Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.
Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.
复制标题
DOI：
10.1093/brain/awx231
复制
发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Houlden H
中科院分区：
文献类型：
--
作者：
Manole A;Jaunmuktane Z;Hargreaves I;Ludtmann MHR;Salpietro V;Bello OD;Pope S;Pandraud A;Horga A;Scalco RS;Li A;Ashokkumar B;Lourenço CM;Heales S;Horvath R;Chinnery PF;Toro C;Singleton AB;Jacques TS;Abramov AY;Muntoni F;Hanna MG;Reilly MM;Revesz T;Kullmann DM;Jepson JEC;Houlden H
核黄素代谢产物是线粒体电子传递链的重要组成部分。Manole等人。描述核黄素反应性神经病的大量患者的遗传学、表型和神经病理学。利用体外和体内模型，他们揭示了这种疾病中的线粒体功能障碍，并验证了核黄素酯作为一种潜在的治疗策略。Brown-Vialetto-Van Laere综合征是一种运动神经、感觉神经和脑神经病变的表型谱，通常伴有共济失调、视神经萎缩和导致呼吸机依赖的呼吸问题。两个核黄素转运蛋白基因SLC52A2和SLC52A3的功能丧失突变最近被认为与Brown-Vialetto-Van Laere综合征有关。然而，核黄素转运体突变的遗传频率、神经病理学和下游后果尚不清楚。通过对132例早发性重症感觉神经病、运动神经病和脑神经病患者的筛查，我们证实了核黄素转运蛋白突变与Brown-Vialetto-Van Laere综合征之间的遗传联系，鉴定了SLC52A2和SLC52A3的22个致病突变，其中14个是新发现的。2例SLC52A3基因突变患者的脑和脊髓神经病理检查显示典型的对称性脑干病变，类似于线粒体疾病的病理，包括下脑神经核团、前角和相应神经的严重神经元丢失，脊髓丘脑和脊髓小脑束以及后柱-内侧丘疹通路的萎缩。线粒体功能障碍此前已被认为与一系列神经退行性疾病有关。由于核黄素代谢物是线粒体电子传输链的关键组成部分，我们假设核黄素运输减少会导致线粒体活性受损，并使用体外和体内模型证实了这一点。SLC52A2患者成纤维细胞中电子传递链复合体I和复合体II活性降低，而全局敲除单个果蝇核黄素转运体同源物显示核黄素水平、下游代谢物和电子传递链复合体I活性降低。这进而导致线粒体膜电位、呼吸链活性和形态的异常。果蝇核黄素转运体基因敲除也导致运动活动严重受损和寿命缩短，这反映了患者的病理，而这些表型可以用一种新的核黄素酯化衍生物部分挽救。我们的发现扩大了Brown-Vialetto-Van Laere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体基因缺陷的下游后果，并验证了核黄素酯作为一种潜在的治疗策略。
Riboflavin metabolites are critical components of the mitochondrial electron transport chain. Manole et al. describe the genetics, phenotypes and neuropathology of a large patient series with riboflavin-responsive neuropathy. Using in-vitro and in-vivo models, they reveal mitochondrial dysfunction in the disorder, and validate riboflavin esters as a potential therapeutic strategy. 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.
登录
查看更多内容
DOI：
10.1093/brain/awt315
发表时间：
2014-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Foley AR;Menezes MP;Pandraud A;Gonzalez MA;Al-Odaib A;Abrams AJ;Sugano K;Yonezawa A;Manzur AY;Burns J;Hughes I;McCullagh BG;Jungbluth H;Lim MJ;Lin JP;Megarbane A;Urtizberea JA;Shah AH;Antony J;Webster R;Broomfield A;Ng J;Mathew AA;O'Byrne JJ;Forman E;Scoto M;Prasad M;O'Brien K;Olpin S;Oppenheim M;Hargreaves I;Land JM;Wang MX;Carpenter K;Horvath R;Straub V;Lek M;Gold W;Farrell MO;Brandner S;Phadke R;Matsubara K;McGarvey ML;Scherer SS;Baxter PS;King MD;Clayton P;Rahman S;Reilly MM;Ouvrier RA;Christodoulou J;Züchner S;Muntoni F;Houlden H
通讯作者：
Houlden H
影响因子：
3.5
作者：
Magrane, Jordi;Cortez, Czrina;Manfredi, Giovanni
通讯作者：
Manfredi, Giovanni
影响因子：
4.2
作者：
Bosch, Annet M.;Abeling, Nico G. G. M.;Waterham, Hans R.
通讯作者：
Waterham, Hans R.
影响因子：
3.9
作者：
Ho, Gladys;Yonezawa, Atsushi;Christodoulou, John
通讯作者：
Christodoulou, John
影响因子：
4.7
作者：
Höglinger, GU;Carrard, G;Hirsch, EC
通讯作者：
Hirsch, EC