Management of alkaptonuria

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.

Evaluations following initial diagnosis

After initial diagnosis it is necessary to establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the following evaluations are recommended: a) complete history and physical examination with particular attention to range of motion in the spine and large joints; b) ophthalmologic evaluation; c) physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs; d) twenty-four hour urine collection for HGA quantification, performed by organic acid analysis; e) electrocardiogram and echocardiogram in individuals older than age 40 years; f) renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi; g) 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.

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.

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 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.

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.

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.
Nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone ( Orfadin ) 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.
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.

In a three-year therapeutic trial, 2 mg of Nitisinone daily reduced urine and plasma HGA by 95% throughout the study duration. Plasma tyrosine averaged 800 mcM 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.


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. 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. No credible studies have demonstrated the clinical efficacy of Ascorbic acid.

Oral bisphosphonate therapy has been suggested to halt the progressive bone loss; however, a prospective study of four affected individuals failed to demonstrate benefit. ( Xagena )

Introne WJ, Gahl WA, GeneReviews, 2013



Altri articoli

Full positive results from the HELIOS-A phase 3 study of Vutrisiran, an investigational RNAi therapeutic in development for the treatment...

Pulmonary hypertension ( PH ) in the setting of left-sided valvular heart disease is common, and significantly increases the risk...

The FDA ( Food and Drug Administration ) has expanded the approved use of the CoreValve System to treat certain...

The FDA ( Food and Drug Administration ) has approved of the self-expanding transcatheter CoreValve System for severe aortic stenosis...

Alkaptonuria ( AKU ) is a rare inherited metabolic disorder with severe premature spondyloarthropathy as a major manifestation. Although joint...

Bicuspid aortic valve ( BAV ) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation,...

Pallister-Killian syndrome ( PKS ) is a sporadic multisystem genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual...

A newly identified genetic variant doubles the risk of calcium buildup in the heart’s aortic valve. Calcium buildup is the...

The SEAS ( Simvastatin and Ezetimibe in Aortic Stenosis ) study has investigated the effects of intensive cholesterol lowering with...