Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
Department of Ophthalmology, University Duisburg-Essen, Essen, Germany.
J Neuromuscul Dis. 2024;11(2):485-491. doi: 10.3233/JND-230181.
The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS).
Here, we identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability.
To address the pathogenicity of the variant, biochemical studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed.
The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum.
Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6-associated phenotypes.
NADH 脱氢酶[泛醌]铁硫蛋白 6（NDUFS6）基因编码线粒体膜呼吸链 NADH 脱氢酶（复合物 I）的辅助亚基。双等位基因 NDUFS6 变体与一种严重疾病相关联，主要报道为致命性婴儿期线粒体疾病（LMID）或 Leigh 综合征（LS）。
在这里，我们在一名伴有轴索神经病的男性患者中发现了 NDUFS6 的纯合变异（c.309+5G>A），皮肤活检显示小纤维丧失，并进一步并发视神经萎缩和边缘智力障碍。
为了确定变异的致病性，对患者来源的白细胞进行了生化研究（mtDNA 拷贝数定量、ELISA、蛋白质组学分析）。
分析显示 NDUFS6 蛋白缺失，同时进一步的三个线粒体 NADH 脱氢酶亚基/组装蛋白（NDUFA12、NDUFS4 和 NDUFV1）减少。白细胞中线粒体拷贝数没有改变，血清中的线粒体生物标志物 GDF15 也没有明显变化。
因此，我们的临床和生化数据综合表明，NDUFS6 是导致伴有视神经萎缩和边缘智力障碍的非常罕见的轴索神经病的原因，从而扩展了（i）神经病的分子遗传图谱和（ii）NDUFS6 相关表型的临床谱。
