SLC19A3 deficiency, also called thiamine metabolism dysfunction syndrome-2 (THMD2; OMIM 607483), is an autosomal recessive neurodegenerative disorder caused by mutations in SLC19A3, the gene encoding thiamine transporter 2. To investigate the molecular mechanisms of neurodegeneration in SLC19A3 deficiency and whether administration of high-dose thiamine prevents neurodegeneration, we generated homozygous Slc19a3 E314Q knock-in (KI) mice harboring the mutation corresponding to the human SLC19A3 E320Q, which is associated with the severe form of THMD2. Homozygous KI mice and previously reported homozygous Slc19a3 knock-out (KO) mice fed a thiamine-restricted diet (thiamine: 0.60 mg/100 g food) died within 30 and 12 days, respectively, with dramatically decreased thiamine concentration in the blood and brain, acute neurodegeneration, and astrogliosis in the submedial nucleus of the thalamus and ventral anterior-lateral complex of the thalamus. These findings may bear some features of thiamine-deficient mice generated by pyrithiamine injection and a thiamine-deficient diet, suggesting that the primary cause of THMD2 could be thiamine pyrophosphate (TPP) deficiency. Next, we analyzed the therapeutic effects of high-dose thiamine treatment. When the diet was reverted to a conventional diet (thiamine: 1.71 mg/100 g food) after thiamine restriction, all homozygous KO mice died. In contrast, when the diet was changed to a high-thiamine diet (thiamine: 8.50 mg/100 g food) after thiamine restriction, more than half of homozygous KO mice survived, without progression of brain lesions. Unexpectedly, when the high-thiamine diet of recovered mice was reverted to a conventional diet, some homozygous KO mice died. These results showed that acute neurodegeneration caused by thiamine deficiency is preventable in most parts, and prompt high-dose thiamine administration is critical for the treatment of THMD2. However, reduction of thiamine should be performed carefully to prevent recurrence after recovery of the disease.
Suzuki, K., Yamada, K., Fukuhara, Y., Tsuji, A., Shibata, K., & Wakamatsu, N. (2017). High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice. PLoS ONE, 12(6). https://doi.org/10.1371/journal.pone.0180279