Evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy: Analysis of a large cohort of eighty-one alkaptonuria patients

• Published in: Molecular genetics and metabolism Vol. 133; no. 3; pp. 324 - 331
• Main Authors: Ranganath, L.R., Heseltine, T., Khedr, M., Fisher, M.F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021
• Subjects: Adult; Aged; Alkaptonuria; Alkaptonuria - complications; Alkaptonuria - drug therapy; Aortic stenosis; Aortic valve replacement; Aortic Valve Stenosis - physiopathology; Cohort Studies; Cyclohexanones - therapeutic use; Enzyme Inhibitors - therapeutic use; Female; Homogentisic acid; Humans; Male; Middle Aged; Nitisinone; Nitrobenzoates - therapeutic use; Ochronosis; Phenotype; Severity of Illness Index; Homogentisic acid; Aortic stenosis; Aortic valve replacement; Alkaptonuria; Ochronosis; Nitisinone
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2021.05.007

A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU. 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. 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. •Aortic stenosis is highly prevalent in alkaptonuria.•Ochronosis is strongly related to aortic jet maximum velocity in alkaptonuria.•Nitisinone decreases ochronosis and homogentisic acid.•Nitisinone also decreases progression of aortic valve disease.