Alternative titles; symbols
SNOMEDCT: 360378009; ICD10CM: E70.29; ORPHA: 56; DO: 9270;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q13.33 | Alkaptonuria | 203500 | Autosomal recessive | 3 | HGD | 607474 |
A number sign (#) is used with this entry because alkaptonuria (AKU) is caused by homozygous or compound heterozygous mutation in the homogentisate 1,2-dioxygenase gene (HGD; 607474) on chromosome 3q13.
Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves (summary by Vilboux et al., 2009).
Alkaptonuria enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed (by Garrod, 1902, on the suggestion of Bateson) and of being 1 of the 4 conditions in the charter group of inborn errors of metabolism. The manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and arthritis, especially characteristic in the spine.
Cunningham et al. (1989) observed rapidly evolving osteoarthrosis of the right hip in a 65-year-old woman who had unusual stress after being forced to abandon a train as a result of a bomb threat and having to carry 2 heavy suitcases. Carrier and Harris (1990) reported the case of a 70-year-old man who underwent bilateral hip and knee total joint arthroplasties for the treatment of ochronotic arthropathy. Dereymaeker et al. (1990) described a patient in whom calcified aortic valve disease secondary to ochronosis necessitated urgent aortic valve replacement.
There are reports of urolithiasis in AKU patients in middle and late adulthood who have already developed the full clinical picture of the disorder (e.g., Sener, 1992). Zibolen et al. (2000) emphasized the increased frequency of urolithiasis in AKU patients younger than 15 years. They reported 5 such patients, in one of whom the diagnosis of urolithiasis had been made at the age of 2 years.
Phornphutkul et al. (2002) provided a review of the natural history of alkaptonuria. They based the review on an evaluation of 58 patients with the disorder ranging in age from 4 to 80 years. They found that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. In the 58 patients reviewed by Phornphutkul et al. (2002), kidney stones were documented in 13 male and 3 female patients. Of the 27 men who were 31 to 60 years old, 8 had prostate stones. The development of prostate stones was not associated with the development of kidney stones. Three patients, each over the age of 50 years, had undergone aortic valve replacement.
Ranganath et al. (2021) examined the clinical phenotype, with a focus on aortic disease, in 81 individuals with alkaptonuria and a mean age of 48.6 years, 51 of whom received nitisinone treatment. The prevalence of aortic stenosis was 22.2% and the prevalence of aortic valve replacement was 6.2%. Aortic valve maximum velocity (Vmax) was found to be directly related to age, systolic blood pressure, serum homogentisic acid, ochronosis score, and alkaptonuria severity score index.
The transmission pattern of AKU in the families reported by Fernandez-Canon et al. (1996) was consistent with autosomal recessive inheritance.
Lustberg et al. (1970) presented evidence that ascorbic acid in high doses decreases binding of C(14)-homogentisic acid (HGA) in connective tissues of rats with experimental alkaptonuria. Long-term therapy in young patients with alkaptonuria is indicated.
Wolff et al. (1989) treated 2 adults and 3 infants with high doses of ascorbic acid and studied the effect on the excretion of homogentisic acid and its toxic oxidation product, benzoquinone acetic acid (BQA). The purpose was to determine whether concentrations in body fluids of the latter substance, the putative toxic metabolite in alkaptonuria, would be reduced. Indeed, disappearance of BQA from the urine was observed in adults, whereas the level of excretion of homogentisic acid did not change. This could have relevance to the pathogenesis of ochronotic arthritis. In 2 of the infants studied (a 4- and a 5-month-old), ascorbic acid may have doubled the amount of homogentisic acid in the urine, presumably through an effect on the immature p-hydroxyphenylpyruvic acid oxidase. Dietary reduction of the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid.
In a 48-year-old man in whom alkaptonuria had been diagnosed during infancy, Mayatepek et al. (1998) studied the effects of 4 different therapeutic 1-month trials consisting of supplementation with ascorbic acid (1 g/day and 10 g/day) or a low-protein diet (0.3 g/kg/day and 1.3 g/kg/day). Administration of ascorbic acid in doses of 1 g/day or more resulted in a significant and constant decrease of urinary BQA, whereas the excretion of HGA could not be substantially reduced. Mild and severe dietary reduction of protein intake alone also substantially reduced the excretion of BQA, whereas the level of HGA excretion could not be drastically reduced. Such an extreme protein restriction would not, however, have been acceptable for a longer period of time. They concluded that supplementation of ascorbic acid in doses of 1 g/day represents a simple and rational treatment in patients with alkaptonuria.
La Du (1998) examined the question 'Are we ready to try to cure alkaptonuria?' He explored the possibilities and indicated that model animal systems, either those representing known spontaneous hereditary deficiencies of homogentisic acid or appropriate 'knockout' animals with created deficiencies of the enzyme, need to be tested before human trials are undertaken. He said that it is to be hoped that some, perhaps all, of the adverse effects of alkaptonuria can be prevented by new molecular therapeutic approaches; however, trading alkaptonuric problems for even more serious metabolic disturbances because of the pronounced toxicity of the later tyrosine metabolites is not an acceptable alternative.
