Description:
<jats:title>Abstract</jats:title><jats:p>Biotin‐thiamine‐responsive basal ganglia disease (<jats:styled-content style="fixed-case">BTBGD</jats:styled-content>) is a potentially treatable disorder caused by mutations in the <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> gene, encoding the human thiamine transporter 2. Manifestation of <jats:styled-content style="fixed-case">BTBGD</jats:styled-content> 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 <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> mutations <jats:styled-content style="fixed-case">p.W94R</jats:styled-content> and <jats:styled-content style="fixed-case">p.Q393*fs</jats:styled-content>. 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. <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> 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 <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> in control cells, but failed to elevate <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> expression in the patient's fibroblasts. These results demonstrate ubiquitously reduced thiamine transporter function in the cerebral gray matter, and neuropathological alterations similar to <jats:styled-content style="fixed-case">W</jats:styled-content>ernicke's disease in <jats:styled-content style="fixed-case">BTBGD</jats:styled-content>. They also suggest that episodes of encephalopathy are caused by a substantially reduced capacity of mutant neuronal cells to increase <jats:styled-content style="fixed-case"><jats:italic>SLC19A3</jats:italic></jats:styled-content> expression, necessary to adapt to stress conditions.</jats:p>