Alkaptonuria

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Alkaptonuria is an inherited condition that causes arthritis, kidney stones, spots of dark pigmentation, and dark urine. Ochronosis, a buildup of dark (blue-black) pigment in certain tissues, is a characteristic feature of alkaptonuria. The first symptom of alkaptonuria is often urine that turns black or very dark when it is exposed to air (oxidation). However, this color change may not occur immediately after urination.

Ochronosis occurs in connective tissues throughout the body, such as the joints, tendons, and ligaments. Pigment changes can be easily seen in the whites of the eyes (sclera), the outer ears, and the hands. Dark pigment can also be found in earwax and in body sweat (perspiration). These pigment changes are usually evident after age 30.

Ochronosis in the joints causes people with alkaptonuria to develop arthritis, typically in early adulthood. Arthritis usually affects the spine and large joints (such as the hips and knees). Many affected individuals require joint replacements later in life.

Over time, the deposits of pigment can harden (calcify). Calcification in joints or ligaments causes them to become rigid and brittle, decreasing their flexibility and making them prone to damage. Calcification of the discs that separate the bones of the spine can cause further back pain. This calcification can also affect the cartilage that makes up the valves of the heart, which allow blood to move through the heart and prevent blood from flowing backward. As a result, the heart valves narrow (stenosis), which can cause the valves to leak (regurgitation).

The body removes the excess pigment in urine. However, removing the large pigment deposits found in people with alkaptonuria can put strain on the kidneys, and this can lead to kidney (renal) failure. Similarly, a buildup of these substances in the kidneys or prostate gland can cause calcium stones to develop. If the body cannot effectively process and remove the pigment and related substances, these products substances can continue to build up in the body, worsening ochronosis, arthritis, and other features of alkaptonuria.

With appropriate medical management, people with alkaptonuria generally have a normal life expectancy.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the HGD gene cause alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisate 1,2-dioxygenase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Phenylalanine and tyrosine are broken down when they are no longer needed or when there are too many of them.

Variants in the HGD gene cause the cell to produce a version of the enzyme that does not function well. As a result, phenylalanine and tyrosine are not completely broken down. Instead, a substance called homogentisic acid, which is produced during the breakdown process, accumulates in the body.

Excess homogentisic acid settles in connective tissues, forming a substance called ochronotic pigment, which causes cartilage and skin to darken. Over time, a buildup of this pigment calcifies, leading to many of the health problems seen in people with alkaptonuria. Excess homogentisic acid is also excreted in urine, making urine turn dark when exposed to air.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Alkaptonuria is rare, affecting 1 in 250,000 to 1 million people in the United States. Alkaptonuria is more common in certain areas of Slovakia (where it has an incidence of about 1 in 19,000 people) and in the Dominican Republic.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of skin pigmentation · Very frequent (99-80%)

An abnormality of the pigmentation of the skin.

Abnormality of vision · Very frequent (99-80%)

Abnormality of eyesight (visual perception).

Aminoaciduria · Very frequent (99-80%)

An increased concentration of an amino acid in the urine.

Arthralgia · Very frequent (99-80%)

Joint pain.

Arthritis · Very frequent (99-80%)

Inflammation of a joint.

Calcification of cartilage · Very frequent (99-80%)

The presence of calcium deposition in cartilage.

Coronary artery calcification · Very frequent (99-80%)

An accumulation of calcium and phosphate in arteries with mineral deposits in the intimal or medial layer of the vessel wall in a coronary artery.

Elevated urinary homogentisic acid · Very frequent (99-80%)

An increased amount of homogentisic acid in the urine.

Other findings in the same source

From: Orphanet

Additional reported features include Hearing abnormality (Very frequent (99-80%)); Intervertebral disk calcification (Very frequent (99-80%)); Joint dislocation (Very frequent (99-80%)); Joint stiffness (Very frequent (99-80%)); Ochronosis (Very frequent (99-80%)); Osteoarthritis (Very frequent (99-80%)); Irregular hyperpigmentation (Very frequent (99-80%)); Joint swelling (Very frequent (99-80%)); Abnormal heart valve morphology (Frequent (79-30%)); Abnormal nail morphology (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Alkaptonuria is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Alkaptonuria. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.