Thiamine, in the form of
thiamine pyrophosphate, is a cofactor for a number of
enzymes which play important roles in energy metabolism. Although dietary
thiamine deficiency states have long been recognised, it is only relatively recently that inherited defects in
thiamine uptake, activation and the attachment of the active cofactor to target
enzymes have been described, and the underlying genetic defects identified.
Thiamine is transported into cells by two carriers, THTR1 and THTR2, and deficiency of these results in
thiamine-responsive megaloblastic anaemia and
biotin-responsive basal ganglia disease respectively. Defective synthesis of
thiamine pyrophosphate has been found in a small number of patients with
episodic ataxia, delayed development and
dystonia, while impaired transport of
thiamine pyrophosphate into the mitochondrion is associated with
Amish lethal microcephaly in most cases. In addition to defects in
thiamine uptake and metabolism, patients with
pyruvate dehydrogenase deficiency and
maple syrup urine disease have been described who have a significant clinical and/or biochemical response to
thiamine supplementation. In these patients, an intrinsic structural defect in the target
enzymes reduces binding of the cofactor and this can be overcome at high concentrations. In most cases, the clinical and biochemical abnormalities in these conditions are relatively non-specific, and the range of recognised presentations is increasing rapidly at present as new patients are identified, often by genome sequencing. These conditions highlight the value of a trial of
thiamine supplementation in patients whose clinical presentation falls within the spectrum of documented cases.