2-aminoadipic 2-oxoadipic aciduria

Summary

2-aminoadipic 2-oxoadipic aciduria (MONDO:0008774) is a disease caused by DHTKD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DHTKD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 922
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0410309	Alpha-aminoadipic aciduria	Very frequent (80-99%)
HP:0034465	2-hydroxyadipic aciduria	Frequent (30-79%)
HP:6000278	Elevated circulating 2-aminoadipic acid concentration	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	2-aminoadipic 2-oxoadipic aciduria
Mondo ID	MONDO:0008774
MeSH	C565453
OMIM	204750, 245130
Orphanet	79154
DOID	DOID:0111453
UMLS	C1859817
MedGen	395350
GARD	0016708
Is cancer (heuristic)	no

Also known as: 2-aminoadipic 2-oxoadipic aciduria · alpha-aminoadipic aciduria · alpha-aminoadipic and alpha-ketoadipic aciduria · AMOXAD · Ketoadipicaciduria

Data availability: 922 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of lysine and hydroxylysine metabolism › 2-aminoadipic 2-oxoadipic aciduria

Related subtypes (4): seizures-intellectual disability due to hydroxylysinuria syndrome, hyperlysinemia, saccharopinuria, inborn disorder of lysine, hydroxylysine, and tryptophan metabolism

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

340 uncertain significance, 199 likely benign, 23 pathogenic, 18 benign, 10 likely pathogenic, 6 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033496	NM_018706.7(DHTKD1):c.1363C>T (p.Arg455Ter)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339491	NM_018706.7(DHTKD1):c.1409del (p.Gly470fs)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1421380	NM_018706.7(DHTKD1):c.186dup (p.Tyr63fs)	DHTKD1	Pathogenic	criteria provided, single submitter
1445495	NM_018706.7(DHTKD1):c.2559C>G (p.Tyr853Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
1455780	NM_018706.7(DHTKD1):c.2461_2462del (p.Glu821fs)	DHTKD1	Pathogenic	criteria provided, single submitter
1936267	NM_018706.7(DHTKD1):c.199_203del (p.His66_Gly67insTer)	DHTKD1	Pathogenic	criteria provided, single submitter
1941313	NM_018706.7(DHTKD1):c.1565G>A (p.Trp522Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
1982990	NM_018706.7(DHTKD1):c.487C>T (p.Arg163Ter)	DHTKD1	Pathogenic	criteria provided, multiple submitters, no conflicts
2006686	NM_018706.7(DHTKD1):c.1879C>T (p.Gln627Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
2030322	NM_018706.7(DHTKD1):c.1544del (p.Pro515fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2044577	NM_018706.7(DHTKD1):c.2347del (p.Ala783fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2083045	NM_018706.7(DHTKD1):c.669del (p.His223fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2127547	NM_018706.7(DHTKD1):c.2401A>T (p.Lys801Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
2230330	NM_018706.7(DHTKD1):c.2583G>A (p.Trp861Ter)	DHTKD1	Pathogenic	criteria provided, multiple submitters, no conflicts
2426487	NC_000010.10:g.(?12143021)(12143200_?)del	DHTKD1	Pathogenic	criteria provided, single submitter
2426489	NC_000010.10:g.(?12111033)(12148415_?)del	DHTKD1	Pathogenic	criteria provided, single submitter
2426491	NC_000010.10:g.(?12130965)(12133703_?)del	DHTKD1	Pathogenic	criteria provided, single submitter
2506034	NM_018706.7(DHTKD1):c.2235T>G (p.Tyr745Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
2633452	NM_018706.7(DHTKD1):c.2061G>A (p.Trp687Ter)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2707238	NM_018706.7(DHTKD1):c.1967del (p.Lys656fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2718150	NM_018706.7(DHTKD1):c.1806_1809del (p.Ser602fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2725954	NM_018706.7(DHTKD1):c.1669C>T (p.Gln557Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
2726845	NM_018706.7(DHTKD1):c.967dup (p.Asp323fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2747798	NM_018706.7(DHTKD1):c.331del (p.Glu111fs)	DHTKD1	Pathogenic	criteria provided, single submitter
2881928	NM_018706.7(DHTKD1):c.1452C>G (p.Tyr484Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
2909924	NM_018706.7(DHTKD1):c.736C>T (p.Arg246Ter)	DHTKD1	Pathogenic	criteria provided, single submitter
1522284	NC_000010.10:g.(?12126519)(12131274_?)dup	DHTKD1	Likely pathogenic	criteria provided, single submitter
1522292	NC_000010.10:g.(?12158694)(12162192_?)del	DHTKD1	Likely pathogenic	criteria provided, single submitter
1678589	NM_018706.7(DHTKD1):c.1859del (p.Leu620fs)	DHTKD1	Likely pathogenic	criteria provided, single submitter
2001269	NM_018706.7(DHTKD1):c.310+2T>C	DHTKD1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DHTKD1	Strong	Autosomal recessive	2-aminoadipic 2-oxoadipic aciduria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHTKD1	Orphanet:329258	Autosomal dominant Charcot-Marie-Tooth disease type 2Q
DHTKD1	Orphanet:79154	2-aminoadipic 2-oxoadipic aciduria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHTKD1	HGNC:23537	ENSG00000181192	Q96HY7	2-oxoadipate dehydrogenase complex component E1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHTKD1	2-oxoadipate dehydrogenase complex component E1	2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHTKD1	Enzyme (other)	yes	1.2.1.105	DH_E1, Transketolase-like_Pyr-bd, 2oxoglutarate_DH_E1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHTKD1	270	ubiquitous	marker	liver, right lobe of liver, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHTKD1	2,099

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHTKD1	Q96HY7	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
OADH complex synthesizes glutaryl-CoA from 2-OA	1	3806.7×	3e-04	DHTKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycolytic process	1	383.0×	0.004	DHTKD1
generation of precursor metabolites and energy	1	343.9×	0.004	DHTKD1
hematopoietic progenitor cell differentiation	1	237.3×	0.004	DHTKD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DHTKD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHTKD1	1.2.1.105	2-oxoglutarate dehydrogenase system

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DHTKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DHTKD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.