Alkaptonuria

The following family members should be tested:

Find other people with Alkaptonuria at:

Specialist for Alkaptonuria include:

Finding a genetic counselor and/or a medical geneticist near you would be an ideal way to make sure you have the information you need to make sure your Alkaptonuria is managed correctly. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Make sure your primary care physician has the appropriate information on Alkaptonuria in order to ensure that you are receiving the proper medical management.

The usual abbreviation for Alkaptonuria is AKU.

As of May 2019, nitisinone has been approved by the FDA. However, it is not currently licensed for the treatment of Alkaptonuria.

People with Alkaptonuria are not expected to have a shorter lifespan than people without Alkaptonuria.

Alkaptonuria is a genetic disease that happens when a person’s body does not have the enzyme homogentisic dioxygenase (HGD). This enzyme helps break down a toxic compound called homogentisic acid, or HGA. When a person cannot break down HGA, it accumulates in the body and leads to a variety of health complications, many of which are not present until adulthood.
There are three main symptoms of Alkaptonuria. The first is HGA in the urine. This causes the urine to turn dark when it is exposed to air. However, darkening may not occur until several hours later. Many people with Alkaptonuria never notice this type of abnormal color to their urine. This may be the only sign of Alkaptonuria in children.
The second symptom is called ochronosis. This is a term that means a person’s connective tissue has a bluish-black color. This color is caused by a buildup of HGA in connective tissue. People can see this coloring in the white parts of their eyes, ear cartilage, and on the skin of their hands from underlying tendons. People with Alkaptonuria may also see this coloring in their ear wax and in their sweat.
The last symptom is arthritis. People with Alkaptonuria typically have arthritis in their spine and in their large joints from the buildup of HGA.

Health problems associated with Alkaptonuria include:

Changes in the HGD gene cause a person’s body to be deficient of the homogentisate 1,2-dioxygenase enzyme. When a person does not have this enzyme, homogentisic acid cannot be broken down into maleyloacetoacetic acid in the tyrosine degradation pathway. When homogentisic acid cannot be broken down, it accumulates in the body.

Changes in the HGD gene cause Alkaptonuria. This gene provides instructions for making the enzyme homogentisate 1,2-dioxygenase that breaks down homogentisic acid. This is the only gene that is known to cause Alkaptonuria. At least 115 different changes that cause Alkaptonuria have been identified in the HGD gene. A database of these changes can be found at http://hgddatabase.cvtisr.sk/variants.php?action=search_unique&select_db=HGD.

Nitisinone is a drug that was originally approved by the FDA to treat another condition, Tyrosinemia Type I. Tyrosinemia is caused by a deficiency of a different enzyme in the same pathway that causes Alkaptonuria. Research has shown that nitisinone is an effective at preventing the buildup of homogentisic acid in the body. Current research is focused on looking at long term use of nitisinone in people with alkaptonuria and the use of nitisinone in children with alkaptonuria. There is some concern about potential side effects of nitisinone. In studies to date, treated individuals had elevated tyrosine in their blood. Some developed corneal crystals as a result. Theoretically, neurological complications associated with elevated tyrosine could result, but in one three year study, side effects were minimal. There was a positive trend showing slowing of aortic stenosis, but there was no difference in the hip range of motion between the treatment and control groups. Studies are ongoing.

The main source for the body’s phenylalanine, an amino acid, comes from protein that we eat. The gene responsible for Alkaptonuria is found in the pathway that breaks down phenylalanine. Therefore, the more protein we eat, the more phenylalanine we have. The more phenylalanine we have, the more homogentisic acid we have as the phenylalanine gets broken down in the body.

A variant is a change in the DNA sequence that is different that what is considered to be "normal." A pathogenic variant is one that has been found to cause disease. The HGD gene currently has over 130 pathogenic variants identified. If you have two known pathogenic variants, this is consistent with a diagnosis of Alkaptonuria. Having one is associated with being an unaffected carrier. Occasionally genetic testing might find a variant that has not been previously seen, and this will be classifed as a "variant of unknown significance" (VUS). When a VUS is found it is not certain if this change is part of normal human genetic variation or if it is a change that will cause Alkaptonuria. Because the diagnosis of Alkaptonuria is based on clinical findings, a person who is identified to have a variant of unknown significance should base their medical management on the presence or absence of the clinical findings of Alkaptonuria.