Suzuki et al. (1999) used 2(-2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) as a therapeutic agent for alkaptonuria. NTBC is a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase, which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid, and had been used in the treatment of type I tyrosinemia (276700). In a murine model of alkaptonuria that had been created with ethylnitrosurea by Montagutelli et al. (1994), they observed a dose-dependent reduction in urinary output of homogentisic acid with administration of NTBC.
Phornphutkul et al. (2002) reported that, in a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone. In a 59-year-old woman, similar reductions were observed after 9 days of treatment. Plasma tyrosine levels in these patients rose, with no clinical signs or symptoms. They emphasized that the long-term safety and efficacy of this treatment requires further evaluation. Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase by rapid, avid binding that is reversible. The agent had been approved by the FDA for the treatment of tyrosinemia type I.
Ranganath et al. (2021) found that nitisinone treatment in a cohort of 51 patients with alkaptonuria reduced serum homogentisic acid, urine homogentisic acid, ochronosis scores, and alkaptonuria severity score index. Nitisinone also decreased aortic valve maximum velocity (Vmax) over time.
In 6 Slovak pedigrees selected from a total of 191 alkaptonuria patients registered at the Institute of Clinical Genetics in Martin, Slovakia, Janocha et al. (1994) demonstrated linkage to microsatellite markers from proximal 3q. Markers on that chromosome were selected for study because of previously demonstrated homology of synteny with mouse chromosome 16. Independently, Pollak et al. (1993) used homozygosity mapping to locate the alkaptonuria gene to 3q2 in a 16-cM region. They studied 2 consanguineous families with 4 affected children and 2 nonconsanguineous families which supported the linkage. They pointed out that Garnica et al. (1981) described coinheritance of alkaptonuria and sucrase-isomaltase deficiency (222900), which maps to 3q25-q26. Furthermore, Steinmann et al. (1984) described coinheritance of neonatal severe hyperparathyroidism and alkaptonuria. The former condition is thought to be the recessive (i.e., homozygous) form of familial hypocalciuric hypercalcemia (145980), which maps to 3q21-q24. In the case reported by Steinmann et al. (1984), both parents, who were related, had familial hypocalciuric hypercalcemia.
In patients with alkaptonuria, Fernandez-Canon et al. (1996) identified missense mutations in the homogentisate 1,2-dioxygenase gene that cosegregated with the disease (607474.0001, 607474.0002), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation.
Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, Gehrig et al. (1997) found 2 novel mutations in the HGD gene (607474.0003, 607474.0004).
Other mutations in the HGD gene were identified in patients with alkaptonuria by Beltran-Valero de Bernabe et al. (1998, 1999), Muller et al. (1999), Rodriguez et al. (2000), Zatkova et al. (2000), and Phornphutkul et al. (2002).
In Turkey, Elcioglu et al. (2003) described a 39-year-old male patient with typical features of alkaptonuria. In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R; 607474.0011) in exon 11 and 342delA (607474.0006) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon.
Vilboux et al. (2009) provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13.
Alkaptonuria was found to be unusually frequent in the Dominican Republic (Milch, 1960) and in Slovakia (Cervenansky et al., 1959). According to O'Brien et al. (1963), more cases (126) had been reported from Czechoslovakia than anywhere else. From Germany 108 had been reported, and from the United States 90.
Vilboux et al. (2009) stated that alkaptonuria affects 1 in 250,000 to 1 million people worldwide
In the course of an ethylnitrosourea mutation study, Guenet (1990) and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes. Affected mice showed high levels of urinary homogentisic acid without signs of ochronosis or arthritis. Montagutelli et al. (1994) demonstrated that the locus, symbolized aku, maps to mouse chromosome 16 in a region of syntenic homology with human 3q.
Stenn et al. (1977) provided evidence that the Egyptian mummy Harwa, dating from 1500 B.C., had alkaptonuria.
A phenocopy (a nongenetically produced phenotype resembling a gene-determined one) of alkaptonuria is provided by the ochronosis that develops after the prolonged use of carbolic acid dressings for chronic cutaneous ulcers (Beddard, 1910; Beddard and Plumtre, 1912). Fortunately this is a thing of the past. Quinacrine (atabrine), after prolonged administration, also causes an ochronotic change with pigmentation in many of the same sites as in alkaptonuria, and probably with a comparable arthrosis (Ludwig et al., 1963). Snider and Thiers (1993) described a case of exogenous ochronosis due to use of bleaching creams that contain hydroquinone by black women to lighten their complexion.
Sandler et al. (1970) raised the question of whether parkinsonism occurs in increased frequency with alkaptonuria, either as a complication or as a syndromal entity separate from ordinary alkaptonuria.
Phornphutkul et al. (2002) provided a review of the natural history of alkaptonuria in the year marking the one-hundredth anniversary of Garrod's description of the disease as the first disorder in humans found to conform to the principles of mendelian autosomal recessive inheritance (Garrod, 1902).
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