Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.
Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.
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DOI：
10.1093/brain/awt315
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Houlden H
中科院分区：
文献类型：
--
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
儿童期发作的运动神经元疾病或神经元病是一组临床异质性疾病。1894年首次描述了一个特别严重的亚组，随后称为Brown-Vialetto-货车-Van Laere综合征，其特征是进行性脑桥延髓麻痹、感觉神经性听力损失和呼吸功能不全。这种进行性神经退行性疾病没有治疗方法，它会导致呼吸衰竭，通常在儿童时期死亡。我们最近报告了编码核黄素转运蛋白RFVT 2的SLC 52 A2的鉴定，作为Brown-Vialetto-Van Laere综合征的新致病基因。货车。我们同时使用外显子组和桑格测序来鉴定有或没有呼吸功能不全的颅神经病和感觉运动神经病患者的SLC 52 A2突变。我们对SLC 52 A2突变患者进行了临床、神经生理学和生物化学表征，对最常见的突变进行了功能分析，并开始了高剂量口服核黄素的治疗方案。我们从13个家族中发现了18例SLC 52 A2复合杂合或纯合突变的患者。受影响的个体共有快速进行性轴突感觉运动神经病的核心表型（表现为感觉共济失调、上肢和轴肌严重无力，下肢明显保留力量）、听力丧失、视神经萎缩和呼吸功能不全。我们证明了SLC 52 A2突变导致核黄素摄取减少和核黄素转运蛋白表达减少，我们报告了SLC 52 A2突变患者对高剂量口服核黄素治疗的反应，包括2例患者的显著和持续的临床和生化改善，13例患者的初步临床反应数据，10例患者的相关生化改善。这个SLC 52 A2特异性队列的临床和生化反应表明，核黄素补充剂可以改善这种神经退行性疾病的进展，特别是在症状发作后不久开始时。
Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.
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影响因子：
4.2
作者：
Haack, Tobias B.;Makowski, Christine;Yao, Yoshiaki;Graf, Elisabeth;Hempel, Maja;Wieland, Thomas;Tauer, Ulrike;Ahting, Uwe;Mayr, Johannes A.;Freisinger, Peter;Yoshimatsu, Hiroki;Inui, Ken;Strom, Tim M.;Meitinger, Thomas;Yonezawa, Atsushi;Prokisch, Holger
通讯作者：
Prokisch, Holger
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：
--
作者：
BRUCHER, JM;DOM, R;CARTON, H
通讯作者：
CARTON, H
影响因子：
2.8
作者：
Ciccolella, Marianna;Catteruccia, Michela;Bertini, Enrico
通讯作者：
Bertini, Enrico
影响因子：
3.9
作者：
Ho, Gladys;Yonezawa, Atsushi;Christodoulou, John
通讯作者：
Christodoulou, John