Lecture on Alkaptonuria

Overview

• Alkaptonuria is an inborn error of metabolism involving the amino acids phenylalanine and tyrosine.
• Related to the metabolic pathway: Phenylalanine → Tyrosine → Para-hydroxyphenylpyruvate → Homogentisate → 4-Maleylacetoacetate → 4-Fumarylacetoacetate → Fumarate and Acetoacetate.
• Phenylalanine and tyrosine are both glucogenic and ketogenic amino acids as they contribute to glucose and fat formation.

Disorders Related to Enzyme Deficiencies

• Phenylalanine hydroxylase deficiency: Leads to Phenylketonuria.
• Tyrosine transaminase deficiency: Leads to Tyrosinemia type 2.
• Para-hydroxyphenylpyruvate hydroxylase deficiency: Causes Neonatal Tyrosinemia.
• Homogentisate oxidase deficiency: Causes Alkaptonuria.
• 4-Maleylacetoacetate isomerase and fumarylacetoacetate hydrolase deficiencies: Lead to Tyrosinemia type 1.

Alkaptonuria Specifics

• Genetics: Autosomal recessive disorder.
• Prevalence: Approximately 1 in 250,000 births.
• Symptoms:
  • Deposition of alkapton bodies in ear pinna, nose cartilage, intervertebral discs.
  • Arthritis due to deposition in connective joint tissues.
  • Dark or black urine on standing when it becomes alkaline.
• Metabolic Pathway:
  • Homogentisate is oxidized by homogentisate oxidase into benzoquinone acetate.
  • Polymerization of benzoquinone acetate gives alkapton which deposits in tissues leading to ochronosis.

Laboratory Diagnosis

• Observation of dark urine upon standing.
• Positive ferric chloride test.
• Strong positive Benedict test due to excretion of homogentisate.

Treatment

• Generally no specific treatment is required; the condition is often benign and asymptomatic.
• Dietary Management: Limit phenylalanine intake to less than 500 mg per day.
• Symptomatic Treatment: Only necessary when symptoms develop in later life (third or fourth decade).

Case Study Discussion

• Case: 9-year-old with black discoloration of ear and nose, and urine turning black on standing.
• Diagnosis: Alkaptonuria.
• Biochemical Pathway Defect: Caused by deficiency in homogentisate oxidase.
• Symptoms:
  • Urine turns dark on standing.
  • Arthritis from joint deposition.
  • Black deposits in ear and nose.
• Recommended Management: Limit phenylalanine in diet.

Summary

• Alkaptonuria results from a defect in the enzyme homogentisate oxidase, leading to accumulation of homogentisate.
• Characterized by ochronosis and potential arthritis.
• Diagnosis primarily through urine discoloration and positive tests.
• Management focuses on dietary phenylalanine limitation and addressing symptoms if they arise.

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