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

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:

• 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 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. 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 are minimal. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and infrequent osteophyte formation. Enthesopathy can be seen at the muscle insertions [Mannoni et al 2004].

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. For laboratories offering biochemical testing, see .

Carriers. Biochemical testing available on a clinical basis 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

• Sequence analysis. Sequence analysis detects the eight HGD mutations found in individuals of Slovak descent (see Targeted mutation analysis) as well as other sequence variants that may occur in any population.
• Targeted mutation analysis. A panel of eight mutations found in individuals of Slovak descent is available for clinical testing.
  
  The four mutations c.481G>A (p.Gly161Arg), c.457dup (p.Asp153GlyfsX26), c.808G>A (p.Gly270Arg), and c.1111dup (p.His371ProfsX4) represent Slovak founder mutations, accounting for 80% of all mutations found in the Slovak population.
  
  The six mutations c.688C>T (p.Pro230Ser), c.899T>G (p.Val300Gly), c.174delA (p.Ser59AlafsX52), c.16-1G>A (p.Tyr6_Gln29del), c.342+1G>A (p.Leu95_Ser114del), and c.140C>T (p.Ser47Leu) are common in other populations, but rare in the Slovak population; mutation frequency in other populations is unknown.

Table 1. Summary of Molecular Genetic Testing Used in Alkaptonuria

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Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
HGD	Targeted mutation analysis	Mutations include those common in the Slovak population	>80%	Clinical
	Sequence analysis	Sequence variants 2	90%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. 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:
  • If the proband is of Slovak descent, targeted mutation analysis for the identified mutations in that population should 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in HGD.

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 thickening causes insufficiency and may necessitate aortic valve replacement. Aortic stenosis has also been described [Cercek et al 2002]. Coronary artery calcification has been demonstrated on chest CT. Cardiac findings usually appear in the sixth decade [Phornphutkul et al 2002].
• 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. The passage of these stones is extremely painful and has occasionally prompted consideration of prophylactic surgery [Phornphutkul et al 2002].

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].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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 of 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.

Prevention of Primary Manifestations

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

A clinical trial investigating the potential benefit of nitisinone in alkaptonuria is currently underway. Nitisinone is approved for use in tyrosinemia type I; its registration does not include alkaptonuria as an indication.

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

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

• Echocardiography to detect aortic dilation and aortic or mitral valve calcification and regurgitation
• CT to detect coronary artery calcification

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 and kidney stones can be identified by ultrasonography and helical abdominal CT.

Agents/Circumstances to Avoid

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

Testing of Relatives at Risk

Alkaptonuria can be detected in sibs of affected individuals by testing for the presence of elevated urinary HGA.

• Young individuals 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.

More recently, 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].

Further investigations to determine the benefits of nitisinone in slowing the progression of joint disease are in progress.

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].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 family members is possible if the disease-causing mutations in the family have been identified.

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

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing 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 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories listed in the GeneTests Laboratory Directory offer molecular genetic testing for prenatal diagnosis of alkaptonuria. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see .

Requests for prenatal testing for conditions such as alkaptonuria that do not affect intellect or life span and have some 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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22. 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]
23. 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]
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25. 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]

Author Notes

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

Dr. Kayser 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 (2007-present)
Chanika Phornphutkul, MD; Brown University (2003-2007)
Pim Suwannarat, MD; Mahidol University (2003-2007)

Revision History

• 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