What's alkaptonuria?
Alkaptonuria is a rare inherited metabolic disorder in which a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD) lets homogentisic acid (HGA) build up. Over years the HGA oxidises and deposits as a dark pigment in cartilage and connective tissue (ochronosis), producing early severe osteoarthritis of the spine and large joints, dark urine, and pigment in the eyes and ears; heart valves can also be affected. It is autosomal recessive. This entry confirms HGD.
| Also indexed as | ORPHA:56, MONDO:0008753 |
|---|---|
| Features mapped | 15 |
| Treatments mapped | 4 |
| Published sources | 17 |
| Last reviewed | 2026-08-04 |
Signs and symptoms
Autosomal recessive inheritance
Alkaptonuria is inherited in an autosomal recessive pattern: both copies of HGD must carry disease variants for a person to be affected.
Ochronosis
Ochronosis is the blue-black darkening of body tissues seen in alkaptonuria. Some of the homogentisic acid that the body cannot break down builds up and deposits in tissues, where it forms a dark pigment that changes their color.
Pigmentation of the sclera
In alkaptonuria, the whites of the eyes (sclera) can take on a dark pigmentation as the ochronotic pigment deposits there. Dark pigment can likewise appear in the cartilage of the ears.
Dark urine
In alkaptonuria, urine darkens when it is left to stand and exposed to air. This happens because homogentisic acid, which builds up in the body, turns dark on contact with air. It is often the first sign noticed, sometimes in infancy as dark-stained diapers.
Elevated urinary homogentisic acid
A high level of homogentisic acid in the urine is the key biochemical marker and confirms the diagnosis.
Kidney stone
Alkaptonuria raises the rate of kidney stones (renal stones) as homogentisic acid and its deposits affect the urinary tract.
Arthropathy
Alkaptonuria leads to an early-onset arthritis that affects especially the spine and the large joints, as the dark pigment builds up in connective tissue. It usually becomes noticeable after about age 30.
Low back pain
Low back pain is an early and common feature of alkaptonuria as pigment deposits stiffen and degrade the spine.
Abnormal heart valve morphology
Alkaptonuria can affect the heart valves. The rate of cardiac valve calcification (hardening from calcium and pigment deposits) is increased in people with the condition.
Abnormal skin pigmentation
Darkening of the skin (and of urine left to stand) reflects the homogentisic acid that accumulates in alkaptonuria and deposits in tissues over time.
Prostatitis
In men with alkaptonuria, inflammation of the prostate (prostatitis) and stones in the prostate can occur as part of the condition.
Osteoarthritis
Over years, the buildup of ochronotic pigment in cartilage leads to a destructive osteoarthritis, one of the defining long-term complications of alkaptonuria.
Calcification of cartilage
Alkaptonuria is a rare inherited disorder in which a faulty enzyme lets a dark substance build up in cartilage and other tissues, causing a condition called ochronosis.
Tendon rupture
In alkaptonuria, tendons weakened by pigment deposits can rupture on their own, without a major injury. Spontaneous tendon ruptures are a recognized complication.
Intervertebral disk calcification
Calcification of the discs between the spinal vertebrae is a characteristic finding in alkaptonuria, seen as wide areas of calcification on spine X-rays.
How it is diagnosed
Alkaptonuria
Diagnosed using: Genetic testing.
“Afterward, a qualitative urine test and subsequent molecular testing via exome sequencing identified two heterozygous pathogenic variants in the HGD gene.”
Alkaptonuria
Diagnosed using: Genome sequencing.
“Whole genome sequencing (WGS) revealed compound heterozygosity for HGD variants: c.808G>A (p.Gly270Arg), likely pathogenic, and c.774+69C>T (VUS).”
Alkaptonuria
Diagnosed using: Sanger sequencing.
“Sanger sequencing identified five unique variants in the HGD gene (NM_000187.4), all of which were homozygous variants.”
Alkaptonuria
Diagnosed using: urinary homogentisic acid measurement.
“Diagnosis was confirmed by elevated urinary HGA.”
Alkaptonuria
Diagnosed using: HGD gene molecular genetic analysis.
“Diagnosis is established through biochemical testing and molecular genetic analysis of the HGD gene.”
Treatment and management
What the research describes, not a recommendation. Treatment decisions belong with your clinician.
This covers treatments that appear in the published research mapped here. Investigational and experimental therapies are not included, so their absence is a boundary of this map, not a sign they do not exist.
nitisinone
Nitisinone is a once-daily oral drug that blocks the enzyme 4-hydroxyphenylpyruvate dioxygenase upstream in the pathway, cutting homogentisic acid production by over 90%; it is the first disease-modifying treatment for alkaptonuria. Because it raises tyrosine, a low-protein diet and monitoring are needed.
Used to help with: Alkaptonuria.
“As a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, nitisinone exerts biochemical efficacy with a greater than 95% reduction of urinary excretion of HGA.”
ascorbic acid (vitamin C)
High-dose vitamin C (ascorbic acid) has been used in alkaptonuria, alongside a protein-restricted diet, in the hope of reducing the later, serious complications by lowering the level of the harmful metabolite.
Used to help with: Alkaptonuria.
“It is expected that treatment with ascorbic acid and a dietary restriction of…”
protein-restricted diet (phenylalanine and tyrosine)
A diet that limits protein, specifically the amino acids phenylalanine and tyrosine, is part of the long-standing supportive treatment for alkaptonuria, aimed at reducing the homogentisic acid that the body produces from these amino acids.
Used to help with: Alkaptonuria.
“Medical treatment is limited to a protein-restricted diet (phenylalanine and…”
total joint replacement
When alkaptonuria has destroyed a joint, total joint replacement is an accepted treatment for the resulting degenerative joint disease, with implant survival comparable to that seen in ordinary osteoarthritis.
Used to help with: Alkaptonuria.
“Total joint replacement is an acceptable treatment for degenerative joint disease in alkaptonuric patients, with implant survival comparable to that found in patients with osteoarthritis.”
What changes how it shows up
Carrying the genetic change is not the whole story. The factors below are described in the research mapped here as changing whether, or how strongly, the condition appears. They modulate how the genotype is expressed; they do not, on their own, cause or cure it.
HGD
Alkaptonuria is caused by changes in the HGD gene. These changes leave the body short of the enzyme homogentisate 1,2-dioxygenase, so homogentisic acid cannot be broken down and builds up in the body.
Described as modulating: Alkaptonuria.
“Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene.”
How to read the evidence labels
Where this comes from
This guide is built from 17 published source(s). Every claim above links back to one of them. Click any source ID to read the original on PubMed.
Take it further
Printed, source-linked documents built from this condition's graph — ready to bring to an appointment or attach to a coverage request. Every claim carries its published source, the same as this guide.