DHTKD1 encodes the E1a component of the 2-oxoadipate dehydrogenase complex (OADHC), a key mitochondrial enzyme in lysine, hydroxylysine, and tryptophan catabolism 1. The protein catalyzes the thiamine diphosphate-dependent decarboxylation of 2-oxoadipate to glutaryl-CoA and CO2, the rate-limiting step in this metabolic pathway 1. DHTKD1 transfers the decarboxylated acyl intermediate to the E2 enzyme (DLST), assembling into a mitochondrial megacomplex 1. Though capable of decarboxylating 2-oxoglutarate in vitro, DHTKD1 shows substrate preference for 2-oxoadipate 2. Biallelic DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria, characterized by urinary accumulation of these metabolites 2. Heterozygous mutations are associated with Charcot-Marie-Tooth disease type 2Q (CMT2Q), causing axonal peripheral neuropathy with sensory deficits and mitochondrial accumulation 3. CMT2Q knock-in mice recapitulate human phenotypes including reduced axon diameter and abnormal myelination 3. DHTKD1 mutations also cause ALS-like presentations with lower motor neuron involvement 4. Rare DHTKD1 variants are enriched in eosinophilic esophagitis, where reduced expression impairs mitochondrial function and increases ROS production 5. Disease-associated missense mutations typically impair folding, stability, or enzyme activity, with some variants disrupting DLST interactions 2.