Clinical Guidance

No correlation is observed between the type of HGD pathogenic variant and amount of HGA excreted or disease severity. While analysis of HGD variants from 172 individuals with alkaptonuria revealed that residual HGA activity ranged from 1% to more than 30%, there was no observed difference in serum HGA, urinary excretion of HGA, or clinical manifestations .

Source: GeneReviews — "Alkaptonuria"

Diagnostic Criteria

No consensus clinical diagnostic criteria for alkaptonuria have been published.

Suggestive Findings

Alkaptonuria should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Dark urine or urine that turns dark on standing. Oxidation of homogentisic acid (HGA) excreted in the urine produces a melanin-like product and causes the urine to turn 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.

Source: GeneReviews — "Alkaptonuria"

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 . Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrine® , the skin-lightening agent hydroquinone, or the antibiotic minocycline . A thorough history combined with lack of excessive HGA excretion in the urine should eliminate false positive diagnoses. Arthritis. While the arthritis of alkaptonuria resembles ankylosing spondylitis in its damage to the spine and large joints, it differs in sparing the sacroiliac joint and in its radiographic appearance.

Source: GeneReviews — "Alkaptonuria"

Management Guidelines

No clinical practice guidelines for alkaptonuria have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Complete history and physical examination with particular attention to range of motion in the spine and large joints

• Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs

• 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

• Measurement of TSH and free thyroxine to evaluate for primary hypothyroidism

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of alkaptonuria in order to facilitate medical and personal decision making

Treatment of Manifestations

In the US, treatment of alkaptonuria remains symptomatic. While the European Medicines Agency has authorized marketing of nitisinone for treatment of alkaptonuria, to date the US Food and Drug Administration has not approved use of nitisinone for treatment of alkaptonuria.

Clinical Guidance

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

Source: GeneReviews — "Alkaptonuria"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Alkaptonuria"

Surveillance Guidelines

Cardiac. Surveillance for cardiac complications every one to two years is advisable after age 40 years,]; surveillance should include echocardiography to detect aortic dilatation and aortic or mitral valve calcification and stenosis. Individuals with symptoms suggestive of coronary artery disease may be candidates for CT imaging, depending on the recommendation of a medical provider. 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.

Thyroid. Assess thyroid function (using TSH and free thyroxine) at the time of initial diagnosis, and monitor for primary hypothyroidism every one to two years thereafter.

Source: GeneReviews — "Alkaptonuria"