Alkaptonuria is a rare inherited metabolic disorder in which the body is unable to properly break down certain amino acids, specifically tyrosine and phenylalanine. Amino acids are the fundamental building blocks of protein.

To understand the problem in AKU, it is helpful to use an analogy. Think of your body’s metabolism as a complex, multi-step recipe for processing the ingredients from your food. When you consume protein, the amino acids phenylalanine and tyrosine enter a specific recipe pathway to be broken down. One of the intermediate ingredients created along the way is a substance called homogentisic acid (HGA).

• In a healthy person, a specific enzyme acts like a dedicated chef that instantly performs the next step in the recipe, breaking HGA down into other useful substances.
• In a person with alkaptonuria, this specific “chef”, the enzyme homogentisate 1,2-dioxygenase, is missing or broken.

Without this enzyme to perform the crucial next step, the recipe stops. The intermediate ingredient, homogentisic acid, cannot be processed further and begins to pile up to massive levels in the body. The body then tries to get rid of this excess HGA through the urine. When the urine is exposed to the air, the HGA oxidizes and turns into a dark, black-like pigment, which is the source of the tell-tale sign of dark urine.

The HGA that is not excreted in the urine slowly deposits in the body’s connective tissues, particularly cartilage. Over many decades, it polymerizes into a blue-black pigment. This process of pigment deposition and the resulting tissue damage is known as ochronosis. It is the slow, relentless progression of ochronosis that causes the severe joint and heart problems that appear in adulthood.

In my experience, one of the earliest signs that tips us off is dark-colored urine in infants, especially when it darkens upon standing. Most people don’t realize they have this condition until joint issues appear later in life.

Alkaptonuria is caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). This enzyme deficiency is, in turn, caused by mutations in the HGD gene.

The HGD gene, located on chromosome 3, contains the instructions for making the HGD enzyme. When the HGD gene is mutated, the instructions are faulty, and the body produces an enzyme that is either completely non-functional or has severely reduced activity. Without a working HGD enzyme, the body cannot break down homogentisic acid, leading to its accumulation.

I often explain to families that this is a genetic glitch in the body’s chemistry set. You can’t catch it from someone, it’s something you’re born with, even if symptoms take decades to appear.

Alkaptonuria is an inherited genetic disorder. It is not contagious and cannot be acquired. It is passed from parents to their children through a specific inheritance pattern known as autosomal recessive inheritance.

This means:

• For a child to have AKU, they must inherit two copies of the mutated HGD gene, one from their mother and one from their father.
• Parents are almost always unaffected carriers. A carrier is a person who has one normal copy of the HGD gene and one mutated copy. Their one normal gene produces enough of the HGD enzyme to prevent them having any signs of the disease. Most carriers are completely unaware of their genetic status.

When two carriers of the HGD gene mutation have a child, there are three possible outcomes for each pregnancy:

• There is a 25% chance that the child will inherit a mutated gene from both parents and will be affected with alkaptonuria.
• There is a 50% chance that the child will inherit one mutated gene and one normal gene and will be an unaffected carrier, like their parents.
• There is a 25% chance that the child will inherit two normal genes and will be neither affected nor a carrier.

Because both parents must carry the same rare faulty gene, the chances of having a child with an autosomal recessive condition like alkaptonuria are higher in communities where marriage between close relatives, such as first cousins, is a common cultural practice. This is because related individuals have a greater likelihood of carrying the same inherited genetic traits.

What I tell parents is this: even if you and your partner are healthy, you could still be carriers. That’s why newborn screening or genetic counseling is important in families with a history of rare conditions like this.

Signs and symptoms of AKU progress slowly over a person’s entire life and can be divided into distinct stages.

In Infancy and Childhood

• The only sign of AKU in a young child is often homogentisic aciduria. This is the classic finding where the child’s urine, upon standing and being exposed to air for several hours, will turn a dark brown or black color. This may be noticed as dark stains on a diaper.
• Otherwise, the child is typically healthy with no other symptoms.

In Early Adulthood (typically in the 20s and 30s)

The first visible signs of pigment deposition (ochronosis) begin to appear.

• Ocular Ochronosis: A blue-black or grayish discoloration may appear in the sclera (the whites of the eyes).
• Auricular Ochronosis: The cartilage of the ear may thicken and turn a bluish-gray color.
• Dark Sweat: Sweat may be discolored and can cause brown or black stains on clothing.
• The earwax may also be black.

In Later Adulthood (typically from age 30 onward)

This is when the debilitating consequences of decades of pigment deposition begin to emerge.

