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Licensed Unlicensed Requires Authentication Published by De Gruyter January 13, 2020

Presentation of 14 alkaptonuria patients from Turkey

Alper Ilker Akbaba, Rıza Köksal Ozgül and Ali Dursun

Abstract

Background

Alkaptonuria (OMIM: 203500) is an inborn error of metabolism due to homogentisate 1,2-dioxygenase homogentisic acid 1,2 dioxygenase (HGD) enzyme deficiency. Due to the enzyme deficiency, homogentisic acid cannot be converted to maleylacetoacetate and it accumulates in body fluids. Increased homogentisic acid is converted to benzoquinones, the resulting benzoquinones are converted to melanin-like pigments, and these pigments are deposited in collagen – this process is called ochronosis. In patients with alkaptonuria, the urine is darkened, which is misinterpreted as hematuria, the incidences of renal stones, arthritis and cardiac valve calcification are increased, and spontaneous tendon ruptures, prostatitis and prostate stones can be encountered. The present study aimed to evaluate the HGD gene mutations in 14 patients with alkaptonuria.

Methods

Fourteen patients diagnosed with alkaptonuria and followed up from 1990 to 2014 were retrospectively evaluated. Their demographic, clinical and treatment-related data were retrieved from hospital files. For mutation analysis, genomic DNAs of the patients were isolated from their peripheral blood samples. Variations in the HGD gene were scanned on the HGD-mutation database (http://hgddatabase.cvtisr.sk).

Results

Among 14 patients, the female/male ratio was 1/1 and the median age was 9 years (range, 6–59 years). All patients were symptomatic at their first visit and the most common symptom was dark urine (71%) followed by arthralgia. Independent of the urinary homogentisic acid concentrations, patients with the presenting symptom of arthralgia were elder. Nine different mutations including p.Ser59AlafsX52, p.Gly161Arg, p.Asn219Ser, p.Gly251Asp, p.Pro274Leu, p.Arg330Ser, p.Gly372Ala, c.656_657insAATCAA and a novel mutation of p.Val316Ile were detected. All of the pediatric-age patients (n = 13) were treated with ascorbic acid at a dose of 250–1000 mg/day.

Conclusions

Nine different HGD gene mutations with a novel one, p.Val316Ile, were detected. The most common mutation was p.Ser59AlafsX52 for the HGD gene followed by p.Gly161Arg and p.asn219Ser, which can be considered specific to the Turkish population.

Acknowledgments

We would like to thank Esin Göksun from the Department of Pediatric Metabolism and the members of the DNA Bank at Hacettepe University for the biobanking assistance. We are grateful to the patients and their families for their collaboration.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was funded by the grant from the State Planning Organization of Turkey (Project number: DPT2006K1206400603, Funder Id: http://dx.doi.org/10.13039/501100004401).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Fernández-Cañón JM, Granadino B, Beltrán-Valero de Bernabé D, Renedo M, Fernández-Ruiz E, et al. The molecular basis of alkaptonuria. Nature Genet 1996;14:19–24.10.1038/ng0996-19Search in Google Scholar

2. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, et al. Natural history of alkaptonuria. New Eng J Med 2002;347:2111–21.10.1056/NEJMoa021736Search in Google Scholar

3. Milch RA. Studies of alkaptonuria: inheritance of 47 cases in eight highly inter-related Dominican kindreds. Am J Hum Genet 1960;12:76–85.Search in Google Scholar

4. Cervenansky J, Sitaj S, Urbanek T. Alkaptonuria and ochronosis. J Bone Joint Surg Am 1959;41:1169–82.10.2106/00004623-195941070-00001Search in Google Scholar

5. Goicoechea De Jorge E, Lorda I, Gallardo ME, Pérez B, Peréz De Ferrán C, et al. Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene. J Med Genet 2002;39:E40.10.1136/jmg.39.7.e40Search in Google Scholar

6. Zatková A, Polaková H, Micutková L, Zvarík M, Bosák V, et al. Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. J Med Genet 2000;37:539–42.10.1136/jmg.37.7.539Search in Google Scholar

7. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. Lancet 1902;ii:1616–20.10.1016/S0140-6736(01)41972-6Search in Google Scholar

8. Knox WE. Sir Archibald Garrod’s inborn errors of metabolism. II. Alkaptonuria. Am J Hum Genet 1958;10:95–124.Search in Google Scholar

9. Wolff JA, Barshop B, Nyhan WL, Leslie J, Seegmiller JE, et al. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res 1989;26:140–4.10.1203/00006450-198908000-00015Search in Google Scholar PubMed

10. Suzuki Y, Oda K, Yoshikawa Y, Maeda Y, Suzuki T. A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J Hum Genet 1999;44:79–84.10.1007/s100380050114Search in Google Scholar PubMed

11. Preston AJ, Keenan CM, Sutherland H, Wilson PJ, Wlodarski B, et al. Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 2014;73:284–9.10.1136/annrheumdis-2012-202878Search in Google Scholar PubMed

12. Manoj Kumar RV, Rajasekaran S. Spontaneous tendon ruptures in alkaptonuria. J Bone Joint Surg Br 2003;85:883–6.10.1302/0301-620X.85B6.13662Search in Google Scholar

13. Gehrig A, Schmidt SR, Müller CR, Srsen S, Srsnova K, et al. Molecular defects in alkaptonuria. Cytogenet Cell Genet 1997;76:14–6.10.1159/000134501Search in Google Scholar PubMed

14. Müller CR, Fregin A, Srsen S, Srsnova K, Halliger-Keller B, et al. Allelic heterogeneity of alkaptonuria in Central Europe. Eur J Hum Genet 1999;7:645–51.10.1038/sj.ejhg.5200343Search in Google Scholar PubMed

15. Sener RN. Prostatic and renal stones and unilateral obstruction of the urinary tract caused by ochronosis. AJR Am J Roentgenol 1992;158:214–5.10.2214/ajr.158.1.1727353Search in Google Scholar PubMed

16. Srsen S, Vondrácek J, Srsnová K, Svác J. Analysis of the life span of alkaptonuric patients. Cas Lek Cesk 1985;124:1288–91. [Article in Slovak].Search in Google Scholar

17. Fernández-Cañón JM, Peñalva MA. Fungal metabolic model for human type I hereditary tyrosinaemia. Proc Natl Acad Sci USA 1995;92:9132–6.10.1073/pnas.92.20.9132Search in Google Scholar PubMed PubMed Central

18. Manning K, Al-Dhalimy M, Finegold M, Grompe M. In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I. Proc Natl Acad Sci USA 1999;96:11928–33.10.1073/pnas.96.21.11928Search in Google Scholar PubMed PubMed Central

19. Granadino B, Beltrán-Valero de Bernabé D, Fernández-Cañón JM, Peñalva MA, Rodríguez de Córdoba S. The human homogentisate 1,2-dioxygenase (HGO) gene. Genomics 1997;43:115–22.10.1006/geno.1997.4805Search in Google Scholar PubMed

20. Beltrán-Valero de Bernabé D, Granadino B, Chiarelli I, Porfirio B, Mayatepek E, et al. Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients. Am J Hum Genet 1998;62:776–84.10.1086/301805Search in Google Scholar PubMed PubMed Central

21. Millucci L, Spreafico A, Tinti L, Braconi D, Ghezzi L, et al. Alkaptonuria is a novel human secondary amyloidogenic disease. Biochim Biophys Acta 2012;1822:1682–91.10.1016/j.bbadis.2012.07.011Search in Google Scholar PubMed PubMed Central

22. Spreafico A, Millucci L, Ghezzi L, Geminiani M, Braconi D, et al. Antioxidants inhibit SAA formation and pro-inflammatory cytokine release in a human cell model of alkaptonuria. Rheumatology (Oxford) 2013;52:1667–73.10.1093/rheumatology/ket185Search in Google Scholar PubMed PubMed Central

23. Mayatepek E, Kallas K, Anninos A, Müller E. Effects of ascorbic acid and low-protein diet in alkaptonuria. Eur J Pediatr 1998;157:867–8.10.1007/s004310050956Search in Google Scholar PubMed

