U01.01.111 Alkaptonuria

Alkaptonuria is a rare inherited metabolic disorder caused by the congenital deficiency of the enzyme homogentisate oxidase. This enzyme is involved in the degradation of the amino acid tyrosine to fumarate, and its absence leads to the accumulation of homogentisic acid, a substance that can form dark pigments in tissues.

Pathophysiology

Deficiency of homogentisate oxidase in the tyrosine degradation pathway.
Accumulation of homogentisic acid in tissues.
Homogentisic acid is deposited in connective tissues, such as cartilage and sclerae, causing a characteristic bluish-black discoloration.

Clinical Findings

Bluish-black discoloration of connective tissues, including ear cartilage and sclerae (known as ochronosis).
Urine turns black upon prolonged exposure to air due to the oxidation of homogentisic acid.
May lead to debiliating arthralgias due to the toxic effects of homogentisic acid on cartilage, often in large joints like the hips and knees.

Inheritance Pattern

Autosomal recessive: Both parents must carry one copy of the mutated gene for the disease to manifest in the offspring.

Points to Remember

Point	Details
Pathophysiology	Deficiency of homogentisate oxidase in the tyrosine degradation pathway.
Clinical Features	Bluish-black connective tissue, ear cartilage, and sclerae.
Urine	Turns black on exposure to air due to homogentisic acid.
Joint Involvement	Debilitating arthralgias from homogentisic acid deposition in cartilage.
Inheritance	Autosomal recessive.

Summary

Alkaptonuria is characterized by bluish-black discoloration of tissues and dark urine due to the accumulation of homogentisic acid.
It is usually benign but may cause joint problems later in life.
Diagnosis is based on the clinical signs and urine testing.

Learning Objective for USMLE Step 1:

Understand the pathophysiology, inheritance, and clinical manifestations of Alkaptonuria, including the role of homogentisate oxidase deficiency in the degradation of tyrosine.

USMLE Step 1 Review Series

Curriculum