Lam Christina, Gallo Linda K, Dineen Richard, Ciccone Carla, Dorward Heidi, Hoganson George E, Wolfe Lynne, Gahl William A, Huizing Marjan
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Pediatrics, Edward Hospital, Naperville, Illinois, USA.
Mol Genet Metab Rep. 2014 Jan 1;1:114-123. doi: 10.1016/j.ymgmr.2014.02.003.
OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the gene located at 19q13.2-13.3. Here we describe two siblings with novel compound heterozygous variants in : c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.
OPA3相关的3-甲基戊二酸尿症，即科斯特夫视神经萎缩综合征，是一种神经眼科综合征，表现为早发性双侧视神经萎缩、迟发性痉挛和锥体外系功能障碍。尿中3-甲基戊二酸和3-甲基谷氨酸的排泄量显著增加。OPA3相关的3-甲基戊二酸尿症是由位于19q13.2 - 13.3的基因突变引起的。在此我们描述了两名携带该基因新型复合杂合变异的同胞：外显子1翻译起始密码子处的c.1A>G（p.1M>V）以及内含子1中的第二个变异c.142 + 5G>C。在cDNA测序中，c.1A>G呈现纯合状态，表明没有c.1A>G变异的等位基因被降解。这可能是由于内含子变异；可能是IVS1 + 5剪接位点变异。年长的女性同胞在出生后第一年最初表现为运动发育迟缓及垂直性眼球震颤，随后被诊断为视神经萎缩。她的弟弟在出生后6个月内出现轻度髋部肌张力增加，随后出现垂直性眼球震颤，到1.5岁时发现尿中3-甲基戊二酸和3-甲基谷氨酸排泄量升高以及视神经萎缩。目前，这两名儿童分别为16岁和7岁，均表现出共济失调步态和构音障碍。对患者细胞的免疫荧光研究显示线粒体形态破碎。因此，尽管OPA3的确切功能尚不清楚，但我们的实验结果和临床总结为所鉴定的OPA3变异的致病性提供了证据，并为该疾病的线粒体病理提供了进一步证据。
