Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

中文翻译：

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核黄素反应性神经病的临床，病理和功能表征

Brown-Vialetto-Van Laere综合征代表运动，感觉和颅神经神经病的表型谱，通常伴有共济失调，视神经萎缩和呼吸问题，导致呼吸机依赖。最近，两个核黄素转运蛋白基因SLC52A2和SLC52A3的功能丧失突变与布朗-维亚莱托-范莱尔综合征相关。然而，核黄素转运蛋白突变的遗传频率，神经病理学和下游后果尚不清楚。通过筛查一大批132例早期发作的严重感觉，运动和颅神经神经病患者，我们证实了核黄素转运蛋白突变与Brown-Vialetto-Van Laere综合征之间有很强的遗传联系，确定了SLC52A2和SLC52A2中的22个致病突变。SLC52A3，其中14个是新颖的。对2例SLC52A3突变的脑和脊髓神经病理学检查显示出类似于线粒体疾病的经典对称性脑干病变，包括下颅神经核，前角和相应神经的严重神经元丢失，脊髓丘脑和小脑脊髓萎缩以及后方柱–内侧盘球菌途径。线粒体功能障碍以前曾与一系列神经退行性疾病有关。由于核黄素代谢产物是线粒体电子转运链的关键组成部分，我们假设核黄素转运减少会导致线粒体活性受损，并在体外和体外实验中证实了这一点。体内模型。在SLC52A2患者的成纤维细胞中，电子转运链复合物I和复合物II的活性降低，而单个果蝇果蝇核黄素转运蛋白同源物的整体敲低表明核黄素，下游代谢产物和电子转运链复合物I活性的水平降低。这进而导致线粒体膜电位，呼吸链活性和形态异常。果蝇中的核黄素转运蛋白敲低还导致运动能力严重受损和寿命缩短，这反映了患者的病理状况，这些表型可以使用核黄素的新型酯化衍生物部分挽救。我们的发现扩大了布朗-维亚莱托-范莱尔综合征的遗传，临床和神经病理学特征，暗示线粒体功能障碍是核黄素转运蛋白基因缺陷的下游结果，并证实核黄素酯是一种潜在的治疗策略。