Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Alkaptonuria
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The incidence of alkaptonuria (AKU) in the US is estimated at 1:250,000 to 1:1,000,000 live births. Worldwide estimates are similar, around 1:111,000 to 1:1,000,000. AKU occurs with high prevalence in the Dominican Republic and northwestern Slovakia, likely as the result of a founder effect. The prevalence of AKU in Slovakia is estimated as 1:19,000.
1 2 3 4 5
Clinical Features
(Signs / symptoms)
AKU is caused by the deficiency of an enzyme which results in the accumulation of homogentisic acid (HGA). AKU has three main features: HGA in urine (oxidation of HGA may cause urine to turn dark on standing), ochronosis (bluish-black pigmentation in connective tissue, such as cartilage, skin, and sclera), and arthritis of the spine and larger joints (ochronic arthropathy). Other manifestations include pigment deposition; aortic or mitral valve calcification or regurgitation and occasionally aortic dilation; stones (renal prostate, gall bladder, and salivary glands); renal failure; respiratory insufficiency; and rupture of tendons, muscles, and ligaments.
1 2 3 4 5 6 7
Natural History
(Important subgroups & survival / recovery)
Though elevated plasma and urinary HGA are present during childhood, individuals are typically asymptomatic until early adulthood. Ochronosis occurs only after age 30 years. A systematic review of 40 patients reported an average age of onset for ocular findings of 40.6 years. Arthritis often begins in the third decade, usually in the spine, and resembles ankylosing spondylitis in its large joint distribution. 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%. Half of individuals require at least one joint replacement by age 55. Joint disease appears to start earlier and progress more rapidly in males than females. Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction. AKU follows a steady progression from early adulthood and leads to motor disabilities requiring physical aids. Pain can be constant, though life span is generally not reduced. Cardiac complications are often life-threatening and may worsen with prognosis.
1 2 3 4 6
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with AKU, the following evaluations 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
• Consultation with a clinical geneticist and/or genetic counselor. (Tier 4)
Although several therapeutic modalities have been investigated, no preventive or curative treatment is available for AKU. (Tier 4)
However, a recent expert review of AKU treatment modalities proposed the following sequential therapeutic strategy:
• During childhood: A vegetarian diet with mineral and vitamin supplements if needed. A low protein diet will theoretically decrease HGA production, possibly reducing HGA accumulation. A study of 12 patients with AKU tested a low protein diet for 1 week followed by a high protein diet for 1 week and reported that HGA excretion was significantly lower with the low protein diet, but only among patients younger than 12. However, the long-term clinical effects are not clear.
• During adulthood: Nitisinone and a mild protein restriction. In trials of adult AKU patients, a daily dose of nitisinone reduced urine and plasma HGA concentrations by 95%, a result sustained during 3 years. No long-term benefit of nitisinone was found on the rheumatologic parameters and, at best, suggested a limited progression of the associated aortic valve disease. (Tier 2)
Joint pain is substantial in individuals with AKU, and close attention to pain control is necessary. Pain management may include physical and occupational therapy and surgical replacement of the large joints. In general, the goal of joint replacement is pain relief rather than increased range of motion. (Tier 4)
A systematic review of 13 AKU cases in the literature reported that most cases had received bilateral arthroplasty, all with satisfactory results. However, the criteria for a satisfactory outcome was not defined and reports of pre- and post-operative outcomes for all cases were not available. (Tier 1)
Specific surgical recommendations include preoperative assessment as well as anesthesia and other considerations. Preoperative assessments should include spinal mobility and cardiovascular system. Degenerative changes of the lumbar spine may complicate regional anesthesia, while calcification of interspinous ligaments make epidural approaches difficult if not impossible. Additionally, excessive pigment deposition may interfere with pulse oximeter monitoring; and stiffness of cartilage in the chest wall may cause failure to wean from mechanical ventilation or dyspnea. (Tier 4)
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
• Surveillance CT scans in affected individuals with coronary artery calcification. (Tier 4)
No evidence for the effectiveness of cardiac surveillance was available for AKU. However, recommendations for management of valvular heart disease (VHD) from unspecified etiology indicate that echocardiography is key to confirm the diagnosis of VHD and assess its severity and prognosis. In asymptomatic patients with aortic stenosis (AS), the wide variability of the rate of progression heightens the need for patients to be educated about the importance of follow-up with echocardiography and reporting symptoms as soon as they develop. Aortic valve replacement (AVR) is the definitive therapy for severe AS and is the traditional treatment for aortic regurgitation (AR). ARV in symptomatic AS patients has been shown to prolong and improve quality of life, even in patients over 80 years of age. Treatment for AS and AR with concomitant aneurysm/dilatation of the ascending aorta generally consists of combined replacement of the aorta and valve with reimplantation of the coronary arteries (Tier 2)
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; renal stones can be identified by ultrasonography and helical abdominal CT. (Tier 4)
Family Management
No family management recommendations have been provided.