Nitisinone can increase the amount of tyrosine in a person’s body. Increased levels of tyrosine can lead to corneal crystals (deposits of tyrosine into a person’s eye). High levels of tyrosine can also cause skin on the palms and feet to become thickened. These side effects can be reversed when tyrosine levels are lowered. Theoretically, neurological issues related to elevated tyrosine can occur, but this has not yet been observed in studies. Research is ongoing.

There are three main symptoms of Alkaptonuria. Most occur only in adulthood. The first is HGA in the urine. This causes the urine to turn dark when it is exposed to air. However, darkening may not occur until several hours later. Many people with Alkaptonuria never notice this type of abnormal color to their urine. This may be the only noticeable sign in children.
The second symptom is called ochronosis. This is a term that means a person’s connective tissue has a bluish-black color. This color is caused by a buildup of HGA in connective tissue. People can see this coloring in the white parts of their eyes, ear cartilage, and on the skin of their hands from underlying tendons. People with Alkaptonuria may also see this coloring in their ear wax and in their sweat.
The last symptom is arthritis. People with Alkaptonuria typically have arthritis in their spine and in their large joints from the buildup of HGA.

Research has not yet determined the long term effects of nitisinone. Nitisinone is known to have a risk on congnitive development. Additionally, children with Alkatoptonuria are not affected by the symptoms that adults are. Because of this, it is not recommended that children be started on nitisinone for the treatment of Alkaptonuria. Instead, nitisinone should be considered for adults.

Every person with Alkaptonuria will have high levels of HGA in their urine, darkened connective tissue, and arthritis.

A genetic counselor can provide you with more information about Alkaptonuria. Genetic counselors are healthcare professionals that have specialized training in medical genetics and counseling to provide personalized help to patients on their genetic health. Genetic counselors can be found on the National Society of Genetic Counselors website.

Unusual symptoms of Alkaptonuria include:

Alkaptonuria is not included in newborn screening as of June, 2016. Parents who are known carriers of the condition can request testing from their doctor for a new baby. Genetic testing is available for Alkaptonuria, but it is not required for the diagnosis. A genetic counselor near you can discuss genetic testing with you. Genetic counselors can be found on the National Society of Genetic Counselors website.

Tests for Alkaptonuria include:

There is clinical research currently being conducted for Alkaptonuria as of May 2019. Most of the current research is focused on treating Alkaptonuria with a drug called NTBC. This drug has been shown to reduce the amount of HGA excreted in the urine, and clinical trials are currently looking at possible long term effects of the drug. More information about the studies can be found on clinicaltrials.gov when searched for alkaptonuria.

Currently, there is no way to predict the severity of the disorder. Different individuals secrete different amounts of HGA, but there is no information on the reason for this. People with Alkaptonuria are encouraged to limit the stress on their spine and large joints by avoiding excessive and intense exercise to help delay arthritis. It has been shown that people who stay active, but avoid these types of activities have better pain management.

Current treatment is aimed at specific symptoms of Alkaptonuria. Such as:

For more information about clinical trials, email Wendy Introne, MD, Staff Clinician at the Office of the Clinical Director, National Human Genome Research Institute located at the National Institutes of Health in Washington, DC at wintrone@nhgri.nih.gov.

Alkaptonuria is progressive. Discolored urine is present at birth. The, ochronosis develops around 30 years of age, and arthritis begins around 50 years of age.

Upon diagnosis of Alkaptonuria, the following exams should be performed to establish the extent of disease:

It has been suggested that high levels of vitamin C can help prevent ochronic pigment from being deposited in the body. However, there have not been any credible studies published that have shown the usefulness of Vitamin C in the treatment of Alkaptonuria.

A licensed dietician can help you with a low protein diet and make sure that you carry it out correctly. Specifically, dieticians that work in metabolic clinics have experience with specialized diets required by other metabolic disorders in addition to Alkaptonuria. Information on metabolic dietitians can be found at the Genetic Metabolic Dieticians International (GMDI) website: http://www.gmdi.org/Resources/Find-a-Metabolic-Dietitian.

The prescription for physical activity for patients with Alkaptonuria includes:

About 50% of people with Alkaptonuria have a joint replacement by the age of 55 to treat arthritis. Joint replacement is an option for anyone who has been diagnosed with Alkaptonuria, and it is primarily considered to reduce pain.

