Concerning “Genetic defects of thiamine transport and metabolism: a review of clinical phenotypes, genetics and functional studies” by Marcé‐Grau et al

Abstract

Dear editors, The clinical disorders that have been linked with genetic defects of thiamine transport and metabolism are often not well-recognized in clinical practice, either in primary or secondary care, thus the well-planned review on this topic by Marcé-Grau and colleagues appears timely and appropriate. However, the statements “In humans, thiamine half-life is 9 to 18 days” and “Thiamine deficiency can develop within 2 to 3 months from a deficient intake” are incorrect and these should be further clarified. About 20 days is the sufficient time to deplete the body s reserves of thiamine. Thus, in a healthy individual, any condition of unbalanced nutrition that last 2 to 3 weeks may lead to severe thiamine deficiency and to the subacute appearance of serious, treatable diseases such as Wernicke s encephalopathy, peripheral neuropathy, and specific cardiovascular disturbances. The half-life of thiamine after intravenous administration is 96 minutes, while its elimination half-life after oral administration is 154 minutes. This short half-life explains the need of administering thiamine three times per day for patients with severe thiamine deficiency in whom a rapid replenishment of this vitamin is needed. This is mandatory when thiamine is administered by mouth, because most absorption of this vitamin takes place primarily in the proximal part of the small intestine by means of a dual mechanisms one saturable at low (physiological) concentrations, and another diffusive at higher concentrations. In healthy individuals, the calculated maximum amount of thiamine that can be absorbed from a single oral dose is about 4.5 mg. Of note, this amount can be reduced by about 70% in individuals with chronic malnutrition and in individuals with genetic defects of thiamine transport and metabolism. Moreover, the discussion on the possible late occurrence of thiamine metabolism dysfunction syndrome 2 (biotinor thiamine-responsive encephalopathy type) (OMIM 607483) was almost completely overlooked in the Review by MarcéGrau and colleagues. Recently, we reported the occurrence of late-onset subacute encephalopathy in a previously healthy young adult of Italian origin, with thiamine transporter 2 (THTR2) gene mutations. This has not been discussed in the Review. A 21-year-old woman presented with coma after 5 days of fever, gait ataxia, and somnolence. Initial brain magnetic resonance imaging (MRI) showed (T2-weighted images) symmetrical high signal intensities in the bilateral paramedian thalami, caudate heads, and in the periaqueductal gray matter. Hyperlactatemia was present; serum thiamine levels were normal. Thiamine intramuscular 600 mg daily in three doses led to complete recovery within few days. Follow-up MRIs showed near-complete resolution of the lesions after 35 days of thiamine treatment. Sequencing analysis of THTR2 gene revealed a base deletion, at homozygote state, in intron 3 in position c.980-4 upstream at donor/acceptor site of exon 4, predicted by computational algorithms to be deleterious. In previous healthy young adults with THTR2 dysfunction, fever may trigger a subacute encephalopathy with peculiar brain MRI findings that is promptly responsive to adequate doses of parenteral thiamine.