Alkaptonuria (OMIM 203500), the first inborn error of metabolism, is a rare autosomal recessive disorder owing to deficiency of homogentisic acid oxidase (HGO) (EC 220.127.116.11). HGO, a homohexamer requiring ferrous iron as a cofactor, converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Without this enzyme, homogentisic acid accumulates and causes ochronosis (pigmentation of connective tissue) and arthritis. Homopolymers of homogentisic acid oxidation products (benzoquinones) destroy cartilage, synovial tissue, and bone by binding to collagen and other elements of connective tissue.
The causative gene, HGD (occasionally AKU or HGO), was mapped to chromosome 3q21-q23 and identified in 1996. HGD contains 14 exons and encompasses 60 kb of genomic DNA. Molecular analysis reveals a spectrum of HGD mutations, reflecting the disorder's clinical variability.
The diagnosis of alkaptonuria often occurs in infancy because the urine turns dark on exposure to air or alkali. Later, the disorder is diagnosed based on typical radiologic findings in the spine or joints or because bone, joints, or tendons appear black during surgical procedures for joint deterioration. Definitive diagnosis is made by measuring gram quantities of homogentisic acid in a 24-hour urine collection using gas chromotography-mass spectrometry (GC-MS) analysis of organic acids.
Alkaptonuria leads to considerable disability in later life. Affected individuals typically have pain from spine and joint destruction in their twenties and thirties and require joint and cardiac valve replacements during their fifties and sicties. Computed tomography (CT) and echocardiographic studies reveal coronary artery calcifications and cardiac-valve deterioration. Dark ear cartilage and brown spots in the sclerae of the eyes serve as telltale signs of the disease.
Therapeutic intervention is aimed at reducing homogentisic acid. Dietary protein restriction and supplemental vitamin C have not proven effective, but a potent reversible inhibitor of p-hydroxyphenylpyruvic acid dioxygenase, nitisinone (Orfadin), reduces urinary excretion of homogentisic acid up to 95 percent. The safety and efficacy of nitisinone are currently being investigated in a clinical trial.