Alkaptonuria

Summary

Alkaptonuria (MONDO:0008753) is a disease caused by HGD (GenCC Strong), with 2 cohort genes and 10 clinical trials. Top therapeutic interventions include nitisinone.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HGD (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 598
• Phenotypes (HPO): 50
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Worldwide	Validated
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 100 000		Slovakia	Validated
Prevalence at birth	1-9 / 1 000 000	0.15	France	Validated
Prevalence at birth	1-9 / 100 000	5.3	Slovakia	Validated
Point prevalence	1-9 / 1 000 000		France	Not yet validated
Point prevalence	1-9 / 1 000 000		United States	Not yet validated
Prevalence at birth	1-9 / 1 000 000	0.25	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000364	Hearing abnormality	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001717	Coronary artery calcification	Very frequent (80-99%)
HP:0002758	Osteoarthritis	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0005645	Intervertebral disk calcification	Very frequent (80-99%)
HP:0007400	Irregular hyperpigmentation	Very frequent (80-99%)
HP:0030764	Ochronosis	Very frequent (80-99%)
HP:0033704	Elevated urinary homogentisic acid	Very frequent (80-99%)
HP:0100593	Calcification of cartilage	Very frequent (80-99%)
HP:0000024	Prostatitis	Frequent (30-79%)
HP:0000366	Abnormality of the nose	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0001650	Aortic valve stenosis	Frequent (30-79%)
HP:0001654	Abnormal heart valve morphology	Frequent (30-79%)
HP:0003418	Back pain	Frequent (30-79%)
HP:0004380	Aortic valve calcification	Frequent (30-79%)
HP:0004382	Mitral valve calcification	Frequent (30-79%)
HP:0004690	Thickened Achilles tendon	Frequent (30-79%)
HP:0007832	Pigmentation of the sclera	Frequent (30-79%)
HP:0040319	Dark urine	Frequent (30-79%)
HP:0100550	Tendon rupture	Frequent (30-79%)
HP:0100773	Cartilage destruction	Frequent (30-79%)
HP:6000027	Oil-drop brown pigmentation of the corneal limbus	Frequent (30-79%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0001658	Myocardial infarction	Occasional (5-29%)
HP:0001718	Mitral stenosis	Occasional (5-29%)
HP:0001878	Hemolytic anemia	Occasional (5-29%)
HP:0002621	Atherosclerosis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0004942	Aortic aneurysm	Occasional (5-29%)
HP:0007906	Ocular hypertension	Occasional (5-29%)
HP:0011034	Amyloidosis	Occasional (5-29%)
HP:0011982	Black pigment gallstones	Occasional (5-29%)
HP:0012119	Methemoglobinemia	Occasional (5-29%)
HP:0025612	Corneal astigmatism	Occasional (5-29%)
HP:0034882	Prostatic calculus	Occasional (5-29%)
HP:6000025	Dark cerumen	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alkaptonuria
Mondo ID	MONDO:0008753
MeSH	D000474
OMIM	203500
Orphanet	56
DOID	DOID:9270
ICD-11	1761652827
NCIT	C84546
SNOMED CT	360378009
UMLS	C0002066
MedGen	1413
GARD	0005775
MedDRA	10001689
NORD	750
Is cancer (heuristic)	no

Also known as: aku · alcaptonuria · alkaptonuria · alkaptonuric ochronosis · hereditary ochronosis · homogentisate 1,2-dioxygenase deficiency · homogentisic acid oxidase deficiency · homogentisic acidura · ochronosis, hereditary

Data availability: 598 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

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 phenylalanine and tyrosine metabolism › disorder of tyrosine metabolism › alkaptonuria

Related subtypes (4): tyrosinemia, hawkinsinuria, TH-deficient dopa-responsive dystonia, oculocutaneous albinism type 1

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

598 retrieved; paginated sample, class counts are floors:

186 pathogenic, 173 likely benign, 102 uncertain significance, 67 likely pathogenic, 25 pathogenic/likely pathogenic, 24 conflicting classifications of pathogenicity, 13 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065535	NM_000187.4(HGD):c.367G>A (p.Gly123Arg)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069590	NM_000187.4(HGD):c.1006+2T>A	HGD	Pathogenic	criteria provided, single submitter
1071746	NM_000187.4(HGD):c.125A>C (p.Glu42Ala)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071828	NM_000187.4(HGD):c.1288del (p.Leu430fs)	HGD	Pathogenic	criteria provided, single submitter
1073765	NM_000187.4(HGD):c.1188+1G>A	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
1075699	NM_000187.4(HGD):c.186T>G (p.Tyr62Ter)	HGD	Pathogenic	criteria provided, single submitter
1075956	NM_000187.4(HGD):c.583G>T (p.Glu195Ter)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076110	NM_000187.4(HGD):c.1185del (p.Met396fs)	HGD	Pathogenic	criteria provided, single submitter
1184269	NM_000187.4(HGD):c.343G>C (p.Gly115Arg)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1264347	NM_000187.4(HGD):c.1031del (p.Gly344fs)	HGD	Pathogenic	no assertion criteria provided
1368315	NM_000187.4(HGD):c.1245del (p.Ser416fs)	HGD	Pathogenic	criteria provided, single submitter
1387389	NM_000187.4(HGD):c.359G>T (p.Cys120Phe)	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
1450820	NM_000187.4(HGD):c.502G>T (p.Glu168Ter)	HGD	Pathogenic	criteria provided, single submitter
1454693	NM_000187.4(HGD):c.1111del (p.His371fs)	HGD	Pathogenic	criteria provided, single submitter
1456230	NM_000187.4(HGD):c.11T>C (p.Leu4Ser)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457863	NM_000187.4(HGD):c.1007-2A>T	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
1458490	NM_000187.4(HGD):c.1269C>A (p.Tyr423Ter)	HGD	Pathogenic	criteria provided, single submitter
156275	NM_000187.4(HGD):c.16-272_87+305del	HGD	Pathogenic	no assertion criteria provided
1691425	NM_000187.4(HGD):c.532G>T (p.Glu178Ter)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188717	NM_000187.4(HGD):c.11T>A (p.Leu4Ter)	HGD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188865	NM_000187.4(HGD):c.365C>T (p.Ala122Val)	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
189061	NM_000187.4(HGD):c.652del	HGD	Pathogenic	criteria provided, single submitter
189127	NM_000187.4(HGD):c.342+1G>T	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
189173	NM_000187.4(HGD):c.674G>A (p.Arg225His)	HGD	Pathogenic	criteria provided, multiple submitters, no conflicts
1986548	NM_000187.4(HGD):c.699G>A (p.Trp233Ter)	HGD	Pathogenic	criteria provided, single submitter
2003221	NM_000187.4(HGD):c.1112dup (p.His371fs)	HGD	Pathogenic	criteria provided, single submitter
2004589	NM_000187.4(HGD):c.133del (p.Ser45fs)	HGD	Pathogenic	criteria provided, single submitter
2026406	NM_000187.4(HGD):c.1157_1160del (p.Leu386fs)	HGD	Pathogenic	criteria provided, single submitter
2064427	NM_000187.4(HGD):c.1188+2T>A	HGD	Pathogenic	criteria provided, single submitter
2069488	NM_000187.4(HGD):c.237_240del (p.Gln80fs)	HGD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
HGD	Strong	Autosomal recessive	alkaptonuria	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HGD	Orphanet:56	Alkaptonuria

