Alkaptonuria

Alkaptonuria is a metabolic genetic disease caused by autosomal recessive variants in HGD. It is not placed in the rankable burden order: only 1 of five axes are scored (cut: three of five), so the remaining 4 stay open [O], not guessed. Mechanism, scored axes, and treatment follow below.

Alkaptonuria is inherited as autosomal recessive and acts by loss-of-function (biallelic; recessive) ([H]). Of the five burden axes, 1 are scored (O) and 4 are open [O] (P, S, M, D); because fewer than three are scored the disease is reported as “not placed — insufficient axis coverage” (rank null), not ranked on partial data.

Gene, inheritance, and molecular mechanism

Alkaptonuria is inherited as Autosomal recessive inheritance [L] and is classified mechanistically as loss-of-function (biallelic; recessive) [H]. HGD encodes homogentisate 1,2-dioxygenase in the tyrosine-degradation pathway. Its deficiency lets homogentisic acid accumulate and polymerise, depositing an ochronotic pigment in connective tissue.

Inheritance source: medgen:esummary:ModeOfInheritance:2026-06-17. Mechanism source: inference:recessive=>loss_of_function; basis=medgen_inheritance(recessive). These are observed, cited inputs; the classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

Urine darkens on standing from infancy; in adulthood ochronotic pigment accumulates in cartilage and a degenerative ochronotic arthropathy of the spine and large joints develops, with cardiac-valve and renal-stone involvement.

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 203500,607474); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Burden axes and why this disease is not placed

For transparency the partial composite over the 1 scored axis/axes is raw_burden = 0.8500, but it is not used to rank the disease (below the ≥ 3-axis cut). The open axes (progression, severity, mortality, disability) are graded [O] with a named obstacle, never imputed.

The natural-history registry passes lift onset (Orphanet, R6) and disability (GBD 2013 disability weights, R7) to registry [L] where an entity-anchored mapping exists, lift severity (HPO Severity-modifier subtree, R8) where the dominant sequela is annotated, and lift progression (curated PMC open-access literature with a frozen-R3-derived tier, R9) where a cited disease-level magnitude for the dominant untreated sequela exists. For some diseases the added disability axis was enough to cross the ≥ 3-axis cut and enter the placed residual order; for this one it was not — and its dominant sequela carries no open HPO severity annotation, so no registry severity tier is available (the open HPO severity annotations elsewhere are feature-level; the OMIM clinical synopsis, the disease-level alternative, is API-key-gated and the key is unobtainable for an individual researcher). Scoring three or more axes at registry grade (via published functional & survival literature) would let this disease enter the rankable residual order; until then it is reported here, never imputed.

Established treatment

The established disease-directed approach is nitisinone (homogentisic-acid lowering) with supportive joint care. Mechanistically: nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing homogentisic-acid production [L]. Its effect on natural history is classified disease-modifying (partial) (efficacy offset e = 0.3000, residual factor R_treat = 0.7000); this offset would apply to the burden score once the disease is placed.

Evidence tier: accession-dated to the GeneReviews NBK1454 Management section [L] (initial posting May 9, 2003; last revision June 10, 2021; retrieved 2026-06-18; corroborating term(s): “nitisinone, joint”).