• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Alkaptonuria

Synonym: Alcaptonuria

, MD and , MD, PhD.

Author Information
, MD
Staff Clinician, Office of the Clinical Director, National Human Genome Research Institute
National Institutes of Health
Washington, DC
, MD, PhD
Clinical Director, National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: August 22, 2013.

Summary

Disease characteristics. Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are the presence of HGA in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Oxidation of the HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark upon standing. Ochronosis occurs only after age 30 years; arthritis often begins in the third decade. Other manifestations include pigment deposition, aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation, renal stones, and prostate stones.

Diagnosis/testing. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between one and eight grams. HGD, the gene encoding homogentisate 1,2-dioxygenase, is the only gene in which mutations are known to cause alkaptonuria.

Management. Treatment of manifestations: Management of joint pain tailored to the individual; physical and occupational therapy to help maintain muscle strength and flexibility; knee, hip, and shoulder replacements when needed; surgical intervention for prostate stones and renal stones as needed; aortic stenosis may necessitate valve replacement.

Surveillance: In individuals older than age 40 years, echocardiography to detect aortic dilation, aortic or mitral valve calcification, and stenosis; CT to detect coronary artery calcification.

Agents/circumstances to avoid: Physical stress to the spine and large joints, including heavy manual labor or high-impact sports, to try to reduce progression of severe arthritis.

Evaluation of relatives at risk: Testing for the presence of elevated urinary HGA in sibs of affected individuals allows early diagnosis and intervention to prevent secondary complications.

Genetic counseling. Alkaptonuria is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway (Figure 1).

Figure 1

Figure

Figure 1. The tyrosine degradation pathway. Alkaptonuria is characterized by deficiency of homogentisate 1,2-dioxygenase, which converts homogentisic acid (HGA) to maleylacetoacetic acid.

Alkaptonuria has three major features (Figure 2):

Figure 2
Panel A

Figure

Figure 2
Panel A. Ochronosis of the sclera of the eye
Panel B. Ochronosis of the antihelix and concha
Panel C. Classic radiographic findings of the lumbar spine with disc flattening, calcification, and osteophyte formation

  • HGA in the urine. Oxidation of the HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark upon standing. Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent. However, darkening may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine.
  • Ochronosis (bluish-black pigmentation of connective tissue). Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis.
    • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision [Chevez Barrios & Font 2004].
    • Ear cartilage pigmentation is first seen in the concha and antihelix, and later in the tragus. The cartilage is slate blue or gray and feels irregular or thickened. Calcification of the ear cartilage may be observed on radiographs.
    • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing.
    • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger.
  • Arthritis often begins in the spine and resembles ankylosing spondylitis in its large-joint distribution. Radiographs of the spine showing flattened and calcified intervertebral disks are pathognomonic. Findings include degeneration of the intervertebral disks followed by disk calcification and eventually fusion of the vertebral bodies. Osteophyte formation and calcification of the intervertebral ligaments also occur. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and osteophyte formation. Enthesopathy can be seen at the muscle insertions [Mannoni et al 2004].

The presence of any of these features should prompt confirmatory biochemical testing.

Testing

Biochemical testing. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between one and eight grams [La Du 2001, Phornphutkul et al 2002]. A normal 24-hour urine sample contains 20-30 mg of HGA [Introne et al 2011].

Carriers. Biochemical testing cannot detect the carrier state.

Molecular Genetic Testing

Gene. HGD, the gene encoding homogentisate 1,2-dioxygenase, is the only gene in which mutations are known to cause alkaptonuria [Pollak et al 1993, Janocha et al 1994, Fernandez-Canon et al 1996].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Alkaptonuria

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
HGDTargeted mutation analysisMutations include those common in the Slovak population 4>80%
Sequence analysisSequence variants 4, 590%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Four mutations (c.481G>A, c.457dup, c.808G>A, and c.1111dup) represent Slovak founder mutations, accounting for 80% of all mutations found in the Slovak population. Six mutations c.688C>T, c.899T>G, c.174delA, c.16-1G>A, c.342+1G>A, and c.140C>T are common in other populations, but rare in the Slovak population; mutation frequency in other populations is unknown.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Analysis by gas chromatography-mass spectrometry detects gram quantities of HGA in a daily urine sample and confirms the diagnosis of alkaptonuria.
  • HGD molecular genetic testing is not required to confirm the diagnosis in the proband but is needed in order to provide carrier and prenatal test result interpretation for at-risk family members. The following genetic testing algorithm is suggested:
    • If the proband is of Slovak descent, targeted mutation analysis for founder mutations in that population may be performed first, followed by sequence analysis for individuals in whom only one or neither mutation is identified.
    • For affected individuals of other populations, HGD sequence analysis should be performed.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The clinical findings of alkaptonuria include darkening of urine upon standing as a result of the presence of HGA and its oxidation products, connective tissue ochronosis, and arthritis of the spine and larger joints. HGA excretion and disease severity can vary significantly within the same family. In some cases, the diagnosis of alkaptonuria is made only after the individual seeks medical attention because of chronic joint pain or after black articular cartilage is noted during orthopedic surgery.

