Thiamine Deficiency‐Mediated Brain Mitochondrial Pathology in A laskan H uskies with Mutation in SLC19A3.1

A laskan H usky encephalopathy ( AHE 1 ) is a fatal brain disease associated with a mutation in SLC19A3.1 ( c.624insTTGC , c.625C>A ). This gene encodes for a thiamine transporter 2 with a predominately ( CNS ) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate ( TPP )‐dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha‐helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP ‐dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation ( OXPHOS ) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain‐specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by W ernicke's and K orsakoff's syndromes, several differences were noted likely arising from a tissue‐specific vs. that from a whole‐body thiamine deficiency.