ALKAPTONURIA SYNDROME-A REVIEW

P. UJWALA RAMA CHANDRA; V. USHA RANI; G. SIREESHA DEVI; B. AMURUTHAVALLI; M. TRINADHA RAO

doi:10.22159/ijcpr.2022v14i6.2060

Authors

P. UJWALA RAMA CHANDRA Department of Pharmacology, Adarsa College of Pharmacy, G. Kothapallli 5333285
V. USHA RANI Department of Pharmacology, Adarsa College of Pharmacy, G. Kothapallli 5333285
G. SIREESHA DEVI Department of Pharmacology, Adarsa College of Pharmacy, G. Kothapallli 5333285
B. AMURUTHAVALLI Department of Pharmacology, Adarsa College of Pharmacy, G. Kothapallli 5333285
M. TRINADHA RAO Department of Pharmacology, Adarsa College of Pharmacy, G. Kothapallli 5333285

DOI:

https://doi.org/10.22159/ijcpr.2022v14i6.2060

Keywords:

Black urine disease, Rare disease, Ochronosis, Ochronotic pigment

Abstract

Alkaptonuria, also called endogenous ochronosis, and also called as Black Urine Disease, is a rare metabolic autosomal recessive disorder. It occurs by complete inhibition of homogentisic acid oxidase enzyme having its deposition in various tissues. Alkaptonuria is caused due to deficiency of homogentisic acid oxidase involved in the metabolism of tyrosine. Dark discolouration of urine, ochronosis at cartilage and connective tissues, arthritis at the third of fourth decade of life, renal stone disease, spontaneous tendon rupture etc. May be seen in alkaptonuria. Disease severity varies among individual patients, even between siblings, and increase with age because of homogentisic acid accumulation. Usually, life span is not shortened in AKU, but the quality of life is severely effected. Several studies have suggested that Nitisinone may be effective in the treatment of alkaptonuria. Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth. Over time patients develop other manifestations of AKU, due to the deposition of HGA in collagenous tissues, namely ochronosis and ochronotic osteoarthropathy. Although this condition does not reduce life expectancy, it significantly affects the quality of life. The natural history of this condition is becoming better understood, despite gaps in knowledge. Clinical assessment of the condition has also improved along with the development of potentially disease-modifying therapy. Furthermore, recent developments in AKU research have to lead to new understanding of the disease, and further study of the AKU arthropathy has the potential to influence therapy in the management of osteoarthritis.

Downloads

Download data is not yet available.

References

Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. 1902. Mol Med. 1996;2(3):274-82. doi: 10.1007/BF03401625, PMID 8784780.

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL. Natural history of alkaptonuria. N Engl J Med. 2002;347(26):2111-21. doi: 10.1056/NEJMoa021736. PMID 12501223.

https://akusociety.org/Information and Support/History–of-Aku; 25 Jan 2020.

Suwannarat P, O’Brien K, Perry MB, Sebring N, Bernardini I, Kaiser Kupfer MI. Use of nitisinone in patients with alkaptonuria. Metabolism Metabolism. 2005;54(6):719-28. doi: 10.1016/j.metabol.2004.12.017. PMID 15931605.

Taylor AM, Wilson PJ, Ingrams DR, Helliwell TR, Gallagher JA, Ranganath LR. Calculi and intracellular ochronosis in the submandibular tissues from a patient with alkaptonuria. J Clin Pathol. 2010;63(2):186-8. doi: 10.1136/jcp.2009.071365. PMID 20154043.

Garcia SF, Egbert B, Swetter SM. Hereditary ochronosis: hyperpigmented skin overlying cartilaginous structures. Cutis. 1999;63(6):337-8. PMID 10388955.

Peker E, Yonden Z, Sogut S. From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol. 2008;74(6):700. doi: 10.4103/0378-6323.45142, PMID 19180686.

Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis, Kraus VB. Rare osteoarthritis: ochronosis, Kashin-Beck disease and Mseleni joint disease. In: Hochberg MC, Smolen SJ, Weinblatt ME, Weisman MH, editors Rheumatology. 5th ed. Vol. 25. St Louis: Mosby; 2005. p. 1825-37. doi: 10.1007/s00296-004-0498-1.

Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA. The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis Rheum. 2011;63(12):3887-96. doi: 10.1002/art.30606, PMID 22127706.

Ranganath L, Taylor AM, Shenkin A, Fraser WD, Jarvis J, Gallagher JA. Identification of alkaptonuria in the general population: a United Kingdom experience describing the challenges, possible solutions and persistent barriers. J Inherit Metab Dis. 2011;34(3):723-30. doi: 10.1007/s10545-011-9282-z, PMID 21311977.