Alkaptonuria does not cause developmental delay or cognitive impairment and does not generally reduce the life span of affected individuals.

Urinary changes. Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent. However, darkening may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine.

Connective tissue. In general, pigmentary changes are observed after age 30 years. Tendon-related findings, including a thickened Achilles tendon, tendonitis, and rupture, have also been observed clinically [Phornphutkul et al 2002] and are demonstrable by MRI.

Joints. Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Joint symptoms involving the spine usually appear in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [Phornphutkul et al 2002].

Lumbar and thoracic spine symptoms precede cervical spine symptoms. The sacroiliac region is usually spared. Limitation of spine flexion directly correlates with degree of disability. Individuals with decreased forward flexion demonstrate impaired function and increased fatigue [Perry et al 2006].

Joint disease appears to start earlier and progress more rapidly in males than in females. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years [Phornphutkul et al 2002]. Small joint involvement is not significant.

Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction [Introne et al 2002].

Other organ involvement

  • Heart. Pigment deposition in the heart and blood vessels leads to aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation. Aortic valve stenosis occurs at a high frequency in the sixth and seventh decades of life. Unlike cardiac valve disease that occurs in the general population, there is no correlation with standard cardiovascular risk factors [Hannoush et al 2012]. Aortic stenosis may necessitate aortic valve replacement. Coronary artery calcification has been demonstrated on chest CT [Phornphutkul et al 2002, Hannoush et al 2012].
  • Renal stones. By age 64 years, 50% of individuals with alkaptonuria have a history of renal stones.
  • Prostate stones. Black prostate stones occur relatively frequently in individuals with alkaptonuria. In one series, eight of 27 men age 31-60 years had prostate stones. Prostate stones may contribute to recurrent infection or urinary obstruction and require surgical removal.

Genotype-Phenotype Correlations

No correlation is observed between the type of HGD mutation and amount of HGA excreted or severity of the disease.

Penetrance

Elevated urinary HGA and ochronotic arthritis occur in all individuals who are homozygous or compound heterozygous for mutations in HGD.

Nomenclature

Occasionally alkaptonuria is referred to collectively (and incorrectly) as ochronosis.

Prevalence

At least 1000 cases of alkaptonuria have been described; this is likely an underestimate [La Du 2001]. The incidence of alkaptonuria in the US is estimated at 1:250,000 to 1:1,000,000 live births.

Alkaptonuria occurs worldwide; a high prevalence has been observed in the Dominican Republic [Milch 1960] and near the Slovakian-Bohemian border, likely as the result of a founder effect [Srsen 1983].The prevalence of alkaptonuria in Slovakia is estimated at 1:19,000 [Zatkova et al 2003].

Differential Diagnosis

Ochronosis. Ochronosis resulting from alkaptonuria may be confused with acquired, reversible pigmentary changes following prolonged use of carbolic acid dressings for chronic cutaneous ulcers [La Du 2001]. Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrine® [Ludwig et al 1963], the skin-lightening agent hydroquinone, or the antibiotic minocycline [Suwannarat et al 2004].

In one case of alkaptonuria, the ochronotic pigment in the eye was misdiagnosed as melanosarcoma, resulting in enucleation of the eye [Skinsnes 1948].

A thorough history combined with lack of excessive HGA excretion in the urine should eliminate false positive diagnoses.

