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Alkaptonuria
This build-up can cause urine to turn black when exposed to air, and over time, lead to serious joint problems and other health issues. It is a lifelong condition affecting individuals from birth.
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Overview
Alkaptonuria is a rare genetic disorder that affects the body's metabolism, specifically the breakdown of two amino acids: phenylalanine and tyrosine. In people with alkaptonuria, an important enzyme is missing or doesn't work correctly, leading to a build-up of a substance called homogentisic acid (HGA) [PMID:31894266].
This build-up of HGA can cause a variety of symptoms, most notably dark-coloured urine, and later in life, damage to joints and other connective tissues. It is a lifelong condition that typically becomes more noticeable with age as HGA accumulates in the body. Alkaptonuria is a very rare condition, affecting approximately 1 in 250,000 to 1,000,000 people globally.
Symptoms & clinical features
The symptoms of alkaptonuria can vary and often develop gradually over time. One of the earliest and most distinctive signs, particularly in infants, is urine that turns dark or black upon standing or exposure to air [PMID:18408151]. However, this sign can sometimes be missed amongst other nappy stains.
Later in life, a key feature is ochronosis, where HGA deposits in connective tissues, turning them dark blue or black. This can affect cartilage, tendons, and skin. Joint pain and stiffness, particularly in the spine and large joints like the hips and knees, typically begin in early to middle adulthood. Other potential issues include kidney stones, prostate stones, and heart valve problems due to HGA deposits [PMID:31894266].
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Affected organs
Alkaptonuria primarily affects connective tissues throughout the body due to the deposition of homogentisic acid. Joints, especially the spine, hips, knees, and shoulders, are commonly affected, leading to degenerative arthritis. Cartilage in these joints can become brittle and damaged.
Other organs that can be impacted include the heart, where HGA deposits may lead to calcification and damage of heart valves, particularly the aortic valve. Kidneys and the prostate gland can also develop stones. The ears may show dark pigmentation of the external cartilage, and the whites of the eyes can develop dark spots due to HGA accumulation.
Risks & severity
The severity of alkaptonuria can vary between individuals, but it is generally a progressive condition. While some symptoms like dark urine may be noticed early, significant joint and heart problems typically develop later in life, often in the 30s or 40s. These degenerative changes can lead to chronic pain and reduced mobility [PMID:18408151].
The most significant risks are progressive degenerative joint disease, which may require joint replacement surgery, and cardiac complications such as aortic valve disease, which can sometimes necessitate surgical intervention. Kidney stones and prostate stones are also potential complications. The condition is lifelong, and management focuses on mitigating symptoms and slowing disease progression.
Genetic causes
Alkaptonuria is caused by changes in the HGD gene. This gene provides instructions for making an enzyme called homogentisate 1,2-dioxygenase. This enzyme normally plays a crucial role in the metabolic pathway that breaks down the amino acids phenylalanine and tyrosine.
When there are pathogenic variants in the HGD gene, the enzyme either isn't produced or doesn't function correctly. This leads to an inability to fully break down homogentisic acid (HGA), causing it to accumulate in the body's tissues and fluids. The build-up of HGA is responsible for the symptoms observed in alkaptonuria.
- HGD homogentisate 1,2-dioxygenaseThe HGD gene provides instructions for the homogentisate 1,2-dioxygenase enzyme, which plays a crucial role in the breakdown of specific amino acids.
Inheritance pattern
Alkaptonuria is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the HGD gene - one from each parent - to develop the condition.
Individuals who inherit only one altered copy of the HGD gene are called carriers. Carriers typically do not show symptoms of alkaptonuria because their one working copy of the gene produces enough functional enzyme. If two carriers have a child together, there is a 25% chance with each pregnancy that the child will inherit two altered copies of the gene and develop alkaptonuria, a 50% chance they will be a carrier, and a 25% chance they will not inherit any altered copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of alkaptonuria is often suspected based on classic symptoms like dark urine or early-onset arthritis in unusual locations. It is confirmed by detecting high levels of homogentisic acid in the urine [PMID:31894266].
Genetic testing for pathogenic variants in the HGD gene can confirm the diagnosis and is important for family screening and genetic counselling. In the UK, genetic testing for inherited metabolic disorders is available via the NHS Genomic Medicine Service. A referral to a clinical genetics service or a metabolic specialist is usually made to arrange appropriate testing under the R-codes relevant to metabolic disorders.
Management & lifestyle
While there is currently no cure for alkaptonuria, management focuses on reducing symptoms and slowing the progression of the disease. A medication called nitisinone is used to reduce the production of HGA, which can help to lessen its accumulation and potentially slow the development of ochronosis and joint damage. Dietary adjustments, such as reducing protein intake (specifically phenylalanine and tyrosine), may also be suggested to further reduce HGA levels.
Long-term management involves regular monitoring by a team of specialists, including rheumatologists for joint health, cardiologists for heart monitoring, and urologists for kidney issues. Physical therapy and pain management are often important for maintaining joint function and improving quality of life. In some cases, joint replacement surgery may be necessary. Genetic counsellors can provide support and information regarding the genetic aspects of the condition and family planning.
UK care pathway
In the UK, suspected cases of alkaptonuria would typically be referred to a specialist metabolic centre or a clinical genetics service within the NHS Genomic Medicine Service. These services can confirm diagnosis through biochemical and genetic testing (often covered by relevant PanelApp R-codes for inherited metabolic disorders).
Following diagnosis, care is usually coordinated by a multidisciplinary team. Genetic counsellors play a crucial role in providing information and support to individuals and families regarding the inheritance pattern and implications of alkaptonuria.
Frequently asked questions
What causes the urine to turn black in alkaptonuria?
The dark discolouration happens because homogentisic acid (HGA), which builds up in the body, is excreted in the urine. When HGA comes into contact with air, it oxidises and turns a dark, often black, colour. This is a tell-tale sign of alkaptonuria.
Is alkaptonuria a painful condition?
Over time, alkaptonuria can cause significant joint pain and stiffness, particularly as the homogentisic acid deposits damage the cartilage. This can lead to a type of degenerative arthritis that progresses with age, causing chronic discomfort.
Can alkaptonuria be cured?
Currently, there is no cure for alkaptonuria. However, treatments like nitisinone and supportive care can help to manage the symptoms, reduce the build-up of homogentisic acid, and slow down the progression of the disease, improving quality of life.
If I am a carrier, will I develop symptoms of alkaptonuria?
No, carriers of alkaptonuria typically do not develop any symptoms of the condition. They have one working copy of the HGD gene, which is usually sufficient to prevent the build-up of homogentisic acid.
How common is alkaptonuria?
Alkaptonuria is a very rare condition. Estimates suggest it affects approximately 1 in 250,000 to 1,000,000 people globally. Its prevalence can vary in different populations.
References
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- Grosicka A, Kucharz EJ. Alkaptonuria. Wiadomosci lekarskie (Warsaw, Poland : 1960). 2009. PMID: 20229718
- Sharabi AF, Goudar RB. Alkaptonuria. 2023. PMID: 32809406
- Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare diseases (Austin, Tex.). 2013. PMID: 25003018
- Thapa M, Bhatia M, Maurya VK. Alkaptonuria. Medical journal, Armed Forces India. 2018. PMID: 30449931
- Gao Y. Alkaptonuria. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2026. PMID: 41451484
- Alkaptonuria. The Hospital. PMID: 29820037