Treatment of genetic defects of thiamine transport and metabolism

<b>Introduction</b>: Thiamine is a key cofactor for energy metabolism in brain tissue. There are four major genetic defects (<i>SLC19A2, SLC19A3, SLC25A19</i> and <i>TPK1</i>) involved in the metabolism and transport of thiamine through cellular and mitochondrial membranes. Neurological involvement predominates in three of them (<i>SLC19A3, SCL25A19</i> and <i>TPK1</i>), whereas patients with <i>SLC19A2</i> mutations mainly present extra-neurological features (e.g. diabetes mellitus, megaloblastic anaemia and sensori-neural hearing loss). These genetic defects may be amenable to therapeutic intervention with vitamins supplementation and hence, constitutes a main area of research. <b>Areas covered</b>: We conducted a literature review of all reported cases with these genetic defects, and focused our paper on treatment efficacy and safety, adverse effects, dosing and treatment monitoring. <b>Expert commentary</b>: Doses of thiamine vary according to the genetic defect: for <i>SLC19A2</i>, the usual dose is 25–200 mg/day (1–4 mg/kg per day), for <i>SLC19A3</i>, 10–40 mg/kg per day, and for <i>TPK1</i>, 30 mg/kg per day. Thiamine supplementation in <i>SLC19A3</i>-mutated patients restores CSF and intracellular thiamine levels, resulting in successful clinical benefits. In conclusion, evidence collected so far suggests that the administration of thiamine improves outcome in <i>SLC19A-2, SLC19A3-</i> and <i>TPK1</i>-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.**引言**：硫胺素（thiamine）是脑组织能量代谢的关键辅因子。目前已明确四种主要的遗传缺陷，分别涉及*SLC19A2*、*SLC19A3*、*SLC25A19*及*TPK1*基因，介导硫胺素经细胞膜与线粒体膜的代谢及转运过程。其中三种缺陷（*SLC19A3*、*SCL25A19*及*TPK1*）以神经系统受累为主要临床表现，而携带*SLC19A2*突变的患者则主要表现为神经系统外症状，例如糖尿病、巨幼细胞性贫血及感音神经性听力损失。此类遗传缺陷可通过维生素补充疗法实现干预，因此成为重要的研究方向。 **综述范围**：我们对所有已报道的此类遗传缺陷病例开展了文献综述，本文重点探讨了治疗的有效性与安全性、不良反应、给药剂量及治疗监测方案。 **专家评述**：硫胺素的给药剂量需根据遗传缺陷类型进行调整：针对*SLC19A2*缺陷，常规剂量为25~200 mg/日（1~4 mg/kg/日）；针对*SLC19A3*缺陷为10~40 mg/kg/日；针对*TPK1*缺陷为30 mg/kg/日。对携带*SLC19A3*突变的患者补充硫胺素，可恢复其脑脊液（cerebrospinal fluid, CSF）及细胞内硫胺素水平，从而获得良好的临床获益。综上所述，目前已有的研究证据表明，补充硫胺素可改善携带*SLC19A2*、*SLC19A3*及*TPK1*突变患者的预后，因此应将研究重点放在此类疾病的早期诊断上。