• Ochronotic Arthropathy (Joint Disease): This is the most common and significant complication of AKU. The black pigment deposits in the cartilage of the joints, making it brittle and causing it to break down. This leads to severe, painful, and early-onset osteoarthritis.
  • The large, weight-bearing joints are most affected, particularly the spine, hips, and knees.
  • Symptoms include chronic pain, stiffness, and a reduced range of motion.
• Spontaneous Tendon Ruptures: The ochronotic pigment can also weaken tendons.
• Cardiovascular Complications: Pigment can deposit on the heart valves, particularly the aortic and mitral valves, causing them to thicken and narrow (stenosis) over time.
• Kidney and Prostate Stones: Individuals with AKU have a higher risk of developing kidney stones and prostate stones.

I’ve often had patients present in their 40s or 50s with unexplained joint pain and black ear cartilage, only to discover alkaptonuria after digging into their history and ordering a urine test.

Alkaptonuria diagnosis is often significantly delayed. Because children are otherwise healthy, the early sign of dark urine is frequently missed or dismissed. Many individuals are not diagnosed until they are adults presenting with severe, early-onset joint pain.

The diagnostic process involves several steps:

1. Clinical Suspicion: A doctor may suspect AKU based on the patient’s history (e.g., lifelong dark urine) and physical signs (pigmentation in the eyes or ears, severe arthritis at a young age).
2. Urine Test for Homogentisic Acid (HGA): The definitive diagnosis is made with a quantitative urine test that measures the amount of HGA being excreted. In a person with AKU, the HGA level in urine will be extremely high (National Organization for Rare Disorders [NORD], 2021).
3. Genetic Testing: A blood test can be performed to sequence the HGD gene. Identifying two disease-causing mutations confirms the diagnosis and is useful for genetic counseling and screening other family members.

One quick test I do is ask patients to leave their urine sample at room temperature. If it darkens within a few hours, it’s highly suggestive, and we then confirm with HGA level testing or genetics.

There is no cure for alkaptonuria, but treatment focuses on slowing progression, relieving symptoms, and preventing complications.

1. Disease-Modifying Therapy: Nitisinone

The most significant advance in AKU management is a drug called nitisinone.

• Mechanism: Nitisinone works by blocking an enzyme earlier in the tyrosine breakdown pathway. By blocking the recipe at an earlier stage, it prevents the production of homogentisic acid in the first place.
• Impact: Clinical trials have shown that it can reduce the level of HGA in the urine by over 99%. It is believed that by stopping the production of HGA, this treatment can halt the entire process of ochronosis, preventing the development and progression of the debilitating arthritis and other complications (NIH Genetic and Rare Diseases Information Center [GARD], 2024).
• Considerations: As a specialized medication for a rare disease, access and cost can be significant considerations depending on the patient’s location and healthcare system.

2. Supportive and Symptomatic Care

This remains a critical part of management for all patients, especially those diagnosed later in life who already have significant joint damage.

• Pain Management: Controlling the pain from ochronotic arthritis is a primary goal. This includes using nonsteroidal anti-inflammatory drugs (NSAIDs) and other pain-relieving medications.
• Physical and Occupational Therapy: Therapy can help to maintain joint mobility, strengthen surrounding muscles, and provide strategies and adaptive equipment to cope with physical limitations.
• Joint Replacement Surgery: Many adults with AKU will eventually require joint replacement surgery, particularly for their hips, knees, or shoulders, to relieve pain and restore function.
• Dietary Management: A low-protein diet can help to reduce the intake of phenylalanine and tyrosine, which in turn can modestly lower the amount of HGA the body produces.

3. Monitoring

 Lifelong, regular follow-up with a multidisciplinary team including a rheumatologist, orthopedic surgeon, and cardiologist, is necessary to monitor for and manage complications.

I often explain that nitisinone has changed the outlook for many patients but it’s not a magic fix. A combined approach with diet, regular monitoring, and symptom relief is still essential.

Alkaptonuria is a rare inherited disease that for most of a person’s life, may present with only curious, harmless signs. However, beneath the surface, the slow and steady accumulation of homogentisic acid leads to ochronosis, a process that causes profound and painful damage to the joints and other tissues in adulthood. While the journey for those diagnosed late often involves managing debilitating arthritis, the future for those diagnosed today is dramatically different. The development of nitisinone, a therapy that can halt the progression of the disease at its source, represents a monumental shift in care. A correct diagnosis, even in adulthood, is the critical first step to accessing this life-altering treatment and to implementing a comprehensive management plan to protect against the long-term consequences of this unique metabolic disorder.

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2024). Alkaptonuria. Retrieved from https://rarediseases.info.nih.gov/diseases/5799/alkaptonuria

National Organization for Rare Disorders (NORD). (2021). Alkaptonuria. Retrieved from https://rarediseases.org/rare-diseases/alkaptonuria/

The AKU Society. (n.d.). What is AKU? Retrieved from https://akusociety.org/what-is-aku/