title: Treatment of genetic defects of thiamine transport and metabolism.
abstract: Thiamine is a key cofactor for energy metabolism in brain tissue. There are four major genetic defects (SLC19A2, SLC19A3, SLC25A19 and TPK1) involved in the metabolism and transport of thiamine through cellular and mitochondrial membranes. Neurological involvement predominates in three of them (SLC19A3, SCL25A19 and TPK1), whereas patients with SLC19A2 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.
  
  
  
  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. Expert commentary: Doses of thiamine vary according to the genetic defect: for SLC19A2, the usual dose is 25-200 mg/day (1-4 mg/kg per day), for SLC19A3, 10-40 mg/kg per day, and for TPK1, 30 mg/kg per day. Thiamine supplementation in SLC19A3-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 SLC19A-2, SLC19A3- and TPK1-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.
authors.affiliation: a Department of Child Neurology, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.|f Department of Child Neurology , Hospital General de Granollers , Barcelona , Spain.
authors.forename: Juan Darío
authors.initials: JD
authors.lastname: Ortigoza-Escobar
authors.affiliation: b Clinical Biochemistry, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.|e Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII , Madrid , Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Molero-Luis
authors.affiliation: c Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics , Hospital Clinic , Barcelona , Spain.|e Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII , Madrid , Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Arias
authors.affiliation: a Department of Child Neurology, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.|b Clinical Biochemistry, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martí-Sánchez
authors.affiliation: d Departamento de Biología Molecular , Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, IDIPAZ, Universidad Autónoma de Madrid , Madrid , Spain.|e Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII , Madrid , Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodriguez-Pombo
authors.affiliation: b Clinical Biochemistry, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.|e Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII , Madrid , Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.affiliation: a Department of Child Neurology, Hospital Sant Joan de Déu , University of Barcelona , Barcelona , Spain.|e Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII , Madrid , Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Dueñas
mesh_terms: D000749:Anemia, Megaloblastic; D001921:Brain / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins; D009154:Mutation; D013831:Thiamine / Q000235:genetics / Q000627:therapeutic use
chemical_list: D026901:Membrane Transport Proteins; D013831:Thiamine
keywords: Leigh syndrome; SCL25A19; SLC19A2; SLC19A3; SLC35F3; SLC44A4; TPK1; Wernicke encephalopathy; biotin; thiamine