Alkaptonuria, or 'black urine disease', is a rare inherited disorder that prevents the body fully breaking down two protein building blocks (amino acids), called tyrosine and phenylalanine.
It results in a build-up of a chemical called homogentisic acid in the body.
A person with alkaptonuria will have inherited a faulty version of a particular gene – the HGD gene (see box) – from both their parents.
Normally, amino acids are broken down into smaller and smaller molecules in a series of chemical reactions. In alkaptonuria, a chemical produced along the way – homogentisic acid – cannot be broken down any further, as it normally would be, and gradually builds up in the body.
One of the earliest signs is dark-stained nappies, as homogentisic acid causes urine to turn black when exposed to air.
If this sign is overlooked, 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 in adults?
Over the course of many years, homogentisic acid levels build up and it forms a larger molecule (polymer) that becomes deposited in tissues throughout the body.
This polymer can be found in almost any area of the body, including the cartilage, tendons, nail beds, eyelids, genital area, eardrums and larynx (voice box). It stains the tissues dark and causes a wide range of symptoms.
Joints and bones
When a person with alkaptonuria reaches their 20s-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 early symptoms of osteoarthritis.
Eventually, cartilage may become brittle and break, leading to joint and spinal destruction. Joint replacement operations are often needed.
Ears and eyes
An obvious sign of alkaptonuria in adults is thickening and blue-black discolouration of ear cartilage. This discolouration is known as ochronosis.
Earwax may be black or reddish-brown.
Also, many people develop brown or grey spots on the white of their eye (see main picture).
Skin and nails
Alkaptonuria can result in discoloured sweat, which can stain clothes and cause some people to have blue or black speckled areas of skin. Nails may also turn a bluish colour.
The skin colour changes are most obvious on areas exposed to the sun and where sweat glands are found – the cheeks, forehead, armpits and genital area.
Homogentisic acid molecules can sometimes build up around the windpipe and larynx. However, it is the stiffening of the spine, which prevents the chest expanding, that can sometimes cause shortness of breath and difficulty breathing.
Heart, kidney and prostate problems
Deposits of homogentisic acid around heart valves can cause these to harden and turn brittle and black. Blood vessels can also become stiff and weaken. This can lead to heart disease and may require heart valve replacements.
It can also lead to kidney stones, bladder stones and prostate stones.
How alkaptonuria is 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 that (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, found on chromosome number 3.
You need to inherit a faulty HGD gene from both your parents to develop alkaptonuria. The chances of this are slim, which is why the disease is rare – affecting just one in 250,000 to 500,000 people worldwide.
If the parents of a person with alkaptonuria each carry only one copy of the faulty gene, they typically will not show signs and symptoms of the condition.
How is alkaptonuria managed?
Alkaptonuria is a lifelong condition – there's currently no treatment or cure.
However, a drug called nitisinone has shown some promise, and painkillers and lifestyle changes may help you to cope with the symptoms.
Nitisinone is not licensed for alkaptonuria – it is offered 'off-license' at the National Alkaptonuria Centre, the treatment centre for all alkaptonuria patients based at Royal Liverpool University Hospital.
Nitisinone prevents the production of homogentisic acid, which causes the damage in alkaptonuria.
It's currently an experimental treatment, while clinical trials into its effectiveness are underway.
The AKU Society (see below) has information on DevelopAKUre – a clinical trial programme for the drug nitisinone. Register your interest for DevelopAKUre.
If the disease is picked up in childhood, you may be able to slow its progression by restricting protein in the diet (this may reduce levels of tyrosine and phenlyalanine).
It's probably not worth persisting with protein restriction into adulthood, although eating excessive amounts of protein may worsen the condition. It's best to monitor your protein intake but not restrict it completely. Speak to your doctor about this.
If alkaptonuria causes pain and stiffness, you may think exercise will make your symptoms worse. But usually, regular exercise that keeps you active and mobile builds up muscle, thereby strengthening the joints. Exercise is also good for relieving stress, losing weight and improving your posture, all of which will ease symptoms.
The AKU Society (see below) recommends avoiding exercise that puts additional strain on the joints (such as boxing, football and rugby) and trying gentle exercise such as yoga, swimming and pilates.
Your GP, or possibly a physiotherapist, will discuss the benefits you can expect from your exercise programme and can give you an exercise plan to follow at home. It is important to follow this plan because there is a small risk that the wrong sort of exercise may damage your joints.
Speak to doctor about painkillers and other techniques to manage pain.
You may want to try transcutaneous electrical nerve stimulation (TENS) – this uses a machine to numb the nerve endings in your spinal cord which control pain, so you can no longer feel it. Treatment with TENS is usually arranged by a physiotherapist.
A diagnosis of alkaptonuria can initially be confusing and overwhelming. Like many people with a long-term health condition, 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 and visit the AKU Society website, a charity offering support to patients, their families and caregivers.
Sometimes, surgery may be necessary if joints are damaged and need replacing, or if heart valves or vessels have hardened.
aortic valve replacement
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 impact on quality of life.
Visit the AKU Society for more information and support.
Many people with alkaptonuria develop brown or grey spots on the surface of their eye
Role of the HGD gene
The body breaks down protein into smaller units called amino acids.
Two particular amino acids – phenylalanine and tyrosine – are broken down further by an enzyme called homogentisate oxidase.
The HGD gene provides instructions for making this enzyme, so if you have two faulty copies of this gene (as in alkaptonuria), this enzyme won't work properly.
The end result is a build-up of a byproduct called homogentisic acid (which would normally be broken down further, if the enzyme worked properly).