Arthritis. The arthritis of alkaptonuria resembles ankylosing spondylitis in its damage to the spine and large joints, although it differs in sparing the sacroiliac joint and in its radiographic appearance. Radiographic findings of the spine also differentiate alkaptonuria from rheumatoid arthritis and osteoarthritis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the following evaluations are recommended:

  • Complete history and physical examination with particular attention to range of motion in the spine and large joints
  • Ophthalmologic evaluation
  • Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs
  • Twenty-four hour urine collection for HGA quantification, performed by organic acid analysis
  • Electrocardiogram and echocardiogram in individuals older than age 40 years
  • Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi
  • Medical genetics consultation

Treatment of Manifestations

Joint pain is substantial in individuals with alkaptonuria, and close attention to pain control is necessary. Optimal pain management should be tailored to the individual with close follow-up and long-term management.

Physical and occupational therapy are important to promote optimal muscle strength and flexibility.

Knee, hip, and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis [Spencer et al 2004].

Treatment of prostate stones and renal stones may include surgical intervention.

Aortic stenosis may necessitate valve replacement.

Prevention of Primary Manifestations

Although several therapeutic modalities have been investigated, no preventive or curative treatment is available. See Therapies Under Investigation.

Prevention of Secondary Manifestations

Maintaining joint range of motion through moderate non-weight-bearing exercise such as swimming may have beneficial effects.

Younger individuals with alkaptonuria should be directed toward non-contact and lower-impact sports.

Surveillance

Cardiac. Surveillance for cardiac complications every one to two years is advisable after age 40 years and should include:

  • Echocardiography to detect aortic dilation and aortic or mitral valve calcification and stenosis; and
  • Surveillance CT scans according to the recommendation of a cardiologist in affected individuals with coronary artery calcification.

Urology. Urologic complications become more prevalent after age 40 years:

  • Routine surveillance is not recommended, but awareness of this potential complication is advised.
  • Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT.

Agents/Circumstances to Avoid

Avoidance of physical stress to the spine and large joints, including heavy manual labor or high-impact sports, may reduce the progression of severe arthritis.

Evaluation of Relatives at Risk

Sibs of affected individuals should be tested for the presence of elevated urinary HGA. Those found to have alkaptonuria should be counseled to avoid high-impact and contact sports. Career considerations include avoidance of occupations involving heavy physical labor. Instruction on joint strengthening and flexibility exercises, in conjunction with appropriate physical activity, can help preserve overall joint mobility and function.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Pharmacologic treatment of alkaptonuria with oral administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) or nitisinone has been proposed [Anikster et al 1998]. Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone is approved for the treatment of tyrosinemia type I.

Nitisinone reduced urinary HGA excretion by at least 69% in two individuals, but at the expense of an elevated plasma tyrosine concentration [Phornphutkul et al 2002]. The only known side effects are elevated plasma tyrosine concentration resulting in photophobia and, rarely, corneal crystals. Theoretically, neurologic complications associated with tyrosinemia type III may develop.

In a pilot study, low-dose nitisinone reduced urinary HGA by up to 95% in nine individuals with alkaptonuria. In the same study, seven individuals were treated for up to 15 weeks with nitisinone while receiving normal protein intake; all had elevated plasma tyrosine concentrations. No ophthalmic, neurologic, or severe dermatologic complications were observed. Two individuals had transient elevations in liver transaminase levels that returned to normal after stopping nitisinone [Suwannarat et al 2005].

In a three-year therapeutic trial, 2 mg of nitisinone daily reduced urine and plasma HGA by 95% throughout the study duration [Introne et al 2011]. Plasma tyrosine averaged 800μM without dietary restriction. Side effects were minimal. One affected individual developed corneal crystals that required discontinuation of nitisinone, and one affected individual had elevated liver transaminases. Statistically significant improvement in hip range of motion and measurements of musculoskeletal function were not observed in the treatment group compared to the control group; however there was a positive trend showing slowing of aortic stenosis. Additional trials are being planned to establish clinical benefit.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

No therapy is proven to prevent or correct the pigmentary changes of ochronosis.

