U01.01.119 Alkaptonuria

Written by

in

Learning Objectives

  • Identify the enzyme deficiency responsible for Alkaptonuria.
  • Recognize the clinical hallmark of ochronosis in connective tissues and sclerae.
  • Explain why urine from these patients turns black upon standing.
  • Understand the relationship between tyrosine catabolism and arthralgia.

1. Pathophysiology and Genetics

Alkaptonuria is an autosomal recessive metabolic disorder involving the degradative pathway of Tyrosine to fumarate. It is caused by a congenital deficiency of the enzyme Homogentisate Oxidase.

When this enzyme is deficient:

  • Homogentisic Acid (HGA) builds up in the blood and tissues.
  • HGA is oxidized into a pigment-forming polymer that deposits in connective tissues.
  • While often considered “benign” because it does not cause intellectual disability, it leads to significant long-term physical complications.

2. Clinical Findings

The symptoms of Alkaptonuria often become more apparent as the patient ages, and the pigment accumulates.

  • Ochronosis: A characteristic bluish-black discoloration of the connective tissue, ear cartilage, and the sclerae (white of the eyes).
  • Urine Changes: The urine is initially normal in color but turns black when exposed to air for a prolonged period due to the oxidation of homogentisic acid.
  • Arthralgias: Homogentisic acid is toxic to cartilage. Over time, this leads to debilitating joint pain and arthritis, particularly affecting the spine and large joints.

Activity

Memory Hook: “Al-KAP-tonuria” sounds like “Black-CAP-tonuria” because the urine turns black like a dark cap was put on it.

3. Metabolic Summary

Feature Description
Deficient Enzyme Homogentisate Oxidase
Accumulated Substance Homogentisic Acid
End Product Blocked Fumarate (TCA cycle intermediate)

Clinical Notes & Corrections:

  • Diagnosis: Diagnosis is confirmed by measuring homogentisic acid in a 24-hour urine collection using gas chromatography-mass spectrometry.
  • Management: Treatment is largely symptomatic. High doses of Vitamin C (ascorbic acid) may be used to decrease the oxidation of HGA, though its long-term effectiveness in preventing joint disease is limited.

Activity