Alkaptonuria

A rare genetic metabolic disorder

Alkaptonuria
Synonyms	Black urine disease, black bone disease, alcaptonuria
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Field	Medical genetics, metabolic medicine
Symptoms	Dark urine, bluish-black discoloration of connective tissues and skin (ochronosis), joint pain, arthritis, heart valve disease, kidney and prostate stones
Complications	Severe arthritis, heart disease, renal stones, pigmentation of skin and eyes
Onset	Symptoms often appear in adulthood (30s–40s), but dark urine may be seen in infancy
Duration	Lifelong
Types	Autosomal recessive metabolic disorder
Causes	Deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD gene mutation)
Risks	Family history, consanguinity, autosomal recessive inheritance
Diagnosis	Urine organic acid analysis, genetic testing, elevated homogentisic acid in urine
Differential diagnosis	Maple syrup urine disease, phenylketonuria, ochronosis from exogenous sources
Prevention	None known
Treatment	Symptomatic management, physical therapy, joint replacement surgery in advanced cases
Medication	Nitisinone (off-label use), pain relievers
Prognosis	Progressive; joint and cardiac complications may reduce quality of life
Frequency	Rare (approximately 1 in 250,000 to 1,000,000 live births)
Deaths	Related to complications (e.g., cardiac or renal)

Urine of a 4-month-old baby with dark urine (on the left) after 10% ammonia and 3% silver nitrate were added. The tube in the middle is a normal control. Color change on alkalinization is not a specific test, and confirmatory investigations are needed.

Intervertebral discs calcification due to ochronosis

Alkaptonuria is a rare genetic disorder characterized by the accumulation of homogentisic acid in the body. This condition is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase, which is necessary for the proper breakdown of tyrosine and phenylalanine, two important amino acids.

Pathophysiology

In individuals with alkaptonuria, the lack of functional homogentisate 1,2-dioxygenase leads to the accumulation of homogentisic acid in the body. This acid is excreted in the urine, which can turn dark upon exposure to air, a hallmark of the condition. Over time, homogentisic acid also deposits in connective tissues, leading to a condition known as ochronosis. This results in the darkening of tissues, particularly affecting the cartilage and skin.

Clinical Features

The clinical manifestations of alkaptonuria typically appear in adulthood, although the darkening of urine can be observed in infancy. The major symptoms include:

• Ochronosis: The deposition of pigment in connective tissues, leading to darkened ear cartilage and sclera of the eyes.
• Arthropathy: Progressive joint disease due to the accumulation of pigment in the cartilage, leading to osteoarthritis, particularly in the spine, knees, and hips.
• Cardiovascular complications: Deposition of pigment in the heart valves can lead to valvular heart disease.
• Renal stones: Increased risk of kidney stones due to the accumulation of homogentisic acid.

Pathophysiology of alkaptonuria (AKU) is due to the absence of functional homogentisate dioxygenase (HGD) in the liver.

Diagnosis

The diagnosis of alkaptonuria is primarily based on clinical features and the detection of elevated levels of homogentisic acid in the urine. Genetic testing can confirm mutations in the HGD gene, which encodes the enzyme homogentisate 1,2-dioxygenase.

Chemical skeletal formula of homogentisic acid, which accumulates in the body fluids of people with alkaptonuria.

Management

There is currently no cure for alkaptonuria, and treatment is primarily supportive. Management strategies include:

• Dietary modification: Reducing intake of phenylalanine and tyrosine may help decrease homogentisic acid levels.
• Pain management: Use of analgesics and anti-inflammatory drugs to manage joint pain.
• Physical therapy: To maintain joint function and mobility.
• Surgical intervention: Joint replacement surgery may be necessary for severe arthropathy.

Prognosis

The prognosis for individuals with alkaptonuria varies. While the condition is chronic and progressive, many individuals can manage symptoms effectively with appropriate care. However, the risk of complications such as severe arthritis and cardiovascular issues can impact quality of life.

Related pages

• Genetic disorder
• Metabolic disorder
• Ochronosis
• Homogentisic acid

External links

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