24. Suwannarat P, O’Brien K, Perry MB, Sebring N, Bernardini I, et al. Use of nitisinone in patients with alkaptonuria. Metabolism 2005;54:719–28.10.1016/j.metabol.2004.12.017Search in Google Scholar PubMed

25. Nag HL, Singh V, Meena S, Saini P. Ochronotic black meniscus during knee arthroscopy. J Nat Sci Biol Med 2013;4:502–4.10.4103/0976-9668.117004Search in Google Scholar PubMed PubMed Central

26. Fisher AA, Davis MW. Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res 2004;2:209–15.10.3121/cmr.2.4.209Search in Google Scholar PubMed PubMed Central

27. Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, et al. Suitability of nitisinone in alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis 2016;75:362-7.10.1136/annrheumdis-2014-206033Search in Google Scholar PubMed

28. Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, et al. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 2011;103:307–14.10.1016/j.ymgme.2011.04.016Search in Google Scholar PubMed PubMed Central

29. Zatkova A, Sedlackova T, Radvansky J, Polakova H, Nemethova M, 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;4:55–65.10.1007/8904_2011_68Search in Google Scholar PubMed PubMed Central

30. Bearn AG. Inborn errors of metabolism: Garrod’s legacy. Mol Med 1996;2:271–3.10.1007/BF03401624Search in Google Scholar

31. Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis 2013;1:e27475.10.4161/rdis.27475Search in Google Scholar PubMed PubMed Central

32. Uyguner O, Goicoechea de Jorge E, Cefle A, Baykal T, Kayserili H, et al. Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations. J Inherit Metab Dis 2003;26:17–23.10.1023/A:1024063126954Search in Google Scholar

33. Beltrán-Valero de Bernabé D, Peterson P, Luopajärvi K, Matintalo P, Alho A, et al. Mutational analysis of the HGO gene in Finnish alkaptonuria patients. J Med Genet 1999;36:922–3.Search in Google Scholar

34. Nemethova M, Radvanszky J, Kadasi L, Ascher DB, Pires DE, et al. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ’black bone disease’ in Italy. Eur J Hum Genet 2016;24:66–72.10.1038/ejhg.2015.60Search in Google Scholar PubMed PubMed Central

35. Ladjouze-Rezig A, Rodriguez de Cordoba S, Aquaron R. Ochronotic rheumatism in Algeria: clinical, radiological, biological and molecular studies – a case study of 14 patients in 11 families. Joint Bone Spine 2006;73:284–92.10.1016/j.jbspin.2005.03.010Search in Google Scholar PubMed

36. Gucev ZS, Slaveska N, Laban N, Danilovski D, Tasic V, et al. Early-onset ocular ochronosis in a girl with alkaptonuria (AKU) and a novel mutation in homogentisate 1,2-dioxygenase (HGD). Prilozi 2011;32:305–11.Search in Google Scholar

37. Rana AQ, Saeed U, Abdullah I. Alkaptonuria, more than just a mere disease. J Neurosci Rural Pract 2015;6:257–60.10.4103/0976-3147.150312Search in Google Scholar PubMed PubMed Central

38. Ranganath LR, Jarvis JC, Gallagher JA. Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol 2013;66:367–73.10.1136/jclinpath-2012-200877Search in Google Scholar PubMed

39. de Haas V, Carbasius Weber EC, de Klerk JB, Bakker HD, Smit GP, et al. The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis 1998;21:791–8.10.1023/A:1005410416482Search in Google Scholar

40. Zeybek CA, Zubarioglu T. Nitisinone: a review. Orphan Drugs Res Rev 2017;7:25–35.10.2147/ODRR.S92995Search in Google Scholar

41. Ranganath LR, Khedr M, Milan AM, Davison AS, Hughes AT, et al. Nitisinone arrests ochronosis and decreases rate of progression of alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre. Mol Genet Metab 2018;125:127–34.10.1016/j.ymgme.2018.07.011Search in Google Scholar PubMed

Received: 2019-04-03
Accepted: 2019-11-19
Published Online: 2020-01-13
Published in Print: 2020-02-25

©2020 Walter de Gruyter GmbH, Berlin/Boston

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