Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

J Inherit Metab Dis. 2019 Jul;42(4):581-597. doi: 10.1002/jimd.12125. Epub 2019 Jun 24.

Abstract

Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free-thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free-thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.

Keywords: Leigh syndrome; Rogers syndrome; SLC19A2; SLC19A3; SLC25A19; TPK1; thiamine; thiamine responsive megaloblastic anemia; thiamine transporter 2 deficiency.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anemia, Megaloblastic
  • Biological Transport
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Diabetes Mellitus
  • Hearing Loss, Sensorineural
  • Humans
  • Leigh Disease
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mutation
  • Phenotype
  • Thiamine / cerebrospinal fluid
  • Thiamine / metabolism*
  • Thiamine / therapeutic use
  • Thiamine Deficiency / congenital
  • Thiamine Deficiency / drug therapy
  • Thiamine Deficiency / genetics*
  • Thiamine Pyrophosphate / metabolism

Substances

  • Biomarkers
  • Membrane Transport Proteins
  • SLC19A3 protein, human
  • Thiamine Pyrophosphate
  • Thiamine

Supplementary concepts

  • Thiamine responsive megaloblastic anemia syndrome