History

Because alkaptonuria is usually autosomal recessive, a family pedigree, in all likelihood, reveals no other affected individuals. However, because many genetically affected individuals are asymptomatic, the low frequency of clinically affected family members may be due to a lack of ascertainment.

Despite the intrinsic biochemical defect and the expectation that all affected individuals should excrete urine that becomes black when left standing, a significant number of people with alkaptonuria do not present with this clinical finding.

The most common history is one of arthritic symptoms confined chiefly to the spine, hips, and knees. Virtually all people with alkaptonuria eventually experience arthritis. Onset of thoracic back pain, lumbar back pain, or both around age 30 years is frequent.

Physical

Slate blue or gray discoloration may be found in the sclerae or ear cartilage.

Calcifications may be palpable in the discolored areas, particularly in the cartilage of the ear.

Joint mobility diminishes, as in osteoarthritis. Ankylosis may be present. Spontaneous fusion of one or more discs may occur, with consequent diminished spinal flexion. Joint effusions, particularly in the knee are common and range of motion may be significantly diminished.

Signs of aortic or mitral valvulitis may be present.

Causes

Inability to convert homogentisic acid to maleylacetoacetic acid results in accumulation of the former. Homogentisic acid is subsequently converted to benzoquinone acetic acid and spontaneously polymerized. Deposition of the polymer in association with cartilage is the initiating pathophysiologic cause of the arthritis.^[25]

Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected joints.

Exogenous agents including quinacrine (Atabrine), carbolic acid, and hydroquinone have been reported to cause an ochronotic picture without the joint disease. All have been reversible.

Differential Diagnoses

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Lodh M, Kerketta JA. Early diagnosis of co-existent ß-thalassemia and alkaptonuria. Indian J Hum Genet. 2013 Apr. 19(2):259-61. [QxMD MEDLINE Link]. [Full Text].
Zatkova A, Sedlackova T, Radvansky J, Polakova H, Nemethova M, Aquaron R, et al. Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. JIMD Rep. 2012. 4:55-65. [QxMD MEDLINE Link]. [Full Text].
Ranganath LR, Norman BP, Gallagher JA. Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease-A review. J Inherit Metab Dis. 2019 Sep. 42 (5):776-792. [QxMD MEDLINE Link].
Lindner M, Bertelmann T. On the ocular findings in ochronosis: a systematic review of literature. BMC Ophthalmology. January 2014. 14:12. [QxMD MEDLINE Link].
Lok ZS, Goldstein J, Smith JA. Alkaptonuria-associated aortic stenosis. J Card Surg. 2013 Jul. 28(4):417-20. [QxMD MEDLINE Link].
Oexie K, Engel K, Tinschert S, et al. Three-generational alkaptonuria in a non-consanguineous family. J Inherit Metab Dis. Dec/2008. Epub:Epub.
US Preventive Services Task Force. Screening for phenylketonuria (PKU): US Preventive Services Task Force Reaffirmation recommendation. Ann Fam Med. 2008 Mar-Apr. 6(2):166. [QxMD MEDLINE Link].
Peker E, Yonden Z, Sogut S. From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol. 2008 Nov-Dec. 74(6):700. [QxMD MEDLINE Link].
Häberle J. Suitability of nitisinone for alkaptonuria. Lancet Diabetes Endocrinol. 2020 Sep. 8 (9):732-733. [QxMD MEDLINE Link].
Ranganath LR, Psarelli EE, Arnoux JB, Braconi D,. Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2020 Sep. 8 (9):762-772. [QxMD MEDLINE Link].
de Haas V, Carbasius Weber EC, de Klerk JB, et al. The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis. 1998 Dec. 21(8):791-8. [QxMD MEDLINE Link].
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O'Brien W, La Du BN, Bunim JJ. Biochemical, pathological and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: review of the world literature (1584-1962). Am J Med. 1963. 34:813-38.
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Upon microscopic examination, amber-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).

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