  • Dietary restriction of phenylalanine and tyrosine has been proposed to reduce the production of HGA, but severe restriction of these amino acids is not practical in the long term and may be dangerous.
  • High-dose vitamin C decreases urinary benzoquinone acetic acid, a derivative of HGA, but has no effect on HGA excretion [Wolff et al 1989]. It has been hypothesized that high-dose ascorbic acid may prevent the deposition of ochronotic pigment, although it does not alter the basic metabolic defect [Wolff et al 1989]. No credible studies have demonstrated the clinical efficacy of ascorbic acid [La Du 2001].
  • Oral bisphosphonate therapy has been suggested to halt the progressive bone loss; however, a prospective study of four affected individuals failed to demonstrate benefit [Aliberti et al 2007].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Alkaptonuria is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with alkaptonuria are obligate heterozygotes (carriers) for a mutant allele causing alkaptonuria.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Biochemical testing. Biochemical genetic testing is not reliable as a method of carrier detection.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Requests for prenatal testing for conditions which (like alkaptonuria) do not affect intellect or life span and have only symptomatic treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alkaptonuria Society
    109 Paget Road
    Cambridge CB2 9JG
    United Kingdom
    Phone: +44(0)7886 709633
    Email: info@alkaptonuria.info
  • Alkaptonuria: A Fact Sheet for Patients
    National Institutes of Health
    Phone: 800-411-1222 (toll-free)
    Email: prpl@cc.nih.gov
  • Medline Plus
  • National Library of Medicine Genetics Home Reference
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Alkaptonuria: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Alkaptonuria (View All in OMIM)

203500ALKAPTONURIA; AKU
607474HOMOGENTISATE 1,2-DIOXYGENASE; HGD

Normal allelic variants. HGD is 54.3 kb in length and has 14 exons coding for a 1715-bp transcript [Granadino et al 1997].

Pathologic allelic variants

Table 2. Selected Pathologic HGD Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.140C>Tp.Ser47LeuNM_000187​.3
NP_000178​.2
c.16-1G>A
(IVS1-1G>A)
p.Tyr6_Gln29del
c.174delAp.Ser59Alafs*52
(Ser59Alafs*31) (R58fs)
c.360T>Gp.Cys120Trp
c.342+1G>A
(IVS5+1G>A)
p.Leu95_Ser114del
c.457dupp.Asp153Glyfs*26
(G152fs)
c.481G>Ap.Gly161Arg
c.688C>Tp.Pro230Ser
c.808G>Ap.Gly270Arg
c.899T>Gp.Val300Gly
c.1102A>Gp.Met368Val
c.1111dup
(111_1112insC)
p.His371Profs*4
(P370fs)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The protein product of HGD is homogentisate 1,2-dioxygenase, an enzyme in the phenylalanine and tyrosine degradation pathway. The enzyme is composed of 445 amino acids and is expressed predominantly in the liver and kidney, with some expression in the small intestine, colon, and prostate [Fernandez-Canon et al 1996]. Homogentisate 1,2-dioxygenase functions in the metabolism of HGA by catalyzing an oxidative cleavage of the benzene ring to yield maleylacetoacetic acid. It requires oxygen, ferrous iron, and sulfhydryl groups.

Abnormal gene product. Most mutant alleles of HGD are predicted to result in complete loss of enzymatic activity.