Alkaptonuria is inherited in an autosomal recessive manner. This means that both copies of the gene have to have changes for the person to show signs and symptoms of the disease. If only one copy of the gene has a change, the person is a carrier for Alkaptonuria and does not have the condition.

Opportunities for joining others with Alkaptonuria can be accessed through RareConnect and Patients Like Me. RareConnect: https://www.rareconnect.org/en/community/alkaptonuria-aku
Patients Like Me: http://www.akusociety.org/patientslikeme To learn about advocacy and how to organize a support group in your area for others with Alkaptonuria or rare disease, see the Genetic Alliance website at http://www.geneticalliance.org/.

To donate to the Alkaptonuria Society, follow their instructions provided on their webpage below. Donations can be made online in single or recurring payments at: http://www.akusociety.org/make-a-donation.html. Donations may also be made offline.
Donations can also be made to the Alkaptonuria Society through Just Giving: https://www.justgiving.com/4w350m3/donation/direct/charity/181892/?targetdevice=desktop#MessageAndAmount

Alkaptonuria is diagnosed based on the detection of a significant amount of HGA in a 24 hour sample of urine. Normal HGA levels in a 24 hour sample is 20-30 mg. Individuals with Alkaptonuria excrete between 1-8 grams of HGA in their urine in one day. Genetic testing is available to look for changes in the HGD gene, but it is not required for diagnosis. Genetic counselors can be found on the National Society of Genetic Counselors website.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office at Toll-free: (800) 411-1222, TTY: (866) 411-1010 or Email: prpl@cc.nih.gov.
For information about clinical trials sponsored by private sources in the U.S. contact: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/.

There are no centers of excellence for Alkaptonuria in the United States that we are aware of as of May 2019.
There is currently one center of excellence for Alkaptonuria in Liverpool, England. The Robert Gregory National Alkaptonuria Centre is home to a team that specializes in treating people with Alkaptonuria: http://www.akusociety.org/national-aku-centre
The Alkaptonuria Society also provides the opportunity to contact an expert: http://www.akusociety.org/contact-an-expert . If you are looking for a metabolic clinic for treatment in the United States, you can search for the clinic or clinics in your state.

In the United States, 1 in 250,000- 1 in 500,000 individuals have Alkaptonuria.

Diagnostic testing for Alkaptonuria is most accurate using HGA levels in urine. Genetic testing can be performed, and is recommended to start with sequence analysis first, which has a detection rate of 90%. Carrier testing is not accurate using urine analysis. Carrier testing and prenatal diagnosis can only be done using genetic testing. The causative mutations in the affected family member must be identified first for accurate carrier screening and prenatal diagnosis.

There is nothing that can cause someone’s Alkaptonuria to worsen. However, the buildup of homogentisic acid affects connective tissue that leads to arthritis. To try and reduce the progression of severe arthritis, physical stress to the spine and large joints should be avoided.

People with Alkaptonuria may follow a low-protein diet to reduce the amount of HGA accumulating in the body. However, there is no medical evidence yet to suggest that a low protein diet alone is enough to treat Alkaptonuria although it may help. Protein does not need to be cut out of the diet completely. There have been no long term studies looking at the effect of a low protein diet on the symptoms of Alkaptonuria.

Carriers (people with only one gene change) do not have symptoms or show signs of Alkaptonuria.

The more a child plays has not been correlated with a higher severity of disease. Instead, it is recommended, as it is with adults, that high impact activities and contact sports are limited.

Women and men are affected with Alkaptonuria in equal numbers. However, men tend to show signs and symptoms about 5-10 years earlier than women do.

Symptom specific treatments for Alkaptonuria include:

Other names for Alkaptonuria include:

Support groups for Alkaptonuria include:

There are not different forms of Alkaptonuria. Many individuals with Alkaptonuria are typically asymptomatic and unaware of their condition until adulthood. Others were diagnosed because their parents noticed discolored urine in their diapers. All individuals with two changes in the HGD gene will have a buildup of HGA, ochronosis, and arthritis. Discolored urine is present from birth. Ochronosis is present around 30 years of age on average, and arthritis begins around 50 years of age on average.

Some diseases that look like Alkaptonuria include: