What’s Alkaptonuria? Symptoms, Causes & Treatment 

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Alkaptonuria, or black urine disease, is a very rare inherited disorder that prevents the body from fully breakdown two amino acids (protein building blocks) called tyrosine and phenylalanine, which results in a build-up of a toxic chemical called homogentisic acid in the body.

Affected individuals lack enough functional levels of an enzyme required to break down homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air.

However, this change may not occur for several hours after urination and often goes unnoticed.

Aside from dark urine that is present from infancy, affected individuals generally do not develop symptoms (asymptomatic) during infancy or childhood and often remain unaware of their condition until adulthood.

In this article:

• What’s Alkaptonuria
• Symptoms
• Causes
• Treatment
• Diagnosis
• Conclusion

What’s Alkaptonuria?

Alkaptonuria is a rare inherited disorder. It occurs when your body can’t produce enough of an enzyme called homogentisic dioxygenase (HGD). This enzyme is used to break down a toxic substance called homogentisic acid.

Enzymes are proteins that make chemical reactions happen.

When you don’t produce enough HGD, homogentisic acid builds up in your body. The buildup of homogentisic acid causes your bones and cartilage to become discolored and brittle. (1, 2, 3)

This typically leads to osteoarthritis, especially in your spine and large joints. People with alkaptonuria also have urine that turns dark brown or black when it’s exposed to air.

Symptoms

What are the early symptoms of alkaptonuria?

One of the earliest signs of the condition is dark-stained nappies or diapers, as homogentisic acid causes urine to turn black when exposed to air for a few hours.

If this sign is missed or overlooked in a baby or child, the disorder may go unnoticed until adulthood, as there are usually no other noticeable symptoms until the person reaches their late 20s to early 30s.

What are the Signs and Symptoms of Alkaptonuria in adults?

As you age, homogentisic acid slowly builds up in tissues throughout the body.

It can build up in almost any area of the body, including the cartilage, tendons, bones, nails, ears, and heart. It stains the tissues dark and causes a wide range of problems such as:

• Joints and bones

When a person with alkaptonuria reaches their 30s, they may start to experience joint problems.

Typically, they’ll have lower back pain and stiffness, followed by knee, hip, and shoulder pain. These are the early symptoms of osteoarthritis.

Eventually, cartilage – a tough, flexible tissue found throughout the body – may become brittle and break, leading to joint and spinal damage. Joint replacement operations may be needed.

• Eyes and ears

Many people develop brown or grey spots on the whites of their eyes.

Another sign in many adults with alkaptonuria is a thickening of ear cartilage. The cartilage may also look blue, grey, or black. This is called ochronosis.

The earwax may be black or reddish-brown.

• Skin and nails

Alkaptonuria can result in discolored sweat, which can stain clothes and cause some people to have blue or black-speckled areas of skin. Nails may also turn a bluish or brownish color.

The skin color changes are most obvious in areas exposed to the sun and where sweat glands are found – the cheeks, forehead, armpits, and genital area.

• Breathing difficulties

If the bones and muscles around the lungs become stiff, it can prevent the chest from expanding and lead to shortness of breath or difficulty breathing.

• Heart, kidney, and prostate problems

Deposits of homogentisic acid around heart valves can cause them to harden and turn brittle and black. Blood vessels can also become stiff and weaken.(4,5,6,7)

This can lead to heart disease and may require heart valve replacements.

The deposits can also lead to kidney stones, bladder stones, and prostate stones.

Causes

What are the causes of alkaptonuria?

Alkaptonuria is caused by a defect in your homogentisate 1, 2-dioxygenase (HGD) gene. It’s an autosomal recessive condition.

This means that both of your parents must have a defective HGD gene to pass the condition on to the child just as it is in those with phenylketonuria

Alkaptonuria is a rare genetic disorder. According to the National Institutes of Health, the condition affects about 1 in 250,000 to 1 million people worldwide, but is more common in Slovakia and the Dominican Republic, affecting about 1 in 19,000 people. (8,9,10,11)

Treatment

How is alkaptonuria treated?

There’s no specific treatment for alkaptonuria. Instead, treatment is focused largely on managing symptoms.

There are many therapies that have been tried, but unfortunately, they haven’t been proven to be effective and may be harmful or unhelpful in the long term.

However, The National Institutes of Health warns that long-term use of vitamin C can sometimes increase the production of kidney stones and has generally proven ineffective for long-term treatment of this condition.

However, a medicine called nitisinone has shown some promise, and painkillers and lifestyle changes may help you cope with the symptoms.

• Nitisinone (NTBC)

Nitisinone is not licensed for alkaptonuria – it’s offered “off label” at the National Alkaptonuria Centre, the treatment center for all alkaptonuria patients, based at Royal Liverpool University Hospital.

