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.