Alkaptonuria (AKU) is a rare, inherited metabolic disorder that prevents the body from fully breaking down two protein building blocks, tyrosine and phenylalanine. This leads to a buildup of a substance called homogentisic acid in the body. The condition has significant historical importance in the field of genetics. It was one of the first diseases to be characterized as an “inborn error of metabolism” by the English physician Sir Archibald Garrod in the early 20th century.
Garrod studied how alkaptonuria was passed down in families and, with the help of biologist William Bateson, realized it followed the principles of recessive inheritance that Gregor Mendel had described. His work established a foundational link between inherited genes and body chemistry, showing how a gene defect could lead to a missing enzyme and result in disease. This concept moved the understanding of such conditions away from being caused by infections and toward a biochemical and genetic basis.
The Genetic Cause of Alkaptonuria
Alkaptonuria is caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene. This gene holds the instructions for making an enzyme that breaks down a molecule called homogentisic acid (HGA), an intermediate product from the metabolism of amino acids tyrosine and phenylalanine. When the HGD gene is mutated, the body produces a deficient enzyme that cannot perform its job correctly.
This genetic defect results in a disruption of the metabolic process. Without a functional homogentisate 1,2-dioxygenase enzyme, HGA cannot be processed further. Consequently, HGA accumulates in the bloodstream and tissues throughout the body.
The condition is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated HGD gene, one from each parent, to develop the disorder. People who have only one copy of the mutated gene are carriers; they do not show symptoms of alkaptonuria but can pass the gene on to their children. This inheritance pattern is why the condition is more likely to appear in the children of parents who are related, such as first cousins.
Signs and Long-Term Health Effects
The accumulation of homogentisic acid (HGA) leads to progressive health problems over a person’s lifetime. One of the earliest and most recognizable indicators of alkaptonuria is urine that darkens to a brown or black color when it is exposed to the air for a period of time. This feature is often noticed in the diapers of infants with the condition, serving as the first clue for diagnosis.
As HGA circulates in the body over years, it deposits onto connective tissues like cartilage, tendons, and skin, forming a bluish-black pigment. This process is known as ochronosis. The discoloration is often most visible in the cartilage of the ears, which may appear gray or blue, and as dark spots on the sclera, the white part of the eyes.
The most severe consequence of long-term HGA deposition is a form of osteoarthritis, referred to as ochronotic osteoarthropathy. This condition develops much earlier than typical age-related arthritis, often beginning in a person’s 30s. The HGA makes the cartilage brittle and prone to erosion, leading to chronic inflammation, stiffness, and joint pain. The spine is frequently the first and most severely affected area, with fusion of the vertebrae being a common outcome. The large weight-bearing joints, such as the hips, knees, and shoulders, are also heavily impacted.
Beyond the joints, the buildup of HGA can affect other parts of the body. The pigment can deposit on heart valves, particularly the aortic and mitral valves, causing them to harden and narrow, a condition known as stenosis. This can eventually require surgical intervention. Additionally, individuals with alkaptonuria have a higher risk of developing kidney stones and, in some cases, prostate stones.
Diagnosis and Treatment Options
Diagnosing alkaptonuria begins with the observation of its characteristic signs, such as darkened urine. A definitive diagnosis is made through a urine test that uses a technique called gas chromatography-mass spectrometry to detect abnormally high levels of homogentisic acid (HGA). To confirm the underlying cause, genetic testing is performed to identify mutations in the HGD gene.
While there is no cure for alkaptonuria, treatment focuses on managing symptoms and slowing the progression of the disease. The primary medication used is nitisinone. This drug works by blocking an enzyme called 4-hydroxyphenylpyruvate dioxygenase, which acts earlier in the same metabolic pathway as HGA production. By inhibiting this step, nitisinone prevents the accumulation of HGA in the body.
Managing the arthritis associated with ochronosis involves a combination of pain relief medications, physical therapy to maintain joint mobility and muscle strength, and occupational therapy to adapt daily activities. For many individuals, severe joint damage makes joint replacement surgery for the hips, knees, or shoulders necessary to restore function and alleviate pain.
Supportive therapies are also used. A diet with restricted intake of protein, specifically the amino acids tyrosine and phenylalanine, can help reduce the amount of HGA the body produces. This dietary approach is often used in conjunction with other treatments. Regular monitoring of heart health and kidney function is necessary to address potential complications as they arise.