Alkaptonuria E70.21

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Alcaptonuria; alcaptonuric osteoarthrosis deformans; Alkaptonuric ochronosis; Ochronosis alkaptonuric; OMIM 203500

History
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Boedeker, 1859; Virchow, 1879; Garrod, 1902

Definition
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Rare, autosomal recessively inherited enzyme defect with missing or reduced activity of homogentisic acid oxidase and consequently deposition of homogentisic acid in connective tissue and cartilage and excretion in urine.

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Occurrence/Epidemiology
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Worldwide (accumulation in certain regions, e.g. the Czech Republic and Slovakia). Prevalence (Germany): 1-9/1 000 000 inhabitants.

Etiopathogenesis
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Autosomal recessive mutations of the HGD gene (homogentisate 1,2-dioxygenase gene; gene locus: 3q21-q23). >70 different mutations have been described.

The cause of the tissue damage is the accumulation of the oxidation product "benzoquinone-acetic acid", which can transform into a black polymer with high affinity to the connective tissue. This polymer induces a series of redox reactions with the formation of free radicals, which additionally damage the connective tissue. The deposition of the polymer can trigger inflammatory reactions that lead to calcification in the affected joints.

Manifestation
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Clinically recognizable usually only from the 3rd decade of life.

Clinical features
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Ochronosis, especially of nose, ears, skin areas over tendons, axillae; calcium deposits in the ear cartilage, black cerumen, possibly blue-grey fingernails, possibly dark urine. Hearing disorders due to the storage of homogentisic acid in the eardrum. Progressive destruction of cartilage due to storage of homogentisic acid in joints with subsequent inflammatory reaction (especially hip, knee, shoulder joint, spine). Heart valve involvement.

Histology
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In cartilage and connective tissue yellow to ochre pigment granules, partly lying freely in the tissue, partly stored in macrophages.

Diagnosis
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Initially light-coloured urine turns brown after prolonged standing (oxidation of the homogentisic acid); brown colouring of the urine accelerated by the addition of alkali Homogentisic acid is excreted in the urine and is detected by gas chromatography-mass spectroscopy.

Differential diagnosis
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Porphyria; myoglobinuria; hematuria; alkaptonuria, symptomatic, melaninuria (in metastatic melanomas of the liver); Addison's disease, temporary symptomatic alkaptonuria (e.g. in premature babies); pseudo-gout.

Therapy
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No causal therapy possible. Long-term therapy with high doses of ascorbic acid (e.g. Ascorvit Drg.) 100 mg/kg bw/day, up to 1 g/day, seems to reduce the binding of homogentisic acid to cartilage, although urinary excretion remains unchanged. Restriction of tyrosine intake reduces the excretion of homogentisic acid in urine. Symptomatic internal and orthopaedic care.

Literature
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Boedeker CW (1859) On Alcapton; a new contribution to the question: which substances of urine can cause copper reduction? Zschr Council Med 7: 130-145
Farzannia A et al (2003) Alkaptonuria and lumbar disc herniation. Report of three cases. J Neurosurg 98: 87-89
Garrod AE (1902) The incidence of alkaptonuria. A study in chemical individuality. Lancet ii: 1616-1620
Garrod AE (1908) The Croonian lectures on metabolism-inborn errors of metabolism. Lecture 1. lancet ii: 1-7
Garrod AE (1908) The Croonian lectures on metabolism-inborn errors of metabolism. 2nd Lancet lecture ii: 73-79
Phornphutkul C et al (2002) Natural history of alkaptonuria. N Engl J Med 347: 2111-2111
Virchow R (1866) A case of general ochronosis of cartilage and cartilage-like parts. Arch Catholic Anat 37: 212
Wolff JA, Barshop B, Nyhan WL et al (1989) Effects of ascorbic acid in alkaptonuria: Alterations in bezoquinone acetic acid and an ontogenic effect in infancy. Pediatric Res 26: 140-144
Zatkova A et al (2003) Rapid detection methods for five HGO gene mutations causing alkaptonuria. Clin Genet 63: 145-149