Alkaptonuria (AKU): symptoms, diagnosis and treatment of black bone disease

Alkaptonuria is an inherited error of metabolism. The body normally breaks down the amino acid tyrosine through a series of steps, and one step needs an enzyme called homogentisate dioxygenase. In AKU this enzyme is missing or does not work. The University of Liverpool describes it as deficiency of this enzyme resulting in accumulation of homogentisic acid (HGA), which deposits as a black pigment in tissues in a process called ochronosis, leading to progressive damage if untreated.

The AKU Society adds that AKU normally affects only one in every 250,000 people worldwide, which is why many GPs will never see a case. Because HGA builds up gradually, the damage it causes accumulates over time rather than appearing all at once. A study from the National Alkaptonuria Centre notes that in certain countries, such as Slovakia, the condition is observed more commonly.

The AKU Society lists the main features as black or dark urine, which is the first symptom most patients experience, osteoarthritis, with every patient experiencing joint pain at some point, black spots in the whites of the eyes appearing as people get older, blue-black discolouration of the ears, and heart complications as HGA builds up in the vessels and valves of the heart. The condition can also affect other areas of the body.

The University of Liverpool news release describes the severe damage as involving the spine and joints, leading to repeat joint surgeries, and adds that people develop stones (kidney, prostate, gall bladder, salivary), fractures due to osteoporosis, ruptures of tendons, ligaments and muscle, and heart valve damage. The National Alkaptonuria Centre paper adds a spondyloarthropathy with progressive kyphoscoliosis and impaired spinal and thoracic mobility, and aortic valve stenosis.

The AKU Society describes the build-up as happening over time, with dark urine as the first symptom and joint damage and other complications accumulating later. How early and how severely the problems develop varies between people.

See a GP if you or your child have urine that turns dark or black on standing, particularly if it has always done so, or if you have early-onset joint pain and stiffness, especially of the spine, with dark staining of the ears or eyes. These features can be mistaken for more common conditions, so it helps to mention the urine colour specifically. A diagnosis in a family usually leads to genetic counselling for relatives.

Other causes of dark urine need urgent attention in their own right, and any blood in the urine, severe pain, fever or an unexplained change should be assessed promptly through your GP or NHS 111.

Diagnosis is made through specialist metabolic or genetic testing arranged by a hospital team after referral. The National Alkaptonuria Centre paper describes AKU as an autosomal recessive disorder resulting from a congenital deficiency in homogentisate-1,2-dioxygenase, and the NHS directory states that the national service is open to patients with a confirmed diagnosis of AKU.

The NHS directory describes the national service as referral by GP, and says the clinic offers expert advice, state-of-the-art imaging and access to an off-label drug, nitisinone. Because the condition is so rare, many people are diagnosed late, after years of joint symptoms, so raising a lifelong history of dark urine can speed a correct diagnosis.

AKU is recessive, meaning a person needs a changed copy of the gene from each parent to be affected. The AKU Society explains that it is caused by a mutation of each of a pair of chromosomes, and that if two people carry the faulty gene their child still has only a 25% chance of developing AKU. People who carry one changed copy are usually unaffected. Relatives of someone with AKU may want to ask their GP about a referral to a clinical genetics service for information about carrier testing and options in family planning.

For many years management was supportive. The National Alkaptonuria Centre paper describes supportive medical management as the mainstay of treatment, including a low-protein diet, analgesia and arthroplasty (joint replacement). Pain control, physiotherapy, and joint replacement when needed remain important parts of care.

Nitisinone is a drug that reduces the formation of homogentisic acid. It is licensed for a different condition, hereditary tyrosinaemia type 1, and the National Alkaptonuria Centre uses it off licence at 2 mg daily for people with AKU. Earlier studies reported a reduction of more than 94% in urinary HGA. The University of Liverpool reported in August 2018 that an observational study of 39 people given 2 mg of nitisinone daily for three years showed that the drug stops the disease by decreasing HGA, and that it not only arrested but partially reversed ochronosis, with less severe osteoarthritis in the spine, knees and elbows and a reduced risk of heart disease.

Nitisinone raises the level of the amino acid tyrosine in the blood, and the centre paper reports a seven- to eight-fold increase over 36 months, which is why people on treatment are monitored. The NHS directory says that all patients taking nitisinone will be carefully monitored in the months following their clinic. Because the dietary and monitoring aspects are specialised, the drug is used only under the national service rather than prescribed in routine primary care.

Living with AKU means managing a long-term, slowly progressive condition. The NHS directory notes that further support is available via the patient group, the AKU Society. Practical steps include asking a physiotherapist for advice on keeping joints moving and protecting the spine and weight-bearing joints, and being aware that tendons and ligaments can rupture, as the University of Liverpool notes.

A rare diagnosis can feel isolating. Patient organisations and the specialist centre can connect people with others who have the same condition, and regular follow-up ensures new problems such as heart valve changes or stones are picked up.

The National Alkaptonuria Service at the Royal Liverpool University Hospital is an NHS service, free to eligible patients, to which a GP refers. The NHS directory says people from Wales and Ireland can apply for funding from their local healthcare provider. The NHS directory describes the national service as the route to specialist advice, imaging and nitisinone.