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Alkaptonuria

Orpha number ORPHA56
Synonym(s) Hereditary ochronosis
Homogentisic acid oxidase deficiency
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Adult
ICD-10
  • E70.2
ICD-O -
OMIM
UMLS
  • C0002066
  • C2931645
MeSH
  • C537862
  • D000474
MedDRA
  • 10001689

Summary

Alkaptonuria is a metabolic disease characterized by the accumulation of homogentisic acid (HGA) and its oxidized product benzoquinone acetic acid (BQA) in various tissues (e.g., cartilage, connective tissue) and body fluids (urine, sweat), leading to a darkening of the urine when it is left exposed to air, grey-blue colouration of the eye sclerae and the ear helix (ochronosis), and a disabling joint disease involving both the axial and peripheral joints (ochronotic arthropathy).

Worldwide birth prevalence is estimated at around 1/111,000-1/1,000,000.

Many affected individuals are asymptomatic and unaware of their condition until adulthood; however, homogentisic aciduria may be recognized early in infancy by dark-stained diapers. After the third decade, unusual pigmentation of the sclera and the skin overlying cartilage begins to be observed, as well as muscular-skeletal symptoms such as back pain and stiffness. Involvement of the large peripheral joints usually occurs several years after spinal changes, often leading to end-stage joint disease. Ochronotic peripheral arthropathy is generally degenerative in nature. From the fourth decade, joint mobility diminishes. Ankylosis may be present. Fractures of vertebrae and long bones are also possible. Other features may include genitourinary (e.g. renal, bladder, prostatic stones) and cardiac (mitral valvulitis, arrhythmias) complications, and respiratory insufficiency due to musculoskeletal involvement.

Patients are homozygous or compound heterozygous for loss-of-function mutations (more than 120 different variants described worldwide) in the HGD gene (3q) encoding homogentisate 1,2-dioxygenase, an enzyme of the phenylalanine and tyrosine catabolic pathway. The inability to breakdown HGA leads to its accumulation. Tissue damage results from the deposition of a melanin-like pigment which is a polymerised form of BQA that has a high affinity for connective tissue. This pigment is able to trigger numerous redox reactions and induce free radical production, causing further damage to the connective tissue.

Diagnosis is suspected upon clinical examination and is based on dosage of HGA in urine using gas chromatography-mass spectroscopy. As many patients present without dark urine, it may be advisable to look for HGA in all patients with radiographic evidence of osteoarthritis. A spinal x-ray will reveal disk degeneration combined with dense calcification, particularly in the lumbar area. Genetic testing confirms the diagnosis.

Differential diagnosis includes acute intermittent porphyria, rheumatoid arthritis, ankylosing spondylitis (see these terms) and osteoarthritis.

Transmission is autosomal recessive. Family members should be referred for genetic counseling.

Treatment is palliative. Dietary restriction (low protein diet) is beneficial, but compliance is often limited. Medical therapy (paracetamol, non-steroidal anti-inflammatory drugs) associated with physiotherapy help to minimize pain and improve the range of joint motion. Older individuals may require removal and fusion of lumbar discs. Hip or knee joint replacement may be necessary. Therapeutic strategies focusing on perturbing the altered phenylalanine-tyrosine pathway have been devised (e.g. nitisinone). However, the long-term effectiveness and safety of this drug have yet to be established. Other possible approaches are aimed at exploring the effects of antioxidant biomolecules in preventing the conversion of HGA to BQA (e.g., N-acetylcysteine). However, previous attempts with vitamin C have been proved to be unsatisfactory.

Life expectancy is not significantly reduced but pain can be constant and progressive functional decline is observed with a loss of mobility, patients often requiring the use of physical aids (crutches, wheelchair). Cardiac complications are often life-threating and may worsen the prognosis.

Expert reviewer(s)

  • Pr Berardino PORFIRIO

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