Ranganath LR, Jarvis JC, Gallagher JA. Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol. 2013 May;66(5):367-73. doi: 10.1136/jclinpath-2012-200877, PMID 23486607.

Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis. 2013;1:e27475. doi: 10.4161/rdis.27475, PMID 25003018.

Fisher AA, Davis MW. Alkaptonuricochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clinical Medicine. 2004 Nov;2(4):209–15. doi: 10.3121/cmr.2.4.209, PMID: 15931360.

Gottschalk BH, Blankenstein J, Guo L. Ochronosis of mitral valve and coronary arteries. The Annal Othoracic Surgery. 2018 Jul;106(1):e19-e20, PMID: 29501639.

Langford B, Besford M, Hall A, Eddowes L, Timmis O, Gallagher JA. Alkaptonuria severity score index revisited: analysing the AKUSSI and its subcomponent features. JIMD Rep. 2018:53-62. doi: 10.1007/8904_2018_98.

Davison AS, Norman BP, Ross GA, Hughes AT, Khedr M, Milan AM. Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC-QTOF-MS. JIMD Rep. 2019 Jul;48(1):67-74. doi: 10.1002/jmd2.12042, PMID 31392115.

Skinsnes Ok. Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye. Arch Pathol (Chic). 1948 Apr;45(4):552-8. PMID: 18891026.

Olive JK, Alnajar A, Gnanashanmugam S, Lamelas J. Transcatheter aortic valve replacement for alkaptonuria-associated aortic stenosis. Ann Thorac Surg. 2019 Dec;108(6):e377-9. doi: 10.1016/j.athoracsur.2019.04.053, PMID 31181205.

Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: review of the literature. Rheumatol Int. 2005 Mar;25(2):81-5. doi: 10.1007/s00296-004-0498-1, PMID 15322814.

Taylor AM, Wilson PJ, Ingrams DR, Helliwell TR, Gallagher JA, Ranganath LR. Calculi and intracellular ochronosis in the submandibular tissues from a patient with alkaptonuria. J Clin Pathol. 2010 Feb;63(2):186-8. doi: 10.1136/jcp.2009.071365, PMID 20154043.

Millucci L, Ghezzi L, Bernardini G, Braconi D, Lupetti P, Perfetto F. Diagnosis of secondary amyloidosis in alkaptonuria. Diagn Pathol. 2014 Sep 26;9(1). doi: 10.1186/s13000-014-0185-9.

Introne WJ, Gahl WA. Alkaptonuria. In: NORD guide to rare disorders. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 431.

La Du BN. Alkaptonuria. In: Royce PM, Steinmann B, editors. Connective tissue and its heritable disorders. Molecular, genetic, and medical aspects. 2nd ed. New York: Wiley-Liss, Ny Particular; 2002. p. 809-25.

Zatkova A. An update on the molecular genetics of alkaptonuria. J Inherited Metabolism Disease. 2011.

Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P. A 3 y randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011;103(4):307-14. doi: 10.1016/j.ymgme.2011.04.016, PMID 21620748.

Pettit SJ, Fisher M, Gallagher JA, Ranganath LR. Cardiovascular manifestations of alkaptonuria. J Inherit Metab Dis. 2011;34(6):1177-81. doi: 10.1007/s10545-011-9339-z.

Phornphutkul C, Introne WJ, Perry MB. Alkaptonuria. N Engl J Med. 2006;347:2111-21.

Fisher AA, Davis MW. Alkaptonuricochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res. 2004;2(4):209-15. doi: 10.3121/cmr.2.4.209, PMID 15931360.

Srsen S, Müller CR, Fregin A, Srsnova K. Alkaptonuria in slovakia: thirty-two years of research on phenotype and genotype. Mol Genet Metab. 2002;75(4):353-9. doi: 10.1016/S1096-7192(02)00002-1, PMID 12051967.

Introne WJ, Gahl WA. Alkaptonuria. 2003 May 9. In: Pagon RA, Adam MP, Ardinger HH, editors. Seattle: University of Washington. Seattle; Feb 16; 2017. p. 1993-2017.

Roth KS. Alkaptonuria. Medscape. Last Update. Aug 7; 2015.

McKusick VA. editor. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: Johns Hopkins University; 2017.

Porfirio B. Alkaptonuria. Orphanetencyclopedia Last Update. Oct 2014.