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HGD	HGNC:4892	ENSG00000113924	Q93099	Homogentisate 1,2-dioxygenase	gencc,clinvar
KALRN	HGNC:4814	ENSG00000160145	O60229	Kalirin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HGD	Homogentisate 1,2-dioxygenase	Catalyzes the conversion of homogentisate to maleylacetoacetate.
KALRN	Kalirin	Promotes the exchange of GDP by GTP.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HGD	Enzyme (other)	yes	1.13.11.5	Homogentis_dOase, RmlC_Cupin_sf, RmlC-like_jellyroll
KALRN	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
liver	1
right lobe of liver	1
frontal pole	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HGD	191	broad	marker	right lobe of liver, liver, gall bladder
KALRN	257	ubiquitous	marker	secondary oocyte, oocyte, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KALRN	1,603
HGD	1,533

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KALRN	O60229	13
HGD	Q93099	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tyrosine catabolism	1	1142.0×	0.020	HGD
EPHB-mediated forward signaling	1	132.8×	0.034	KALRN
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.034	KALRN
p75 NTR receptor-mediated signalling	1	93.6×	0.034	KALRN
NRAGE signals death through JNK	1	92.1×	0.034	KALRN
EPH-Ephrin signaling	1	82.8×	0.034	KALRN
RHOG GTPase cycle	1	74.2×	0.034	KALRN
Death Receptor Signaling	1	69.6×	0.034	KALRN
G alpha (12/13) signalling events	1	68.8×	0.034	KALRN
MAPK6/MAPK4 signaling	1	68.0×	0.034	KALRN
MAPK family signaling cascades	1	51.4×	0.040	KALRN
RHOA GTPase cycle	1	37.3×	0.051	KALRN
RAC1 GTPase cycle	1	30.5×	0.053	KALRN
RHO GTPase cycle	1	30.1×	0.053	KALRN
G alpha (q) signalling events	1	28.7×	0.053	KALRN
Axon guidance	1	22.6×	0.059	KALRN
GPCR downstream signalling	1	21.7×	0.059	KALRN
Nervous system development	1	21.5×	0.059	KALRN
Signaling by GPCR	1	20.0×	0.060	KALRN
Signaling by Rho GTPases	1	17.1×	0.064	KALRN
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.064	KALRN
Developmental Biology	1	7.2×	0.140	KALRN
Signal Transduction	1	5.1×	0.187	KALRN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-tyrosine catabolic process	1	1404.3×	0.005	HGD
L-phenylalanine catabolic process	1	1053.2×	0.005	HGD
ephrin receptor signaling pathway	1	172.0×	0.019	KALRN
regulation of small GTPase mediated signal transduction	1	72.0×	0.035	KALRN
vesicle-mediated transport	1	48.1×	0.037	KALRN
axon guidance	1	45.3×	0.037	KALRN
protein phosphorylation	1	34.0×	0.042	KALRN
nervous system development	1	23.0×	0.054	KALRN
intracellular signal transduction	1	19.1×	0.058	KALRN
signal transduction	1	8.0×	0.121	KALRN

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Nitisinone	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
HGD	0	0
KALRN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HGD	1.13.11.5	homogentisate 1,2-dioxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	HGD, KALRN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HGD	0	—
KALRN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01390077	PHASE2/PHASE3	COMPLETED	Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
NCT01916382	PHASE3	UNKNOWN	Suitability of Nitisinone in Alkaptonuria 2
NCT00107783	PHASE2	COMPLETED	Long-Term Study of Nitisinone to Treat Alkaptonuria
NCT01828463	PHASE2	COMPLETED	Dose Response Study of Nitisinone in Alkaptonuria
NCT00005909	Not specified	RECRUITING	Study of Alkaptonuria
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT04142671	Not specified	UNKNOWN	Individualised Gait Modification Strategies in Alkaptonuria Patients
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere
NCT04510142	Not specified	COMPLETED	Questionnaire Follow=up Study Sonia 2
NCT04761588	Not specified	COMPLETED	Evaluation of TYR Sphere in France

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NITISINONE	4	4
CHEMBL23996	0	4