Nitisinone reduces the level of homogentisic acid in the body. Research into its effectiveness for alkaptonuria is ongoing and there have been some promising results so far. (12,13)

• Diet

If the condition is diagnosed in childhood, it may be possible to slow its progression by restricting protein in the diet, as this may reduce levels of tyrosine and phenylalanine in your body.

A low-protein diet can also be useful in reducing the risk of potential side effects when taking nitisinone for alkaptonuria during adulthood. Your doctor or dietitian can advise you about this.(14, 15,16)

• Exercise

If alkaptonuria causes pain and stiffness, you may think exercise will make your symptoms worse. But regular gentle exercise can actually help by building muscle and strengthening your joints.

Exercise is also good for relieving stress, losing weight, and improving your posture, all of which can ease your symptoms.

The AKU Society recommends avoiding exercises that put additional strain on the joints, such as boxing, football, and rugby and trying gentle exercises such as yoga, swimming, and pilates instead.

Your GP or a physiotherapist can help you come up with a suitable exercise plan to follow at home. It’s important to follow this plan as there’s a risk the wrong sort of exercise may damage your joints. (17,18)

• Pain relief

Speak to a doctor about painkillers and other techniques to manage pain. (19)

• Emotional support

A diagnosis of alkaptonuria can be confusing and overwhelming at first. Like many people with long-term health conditions, those who find out they have alkaptonuria may feel anxious or depressed.

But there are people you can talk to who can help. Talk to your GP if you feel you need support to cope with your illness. You could also visit the AKU Society website, a charity offering support to patients, their families, and carriers.(20,21,22)

• Surgery

Sometimes surgery may be necessary if joints are damaged and need replacing, or if heart valves or vessels have hardened.(23,3)

Your doctor may recommend:

• hip replacement
• knee replacement
• aortic valve replacement

Diagnosis

How is alkaptonuria diagnosed?

Your doctor may suspect you have alkaptonuria if your urine turns dark brown or black when it’s exposed to air. They may also test you for the condition if you develop early-onset osteoarthritis.

Your doctor can use a test called gas chromatography to look for traces of homogentisic acid in your urine. They can also use DNA testing to check for the mutated HGD gene.

Family history is very useful in making a diagnosis of alkaptonuria. However, many people don’t know they carry the gene. Your parents might be carriers without realizing it because a carrier is asymptomatic.

Outlook

What is the long-term outlook for people with Alkaptonuria?

People with alkaptonuria have a normal life expectancy. However, they will usually experience severe symptoms, such as pain and loss of movement in the joints, which considerably affect their quality of life.

Working and carrying out strenuous physical activity will usually become very difficult, and eventually, you may need mobility aids such as a wheelchair to get around.

How is alkaptonuria inherited?

Each cell in the body contains 23 pairs of chromosomes. These carry the genes you inherit from your parents.

One of each pair of chromosomes is inherited from each parent, which means (with the exception of the sex chromosomes) there are two copies of each gene in each cell.

The gene involved in alkaptonuria is the HGD gene. This provides instructions for making an enzyme called homogentisate oxidase, which is needed to break down homogentisic acid.

You need to inherit two copies of the faulty HGD gene (one from each parent) to develop alkaptonuria. The chances of this are slim, which is why the condition is very rare.

The parents of a person with alkaptonuria will often only carry one copy of the faulty gene themselves, which means they will not have any signs or symptoms of the condition.

Conclusion

Alkaptonuria is a rare inherited disorder. It occurs when your body can’t produce enough of an enzyme called homogentisic dioxygenase (HGD). This enzyme is used to break down a toxic substance called homogentisic acid.

When you don’t produce enough HGD, homogentisic acid builds up in your body. The buildup of homogentisic acid causes your bones and cartilage to become discolored and brittle.

One of the earliest signs of the condition is dark-stained nappies or diapers, as homogentisic acid causes urine to turn black when exposed to air for a few hours.

If this sign is missed or overlooked in a baby or child, the disorder may go unnoticed until adulthood, resulting in visible symptoms such as joint and bone pain, brown or grey-colored spots on the eyes, and blue or black-speckled areas on the skin.

Your doctor may suspect you have alkaptonuria if your urine turns dark brown or black when it’s exposed to air.

There’s no specific treatment for alkaptonuria. Instead, treatment is focused largely on managing symptoms with diet, exercise, pain relief, emotional support, and surgery. 

You could also visit the AKU Society website, a charity offering support to patients, their families, and carriers

People with alkaptonuria have a normal life expectancy. However, they will usually experience severe symptoms, such as pain and loss of movement in the joints, which considerably affect their quality of life.

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