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Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a potentially treatable disorder caused by mutations in the SLC19A3 gene, encoding the human thiamine transporter 2. Manifestation of BTBGD as acute encephalopathy triggered by a febrile infection has been frequently reported, but the underlying mechanisms are not clear. We investigated a family with two brothers being compound heterozygous for the SLC19A3 mutations p.W94R and p.Q393*fs. Post-mortem analysis of the brain of one brother showed a mixture of acute, subacute and chronic changes with cystic and necrotic lesions and hemorrhage in the putamen, and hemorrhagic lesions in the caudate nucleus and cortical layers. SLC19A3 expression was substantially reduced in the cortex, basal ganglia and cerebellum compared with an age-matched control. Importantly, exposure of fibroblasts to stress factors such as acidosis or hypoxia markedly upregulated SLC19A3 in control cells, but failed to elevate SLC19A3 expression in the patient's fibroblasts. These results demonstrate ubiquitously reduced thiamine transporter function in the cerebral gray matter, and neuropathological alterations similar to Wernicke's disease in BTBGD. They also suggest that episodes of encephalopathy are caused by a substantially reduced capacity of mutant neuronal cells to increase SLC19A3 expression, necessary to adapt to stress conditions.