D013 Thiamine deficiency in CSF of Huntington’s disease presymptomatic carriers evidences etiological relevance and value as predictive biomarker

<h3></h3> Thiamine (Vit B1) deficiencies (acquired or genetic) result in encephalopathies, some of which affect particularly the striatum, like that by mutations of the brain endothelium thiamine transporter (SLC19A3=ThTr2; OMIM #607483, Biotin and thiamine-responsive basal ganglia disease). Transcriptomic analyses of brain tissue from Huntington’s disease (HD) patients and mice revealed decreased expression of SLC19A31 and TPK12 –the kinase converting thiamine into the enzyme cofactor TPP-. Accordingly, HD patients show reduced thiamine levels in CSF (TMP) and brain parenchyma (TPP).¹ Furthermore, high dose thiamine-biotin administration to HD mice attenuated their oligodendrocyte maturation deficit,² and their radiological, neuropathological, and motor phenotypes,¹ thus evidencing the potential of high dose thiamine-biotin therapy for HD. The currently enrolling, multicentric clinical trial HUNTIAM (NCT04478734) is designed to rule out toxicity of high dose thiamine-biotin in HD patients, and to assess normalization of CSF thiamine after one-year treatment. Here we report that HUNTIAM patients treated for three or more months (one third of estimated enrollment) did not experience treatment-associated side effects. Initial data on potential normalization of CSF thiamine will be available soon. Remarkably, in a longitudinal cohort of HD presymptomatic carriers, we have interrogated the evolution of their CSF thiamine levels in relation to their neuropsychological, neurological, and biomarker progression. Our preliminary data show that decrease in CSF thiamine levels precedes onset of motor symptoms and that its yearly evolution correlates with that of prodromal signs (like SWRT decline). These results underscore the etiological relevance of decreased CSF thiamine content and its predictive value as disease-onset biomarker. <h3>References</h3> Picó S, <i>et al</i>. CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington9s disease. <i>Sci Transl Med</i> 2021;<b>13</b>:eabe7104. Lim RG, <i>et al</i>. Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation. <i>Nat Commun</i> 2022;<b>13</b>:7791.