Encephalopathy due to hydroxykynureninuria

Summary

Encephalopathy due to hydroxykynureninuria (MONDO:0009372) is a disease caused by KYNU (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KYNU (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001298	Encephalopathy	Obligate (100%)
HP:0004365	Abnormality of tryptophan metabolism	Obligate (100%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0001947	Renal tubular acidosis	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0005957	Breathing dysregulation	Frequent (30-79%)
HP:0008527	Congenital sensorineural hearing impairment	Frequent (30-79%)
HP:0010280	Stomatitis	Frequent (30-79%)
HP:0001259	Coma	Occasional (5-29%)
HP:0002448	Progressive encephalopathy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy due to hydroxykynureninuria
Mondo ID	MONDO:0009372
MeSH	C536081
OMIM	236800
Orphanet	79155
DOID	DOID:0112257
ICD-11	1145853843
SNOMED CT	72945002
UMLS	C0268474
MedGen	78681
GARD	0010039
Is cancer (heuristic)	no

Also known as: kynureninase deficiency · Xanthurenic aciduria

Data availability: 6 ClinVar variants · 4 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 amino acid metabolism › inborn disorder of tryptophan metabolism › encephalopathy due to hydroxykynureninuria

Related subtypes (2): familial hypertryptophanemia, 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

6 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 benign, 1 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
160355	NM_003937.3(KYNU):c.592A>G (p.Thr198Ala)	KYNU	Pathogenic	no assertion criteria provided
978270	NM_003937.3(KYNU):c.326G>C (p.Trp109Ser)	KYNU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685366	NM_003937.3(KYNU):c.773T>C (p.Val258Ala)	KYNU	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3584372	NM_003937.3(KYNU):c.643A>T (p.Ile215Phe)	KYNU	Uncertain significance	criteria provided, single submitter
3584375	NM_003937.3(KYNU):c.1273T>C (p.Cys425Arg)	KYNU	Uncertain significance	criteria provided, single submitter
1300104	NM_003937.3(KYNU):c.955+26C>T	KYNU	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
KYNU	Strong	Autosomal recessive	encephalopathy due to hydroxykynureninuria	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KYNU	Orphanet:521438	Congenital vertebral-cardiac-renal anomalies syndrome
KYNU	Orphanet:79155	Hydroxykynureninuria

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
KYNU	HGNC:6469	ENSG00000115919	Q16719	Kynureninase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KYNU	Kynureninase	Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-OHAA), respectively.

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)
KYNU	Enzyme (other)	yes	3.7.1.3	Kynureninase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
endometrium epithelium	1
palpebral conjunctiva	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KYNU	236	ubiquitous	marker	endometrium epithelium, palpebral conjunctiva, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KYNU	1,683

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KYNU	Q16719	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Tryptophan catabolism	1	761.3×	0.004	KYNU
Metabolism of amino acids and derivatives	1	67.6×	0.022	KYNU
Metabolism	1	11.6×	0.086	KYNU

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
response to vitamin B6	1	8426.0×	6e-04	KYNU
obsolete anthranilate metabolic process	1	5617.3×	6e-04	KYNU
obsolete L-kynurenine catabolic process	1	4213.0×	6e-04	KYNU
L-tryptophan catabolic process	1	2808.7×	6e-04	KYNU
obsolete L-tryptophan catabolic process to L-kynurenine	1	2808.7×	6e-04	KYNU
NAD+ biosynthetic process	1	1872.4×	7e-04	KYNU
‘de novo’ NAD+ biosynthetic process from L-tryptophan	1	1872.4×	7e-04	KYNU
quinolinate biosynthetic process	1	1532.0×	7e-04	KYNU
response to type II interferon	1	526.6×	0.002	KYNU

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KYNU	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
L-KYNURENINE	1	KYNU

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KYNU	21	Binding:21

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KYNU	3.7.1.3	kynureninase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
L-KYNURENINE	1	KYNU

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	1	KYNU
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.