Journal
MOLECULAR GENETICS AND METABOLISM
Volume 133, Issue 3, Pages 324-331Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2021.05.007
Keywords
Homogentisic acid; Ochronosis; Alkaptonuria; Aortic stenosis; Aortic valve replacement; Nitisinone
Funding
- NHS England Highly Specialized Services (HSS) in establishing the UK National Alkaptonuria Centre in the Royal Liverpool University Hospital
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In a large cohort of alkaptonuria (AKU) patients, a high prevalence of aortic valve disease was found to be strongly associated with ochronosis and disease severity. Nitisinone was shown to decrease ochronosis and had a significant effect on Vmax.
Aims: A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU. Methods and results: Eighty-one patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Nine only attended once. Fifty-one attended more than once and received nitisinone 2 mg daily. Twenty-one attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, standard transthoracic echocardiography, as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of aortic stenosis and aortic valve replacement were 22.2 and 6.2% in the current group. Aortic maximum velocity (Vmax) was directly related to varying degrees to age (R = 0.58, p < 0.001), systolic blood pressure (R = 0.32, p < 0.05), serum homogentisic acid (sHGA) (R = 0.28, p < 0.05), ochronosis scores (R = 0.72, p < 0.001), and alkaptonuria severity score index (AKUSSI) (R = 0.58, p < 0.001) on linear regression analysis. Age and ochronosis scores were significantly related to Vmax on multiple regression analysis (p < 0.005). Nitisinone decreased sHGA, 24-h urine HGA (uHGA24), ochronosis scores and AKUSSI significantly at all visits post-nitisinone. Nitisinone decreased Vmax change scores at final visit comparison, with a similar pattern at earlier visits. Conclusion: Aortic valve disease is highly prevalent in this NAC cohort, and strongly associated with ochronosis and disease severity. Nitisinone decreases ochronosis and had a similar significant effect on Vmax. (C) 2021 Elsevier Inc. All rights reserved.
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