严重的早发性脑病，一系列广泛的神经系统特征与 RTN4IP1 双等位基因突变相关，应提示在综合征性神经表现和非综合征性隐性视神经病变中进行 RTN4IP1 筛查。
