First decade anniversary of the United Kingdom National Alkaptonuria Centre.

Dear editor, On April 1st 2012, NHS England Highly Specialised Services (HSS) commissioned the National Alkaptonuria Service for adults in the Department of Clinical Biochemistry & Metabolic Medicine at the Royal Liverpool University Hospital.1 The service is called the Robert Gregory National Alkaptonuria Centre (NAC) in memory of the alkaptonuria (AKU) patient who founded the Alkaptonuria Society (AKUS) in 2003.The AKUS is embedded in the NAC and crucial to its functioning and success, ensuring patients are at the centre of the service. The NAC serves as a notable example of power of collaboration between the medical community and patients. Since 2012, 89 patients have attended the NAC. While patients from England and Scotland can access the service free of charge, patients from Wales, Ireland, Germany, Pakistan, Indonesia and the USA have been treated at the NAC on the basis of a fee. The NAC is a one-stop service providing assessment, treatment including nitisinone and monitoring of therapy and disease, with visits lasting 3–4 days. NAC provides a full-range of multidisciplinary specialists (metabolism, rheumatology, cardiology, pain management, dietetic, psychological, ENT, ophthalmology, gait specialists, nuclear medicine, radiology) to manage their condition. An encrypted system PATIENTS KNOW BEST® (PKB) enables real-time communication between patients and the NAC team. Nitisinone 2 mg has been used as off-label therapy in the NAC since 2012, after approval by the HSS based on the published data at the time from the National Institutes of Health, USA.2 Experience gained in the NAC has been instrumental in designing and carrying out the DevelopAKUre programme3 funded by the European Commission to develop nitisinone as therapy for AKU adults. This consisted of a 4-week dose-ranging study of nitisinone in AKU (SONIA 1; suitability of nitisinone in alkaptonuria 1), a cross-sectional natural history study (SOFIA; subclinical ochronosis features in alkaptonuria) and a 4-year randomised nitisinone outcomes clinical trial (SONIA 2).4-6 Successful completion of SONIA 2 resulted in the approval of nitisinone 10 mg as the first disease-modifying therapy for AKU by the European Medicines Agency in September 2020. The NAC is in the process of switching the nitisinone dose from 2 to 10 mg.7 Nitisinone use is associated with inevitable hypertyrosinaemia which has significant side effects such corneal dendritiform keratopathy. Protein restriction is required as soon as nitisinone is started to reduce tyrosine to safe levels. Specialist dietitian input is required to ensure diet is manipulated safely without impacting health (e.g. muscle wasting). There is no evidence of benefit for protein restriction in AKU patients who are not on nitisinone. The NAC has generated new knowledge about AKU and its management (Table S1); with a few examples being prevalent cataract before and after nitisinone, nitisinone-associated vitiligo, characterising spine and joint disease and demonstrating lack of cognitive impairment during nitisinone therapy of adults with AKU.8-11 The NAC permitted research collaboration between the NAC and the University of Liverpool, allowing cutting edge research into AKU to be pioneered and carried out with examples including development of conditional mouse models of AKU including liver and kidney knockouts in which new therapies are tested such as tyrosine-reducing therapies, as well as enzyme replacement therapies involving gene and mRNA administration.12 A new mechanism of joint damage in AKU was developed and found to apply in osteoarthritis.13 Unachieved goals and further challenges: The NAC is commissioned to treat patients who 16 or older. We are collaborating with colleagues to study subclinical ochronsis in the paediatric AKU cohort in the UK (called the SOFIA-Paediatric). It is hoped that this will give an evidence-based answer as to when to start nitisinone. Home tyrosine monitoring is conveniently done using dried blood spots (DBS) and there is a good agreement between DBS and venous samples in tyrosine measurements. Unfortunately, some of our patients had difficulties in using DBS (dexterity issues in elderly patients due to advanced arthropathy, difficulty in finger pricking due to thick skin, too much/too little blood put on the card). As a result, we have developed an assay system using the MitraTM sampling device, which offers a more user-friendly and robust alternative.14 Preliminary feedback from patients has been positive and we are in the process of integrating this into the patient pathway. In the UK, starting as we did in 2003 when there was little in terms of opportunities to identify, support and manage patients with AKU, we have come a long way in redressing the balance, but further work is needed in the years ahead. Lakshminarayan R. Ranganath received fees for lectures and consultations from Swedish Orphan Biovitrum. Milad Khedr, Nick Sireau, George Bou-Gharios, and Jim A. Gallagher declare no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. TABLE S1. Contributions to AKU knowledge and patient care over the last decade Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.