Which of the following amino acid disorders is characterized by accumulation of homogentisic acid, dark urine upon standing, and ochronosis (blue-black pigmentation of connective tissues)?

Explanation

## Alkaptonuria: Clinical and Biochemical Features **Key Point:** Alkaptonuria is an autosomal recessive disorder caused by deficiency of **homogentisate 1,2-dioxygenase**, the enzyme responsible for breaking down homogentisic acid (an intermediate in tyrosine metabolism). ### Pathophysiology 1. **Enzyme defect:** Homogentisate 1,2-dioxygenase cannot convert homogentisic acid → maleylacetoacetic acid 2. **Metabolic consequence:** Homogentisic acid accumulates and is excreted in urine 3. **Oxidation:** Upon standing or exposure to air, homogentisic acid oxidizes and polymerizes → **dark brown/black urine** ### Clinical Features **High-Yield:** The classic triad of alkaptonuria: - **Dark urine** (turns black on standing or with alkali) - **Ochronosis** (blue-black pigmentation of connective tissues, sclera, cartilage) - **Arthropathy** (degenerative joint disease in later life) **Mnemonic:** **DARK** — Dark urine, Arthropathy, Reddish-brown pigmentation, Kidney stones (rarely) ### Diagnostic Clue **Clinical Pearl:** The dark urine is pathognomonic and often noticed in infants' diapers. Unlike PKU, alkaptonuria is **benign in childhood** but causes progressive arthritis and cardiovascular complications in adulthood [cite:Harrison 21e Ch 397]. ### Comparison with Other Amino Acidurias | Disorder | Enzyme Defect | Key Metabolite ↑ | Clinical Hallmark | | --- | --- | --- | --- | | **Alkaptonuria** | Homogentisate 1,2-dioxygenase | Homogentisic acid | Dark urine, ochronosis | | PKU | Phenylalanine hydroxylase | Phenylalanine | Intellectual disability, mousy odor | | MSUD | Branched-chain α-ketoacid dehydrogenase | Branched-chain amino acids | Sweet urine, neurological crisis | | Tyrosinemia I | Fumarylacetoacetase | Tyrosine, methionine | Liver failure, renal tubular dysfunction |