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Alkaptonuria

Nature Reviews Disease Primers volume 10, Article number: 16 (2024) Cite this article

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Abstract

Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients’ quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.

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Fig. 1: Clinical features of ochronosis.
Fig. 2: Prevalence of AKU worldwide.
Fig. 3: Tyrosine catabolism and AKU.
Fig. 4: Overview of the HGD gene and HGD protein.
Fig. 5: Pathogenic mechanism of AKU.

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Acknowledgements

A.S. acknowledges funding from Ministero dell’Università e della Ricerca (MUR) for her research (grants P2022RYR5W-PRIN 2022 PNRR and Tuscany Health Ecosystem (THE)-PNRR). W.J.I. is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors thank the anonymous patient for their contribution in Box 3.

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Authors and Affiliations

  1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy

    Giulia Bernardini, Daniela Braconi, Ottavia Spiga, Michela Geminiani & Annalisa Santucci

  2. Institute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia

    Andrea Zatkova

  3. Geneton Ltd, Bratislava, Slovakia

    Andrea Zatkova

  4. AKU Society, Cambridge, UK

    Nick Sireau

  5. 2nd Department of Radiology, Medical University of Gdansk, Gdansk, Poland

    Mariusz J. Kujawa

  6. Human Biochemical Genetics Section, Medical Genetics Branch, Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Wendy J. Introne

  7. Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences University of Liverpool, Liverpool, UK

    James A. Gallagher & Lakshminarayan R. Ranganath

  8. Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK

    Lakshminarayan R. Ranganath

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Contributions

Introduction (G.B. and D.B.); Epidemiology (W.J.I. and N.S.); Mechanisms/pathophysiology (A.Z., G.B., D.B., A.S., L.R.R. and M.J.K.); Diagnosis, screening and prevention (M.J.K. and W.J.I.); Management (L.R.R., W.J.I., J.A.G., O.S. and M.G.); Quality of life (L.R.R. and N.S.); Outlook (G.B., D.B., A.S. and A.Z.); Overview of the Primer (G.B.).

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Correspondence to Giulia Bernardini.

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Bernardini, G., Braconi, D., Zatkova, A. et al. Alkaptonuria. Nat Rev Dis Primers 10, 16 (2024). https://doi.org/10.1038/s41572-024-00498-x

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  • DOI: https://doi.org/10.1038/s41572-024-00498-x

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