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. Specifically, younger individuals with AKU should be directed toward non-contact and lower-impact sports. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
1 3 4
Prevalence of Genetic Mutations
Pathogenic variants in HGD account for 90% of cases of AKU. (Tier 4)
No information on carrier frequency or prevalence was identified.
Relative Risk
(Include any high risk racial or ethnic subgroups)
Elevated urinary HGA and ochronotic arthritis occur in all individuals who are homozygous or compound heterozygous for pathogenic variants in HGD. (Tier 4)
A systematic review of 40 patients indicated that 83% of patients had scleral pigmentation. (Tier 1)
By age 64 years, 50% of individuals with AKU have a history of renal stones. (Tier 4)
A case series of 76 AKU patients who underwent transthoracic echocardiography found the following results: 6 (8%) had aortic valve replacements, 12 (16%) had aortic sclerosis, 7 (9%) had aortic stenosis ranging from mild to severe, 15 had aortic regurgitation, and 7 had aortic root dilation. Among 40 patients who also underwent CT scans, 17 had coverage suitable for evaluation of coronary or valvular calcification. Among these 17, valvular calcification was present in 8 (47%) and 3 (18%) had evidence of significant coronary calcification. By the age of 60, 100% of individuals had evidence of significant intracardiac calcification. Among 40 patients, 26 (65%) patients had evidence of significant vascular calcification in the aorta. (Tier 5)
No information on relative risk was identified.
HGA excretion and disease severity can vary significantly within the same family. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified in this report include imaging surveillance, surgical management, avoidance of stressors to spine and large joins, a low protein diet, and nitisinone. The only side effect of nitisonone is the expected rise of plasma tyrosine, and corneal lesions have been observed due to the poor solubility of tyrosine.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
In some individuals, the diagnosis of AKU is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. Urine darkening, though present in infancy, may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine. (Tier 4)
In a systematic review of 40 patients with AKU, the initial diagnosis was not determined correctly in six cases. (Tier 1)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Aortic/cardiac disease / Cardiology follow-up with periodic echocardiogram
1C 1
1. Evidence extrapolated from guidelines for valvular heart disease of unspecified etiology.
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. WJ Introne, WA Gahl. Alkaptonuria. 2003 May 09 [Updated 2016 May 12]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
2. Lindner M, Bertelmann T. On the ocular findings in ochronosis: a systematic review of literature. BMC Ophthalmol. (2014) 14:12.
3. Alkaptonuria. Orphanet encyclopedia,
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Alkaptonuria; aku. MIM: 203500: 2016 Jul 09. World Wide Web URL:
5. Kastsiuchenka, S.. Anesthesia recommendations for patients suffering from alkaptonuria. Orphananesthesia. (2013) Website:
6. Arnoux JB, Le Quan Sang KH, Brassier A, Grisel C, Servais A, Wippf J, Dubois S, Sireau N, Job-Deslandre C, Ranganath L, de Lonlay P. Old treatments for new insights and strategies: proposed management in adults and children with alkaptonuria. J Inherit Metab Dis. (2015) 38(5):791-6.
7. Ozmanevra R, Guran O, Karatosun V, Gunal I. Total knee arthroplasty in ochronosis: a case report and critical review of the literature. Eklem Hastalik Cerrahisi. (2013) 24(3):169-72.
8. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Lung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012): the joint task force on the management of valvular heart disease of the european society of cardiology (esc) and the european association for cardio-thoracic surgery (eacts). Eur J Cardiothorac Surg. (2012) 42(4):S1-44.
9. Hannoush H, Introne WJ, Chen MY, Lee SJ, O'Brien K, Suwannarat P, Kayser MA, Gahl WA, Sachdev V. Aortic stenosis and vascular calcifications in alkaptonuria. Mol Genet Metab. (2012) 105(2):198-202.
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