References

Literature Cited

  1. Aliberti G, Pulignano I, Pisani D, Rocchietti March M, Del Porto F, Proietta M. Bisphosphonate treatment in ochronotic osteoporotic patients. Clin Rheumatol. 2007;26:729–35. [PubMed: 16924393]
  2. Anikster Y, Nyhan WL, Gahl WA. NTBC and alkaptonuria. Am J Hum Genet. 1998;63:920–1. [PMC free article: PMC1377415] [PubMed: 9718357]
  3. Chevez Barrios P, Font RL. Pigmented conjunctival lesions as initial manifestation of ochronosis. Arch Ophthalmol. 2004;122:1060–3. [PubMed: 15249376]
  4. Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996;14:19–24. [PubMed: 8782815]
  5. Goicoechea De Jorge E, Lorda I, Gallardo ME, Pérez B, Peréz De Ferrán C, Mendoza H, Rodríguez De Córdoba S. Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene. J Med Genet. 2002;39:E40. [PMC free article: PMC1735184] [PubMed: 12114497]
  6. Granadino B, Beltran-Valero de Bernabe D, Fernandez-Canon JM, Penalva MA, Rodriguez de Cordoba S. The human homogentisate 1,2-dioxygenase (HGO) gene. Genomics. 1997;43:115–22. [PubMed: 9244427]
  7. Hannoush H, Introne WJ, Chen MY, Lee S-J, O’Brien K, Suwannarat P, Kayser MA, Gahl WA, Sachdev V. Aortic stenosis and vascular calcifications in alkaptonuria. Mol Genet Metab. 2012;105:198–202. [PMC free article: PMC3276068] [PubMed: 22100375]
  8. Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011;103:307–14. [PMC free article: PMC3148330] [PubMed: 21620748]
  9. Introne WJ, Phornphutkul C, Bernardini I, McLaughlin K, Fitzpatrick D, Gahl WA. Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation. Mol Genet Metab. 2002;77:136–42. [PubMed: 12359141]
  10. Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, Guenet JL, Grimm T, Kress W, Muller CR. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics. 1994;19:5–8. [PubMed: 8188241]
  11. La Du BN. Alkaptonuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2109-23.
  12. Ludwig GD, Toole JF, Wood JC. Ochronosis from quinacrine (atabrine). Ann Intern Med. 1963;59:378–84. [PubMed: 14065956]
  13. Mannoni A, Selvi E, Lorenzini S, Giorgi M, Airo P, Cammelli D, Andreotti L, Marcolongo R, Porfirio B. Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum. 2004;33:239–48. [PubMed: 14978662]
  14. Milch RA. Studies of Alcaptonuria: Inheritance of 47 Cases in Eight Highly Inter-related Dominican Kindreds. Am J Hum Genet. 1960;12:76–85. [PMC free article: PMC1932065] [PubMed: 17948450]
  15. Perry MB, Suwannarat P, Furst GP, Gahl WA, Gerber LH. Musculoskeletal findings and disability in alkaptonuria. J Rheumatol. 2006;33:2280–5. [PubMed: 16981292]
  16. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002;347:2111–21. [PubMed: 12501223]
  17. Pollak MR, Chou YH, Cerda JJ, Steinmann B, La Du BN, Seidman JG, Seidman CE. Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nat Genet. 1993;5:201–4. [PubMed: 8252048]
  18. Skinsnes OK. Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye. Arch Pathol (Chic). 1948;45:552–8. [PubMed: 18891026]
  19. Spencer JM, Gibbons CL, Sharp RJ, Carr AJ, Athanasou NA. Arthroplasty for ochronotic arthritis: no failure of 11 replacements in 3 patients followed 6-12 years. Acta Orthop Scand. 2004;75:355–8. [PubMed: 15260431]
  20. Srsen S. Analysis of the causes of the relatively frequent incidence of alkaptonuria in Slovakia. Cas Lek Cesk. 1983;122:1585–7. [PubMed: 6652675]
  21. Srsen S, Muller CR, Fregin A, Srsnova K. Alkaptonuria in Slovakia: thirty-two years of research on phenotype and genotype. Mol Genet Metab. 2002;75:353–9. [PubMed: 12051967]
  22. Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005;54:719–28. [PubMed: 15931605]
  23. Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA. Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain. Arthritis Rheum. 2004;50:3698–701. [PubMed: 15529343]
  24. Wolff JA, Barshop B, Nyhan WL, Leslie J, Seegmiller JE, Gruber H, Garst M, Winter S, Michals K, Matalon R. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res. 1989;26:140–4. [PubMed: 2771520]
  25. Zatkova A, Chmelikova A, Polakova H, Ferakova E, Kadasi L. Rapid detection methods for five HGO gene mutations causing alkaptonuria. Clin Genet. 2003;63:145–9. [PubMed: 12630963]
  26. Zatkova A, de Bernabe DB, Polakova H, Zvarik M, Ferakova E, Bosak V, Ferak V, Kadasi L, de Cordoba SR. High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots. Am J Hum Genet. 2000;67:1333–9. [PMC free article: PMC1288576] [PubMed: 11017803]

Chapter Notes

Author Notes

Dr. Introne is a pediatrician, clinical geneticist, and biochemical geneticist.

Dr. Gahl is a pediatrician, clinical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases.

Author History

William A Gahl, MD, PhD (2003-present)
Wendy J Introne, MD (2003-present)
Michael A Kayser, DO; Saint Francis Hospital, Tulsa (2007-2013)
Chanika Phornphutkul, MD; Brown University (2003-2007)
Pim Suwannarat, MD; Mahidol University (2003-2007)

Revision History

  • 22 August 2013 (me) Comprehensive update posted live
  • 10 March 2011 (me) Comprehensive update posted live
  • 2 July 2009 (cd) Revision: sequence analysis available clinically
  • 4 December 2007 (me) Comprehensive update posted to live Web site
  • 26 June 2006 (ca) Revision: targeted mutation analysis available for eight mutations
  • 24 May 2005 (me) Comprehensive update posted to live Web site
  • 9 May 2003 (me) Review posted to live Web site
  • 4 March 2003 (ps) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview ‘Alkaptonuria’ is in the public domain in the United States of America.

Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1454PMID: 20301627
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...