Alkaptonuria

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Fernândez-Canon, J. M. et al. The molecular basis of alkaptonuria. Nat. Genet. 14, 19–24 (1996). The authors describe the cloning of the human HGD gene and demonstrate for the first time, to our knowledge, that it harbours missense variants that co-segregate with the disease in the families.

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Vilboux, T. et al. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum. Mutat. 30, 1611–1619 (2009).

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Phornphutkul, C. et al. Natural history of alkaptonuria. N. Engl. J. Med. 347, 2111–2121 (2002). This is the reference study for the definition of the natural history of AKU.

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Gallagher, J. A., Ranganath, L. R. & Zatkova, A. in Brenner’s Encyclopedia of Genetics 2nd edn (eds Malay, S. & Hughes, K.) 71–75 (Elsevier, 2013).

Chow, W. Y. et al. Pigmentation chemistry and radical-based collagen degradation in alkaptonuria and osteoarthritic cartilage. Angew. Chem. Int. Ed. 59, 11937–11942 (2020). The authors propose that collagen degradation in AKU occurs via transient glycyl radicals, and this process is enhanced due to the redox environment generated by pigmentation.

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Bernini, A. et al. A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in alkaptonuria. Sci. Rep. 11, 22562 (2021).

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Ranganath, L. R. et al. Reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy: analysis of data from the United Kingdom National Alkaptonuria Centre. JIMD Rep. 55, 75–87 (2020).

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Dewan, K., MacDonald, C. B. & Shires, C. B. Blue man: ochronosis in otolaryngology. Clin. Case Rep. 10, e05717 (2022).

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Millucci, L. et al. Amyloidosis, inflammation, and oxidative stress in the heart of an alkaptonuric patient. Mediators Inflamm. 2014, 258471 (2014).

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Millucci, L. et al. Diagnosis of secondary amyloidosis in alkaptonuria. Diagn. Pathol. 9, 185 (2014).

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Millucci, L. et al. Secondary amyloidosis in an alkaptonuric aortic valve. Int. J. Cardiol. 172, e121–e123 (2014).

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Křížek, V. Urolithiasis and prostatolithiasis in alcaptonuria with ochronosis. Int. Urol. Nephrol. 3, 245–250 (1971).

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Introne, W. J. et al. Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation. Mol. Genet. Metab. 77, 136–142 (2022).

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Lazaro, J. S., Lutz, R. & Deirmengian, G. K. Bilateral patellar tendon rupture following total knee arthroplasty in a patient with alkaptonuria: a case report. Cureus 15, e38597 (2023).

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Zatkova, A., Ranganath, L. & Kadasi, L. Alkaptonuria: current perspectives. Appl. Clin. Genet. 13, 37–47 (2020).

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Ranganath, L. R. & Cox, T. F. Natural history of alkaptonuria revisited: analyses based on scoring systems. J. Inherit. Metab. Dis. 34, 1141–1151 (2011). The authors applied advanced statistical methods to describe the natural history by quantitating the features of AKU, revealing distinct phases of the disease: a pre-ochronotic phase and an ochronotic phase.

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Introne, W. J., Perry, M. & Chen, M. Alkaptonuria. GeneReviews [Internet] www.ncbi.nlm.nih.gov/books/NBK1454/ (updated 10 June 2021).

Milch, R. A. Studies of alcaptonuria: inheritance of 47 cases in eight highly inter-related Dominican kindreds. Am. J. Hum. Genet. 12, 76–85 (1960).

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Al-Sbou, M., Mwafi, N. & Lubad, M. A. Identification of forty cases with alkaptonuria in one village in Jordan. Rheumatol. Int. 32, 3737–3740 (2012).

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Al-Sbou, M. & Mwafi, N. Nine cases of alkaptonuria in one family in southern Jordan. Rheumatol. Int. 32, 621–625 (2012).

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Sakthivel, S. et al. Mutation screening of the HGD gene identifies a novel alkaptonuria mutation with significant founder effect and high prevalence. Ann. Hum. Genet. 78, 155–164 (2014).

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Srsen, S. & Varga, F. Screening for alkaptonuria in the newborn in Slovakia. Lancet 2, 576 (1978).

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Zatková, A. et al. High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots. Am. J. Hum. Genet. 67, 1333–1339 (2000).

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Zatkova, A. An update on molecular genetics of alkaptonuria (AKU). J. Inherit. Metab. Dis. 34, 1127–1136 (2011).

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Zatkova, A. 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. 4, 55–65 (2012). The authors report on the establishment of a disease-specific HGD mutation database that summarizes all AKU gene variants identified so far in patients with AKU. This database is still active and regularly updated.

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Soltysova, A., Kuzin, A., Samarkina, E. & Zatkova, A. Alkaptonuria in Russia. Eur. J. Hum. Genet. 30, 237–242 (2022).

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Cox, T. F. & Ranganath, L. A quantitative assessment of alkaptonuria: testing the reliability of two disease severity scoring systems. J. Inherit. Metab. Dis. 34, 1153–1162 (2011).

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Perry, M. B., Suwannarat, P., Furst, G. P., Gahl, W. A. & Gerber, L. H. Musculoskeletal findings and disability in alkaptonuria. J. Rheumatol. 33, 2280–2285 (2006).

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Ranganath, L. R., Khedr, M., Vinjamuri, S. & Gallagher, J. A. Frequency, diagnosis, pathogenesis and management of osteoporosis in alkaptonuria: data analysis from the UK National Alkaptonuria Centre. Osteoporos. Int. 32, 927–938 (2021).

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Ranganath, L. R. et al. Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria. J. Inherit. Metab. Dis. 43, 737–747 (2020).

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Mistry, J. B., Bukhari, M. & Taylor, A. M. Alkaptonuria. Rare Dis. 1, e27475 (2013).

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Kitahara, Y., Kaku, N., Tagomori, H. & Tsumura, H. Alkaptonuria with rapidly destructive arthropathy of the hip: a case report and literature review. Acta Orthop. Traumatol. Turc. 55, 563–568 (2021).

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Ranganath, L. R., Khedr, M., Mistry, A., Vinjamuri, S. & Gallagher, J. A. Treatment of osteoporotic fractures in alkaptonuria by teriparatide stimulates bone formation and decreases fracture rate – a report of two cases. Bone Rep. 15, 101151 (2021).

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Gómez-Lechón Quirós, L. et al. Family history of ochronotic arthropathy. Rheumatol. Int. 41, 1869–1874 (2021).

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Taylor, A. M. et al. The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis Rheum. 63, 3887–3896 (2011).

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Taylor, A. M. et al. Identification of trabecular excrescences, novel microanatomical structures, present in bone in osteoarthropathies. Eur. Cell Mater. 23, 300–309 (2012).

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Ebrahim, I. C., Hoang, T. D., Vietor, N. O., Schacht, J. P. & Shakir, M. K. M. Dilemmas in the diagnosis and management of osteoporosis in a patient with alkaptonuria: successful treatment with teriparatide. Clin. Case Rep. 10, e6729 (2022).

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