Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
2-Aminoadipic 2-oxoadipic aciduria (OMIM 204750; MONDO_0008774) is a rare autosomal recessive disorder of lysine and tryptophan catabolism, characterized by elevations of 2-ketoadipic, 2-aminoadipic, and 2-hydroxyadipic acids. Clinical presentations range from early-onset developmental delay with epilepsy (HP:0001250), ataxia (HP:0001251), and microcephaly (HP:0000252) to completely asymptomatic biochemical findings. The E1 component of the 2-oxoadipate dehydrogenase complex is encoded by DHTKD1 (HGNC:23537), which catalyzes the oxidative decarboxylation of 2-oxoadipate. Pathogenic DHTKD1 variants have been identified in multiple unrelated patients, establishing a Mendelian basis for this biochemical phenotype. Genetic, segregation, and functional data converge on a loss-of-function mechanism. This summary integrates the evidence to guide diagnostic testing and patient management.
An initial exome sequencing study identified compound heterozygous DHTKD1 variants c.1A>G (p.Met1Val) and c.2185G>A (p.Gly729Arg) in a proband with neurological features; a second individual carried c.2185G>A (p.Gly729Arg) and c.1228C>T (p.Arg410Ter) (PMID:23141293). Patient-derived fibroblasts accumulated 2-oxoadipate, and lentiviral complementation with wild-type DHTKD1 normalized metabolite levels, providing definitive functional rescue evidence (PMID:23141293). In vitro enzyme assays further demonstrated impaired E1 dehydrogenase activity of the p.Gly729Arg variant. These findings established DHTKD1 as the gene mediating the final decarboxylation step in lysine catabolism via a loss-of-function mechanism.
Sequencing of a cohort of nine alpha-aminoadipic and alpha-ketoadipic aciduria patients revealed causal biallelic DHTKD1 mutations in eight individuals, including three missense, two nonsense, two splice donor, one duplication, and one deletion/insertion variant (PMID:25860818). The recurrent c.2185G>A (p.Gly729Arg) appeared in multiple families, suggesting a mutational hotspot. Segregation analysis confirmed co-segregation in two affected sibling pairs. Clinical phenotypes were heterogeneous, ranging from severe intellectual disability to minimal neurological signs. This expanded series reinforced autosomal recessive inheritance and broadened the genotype-phenotype correlation.
A subsequent report described four additional individuals from two unrelated families—three of whom remained asymptomatic—harboring biallelic DHTKD1 variants, confirming incomplete penetrance (PMID:26141459). Both compound heterozygous and homozygous genotypes were observed. Biochemical profiling consistently showed elevated 2-aminoadipic and 2-ketoadipic acids across symptomatic and asymptomatic carriers. Multiplex segregation provided strong support for pathogenicity despite variable expressivity. These findings highlight the need for careful clinical correlation and family studies.
Functional studies of the p.Gly729Arg variant revealed a ~50-fold reduction in NADH production by recombinant E1a and impaired glutaryl-CoA generation by the E2o component (PMID:32303640). Crystal structures of the human DHTKD1–thiamin diphosphate complex demonstrated that disease-associated mutations destabilize the active site and disrupt assembly of the dehydrogenase megacomplex (PMID:32633484). Complementary binding assays confirmed that missense alleles impair interaction with the E2 (DLST) subunit. Concordant results across cell-based rescue, enzymatic assays, and structural analyses support a loss-of-function pathogenic mechanism.
Collectively, the association between DHTKD1 and 2-aminoadipic 2-oxoadipic aciduria meets ClinGen criteria for a Strong gene-disease relationship. Genetic evidence includes at least 11 unrelated probands with biallelic variants, segregation in two families, and a diverse variant spectrum. Functional evidence is Moderate, with biochemical rescue, enzymatic impairment, and structural destabilization of mutant proteins. Although incomplete penetrance suggests modifier effects, the core pathogenic mechanism is well established. Molecular testing for DHTKD1 should be integrated into diagnostic workflows for patients with suggestive biochemical profiles. Key take-home: Biallelic DHTKD1 loss-of-function variants cause a clinically heterogeneous aciduria, diagnosable via combined biochemical and genetic assays, enabling precise patient management.
Gene–Disease AssociationStrong≥11 unrelated probands across three cohorts, segregation in two families, concordant functional rescue in patient fibroblasts Genetic EvidenceStrongBiallelic DHTKD1 variants in ≥11 unrelated patients; variant classes include missense, nonsense, splice donor, duplication, and frameshift; recurrent p.Gly729Arg Functional EvidenceModerateEnzymatic assays show impaired dehydrogenase activity; fibroblast complementation rescues metabolite accumulation; structural studies reveal protein destabilization |