Natacha Sloboda1, Arnaud Wiedemann2, Marc Merten3, Amerh Alqahtani1, Elise Jeannesson3, Alain Blum4, Sophie Henn-Ménétré5, Jean-Louis Guéant3, Emeline Renard2, François Feillet6. 1. Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France. 2. Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France; INSERM UMRS 1256 NGERE, Nutrition, Genetics, and Environmental Risk Exposure, National Center of Inborn Errors of Metabolism, Faculty of Medicine of Nancy, University of Lorraine and University Regional Hospital Center of Nancy, Vandoeuvre-les-Nancy F-54000, France. 3. INSERM UMRS 1256 NGERE, Nutrition, Genetics, and Environmental Risk Exposure, National Center of Inborn Errors of Metabolism, Faculty of Medicine of Nancy, University of Lorraine and University Regional Hospital Center of Nancy, Vandoeuvre-les-Nancy F-54000, France; Biochemistry and Molecular Biology Laboratory (Nutrition, Metabolism), CHRU de Nancy, Nancy, France. 4. Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France; Radiology Unit Guilloz, University Hospital, Hôpital Central, Nancy, France. 5. Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France; Pharmacy Unit, University Hospital, CHU Brabois, Vandoeuvre les Nancy, France. 6. Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France; INSERM UMRS 1256 NGERE, Nutrition, Genetics, and Environmental Risk Exposure, National Center of Inborn Errors of Metabolism, Faculty of Medicine of Nancy, University of Lorraine and University Regional Hospital Center of Nancy, Vandoeuvre-les-Nancy F-54000, France. Electronic address: f.feillet@chru-nancy.fr.
Abstract
AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5 years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2 mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500 μmol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500 μmol/L.
AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND:Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKUpatients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKUpatient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5 years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2 mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500 μmol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500 μmol/L.
Authors: Andrew S Davison; Brendan P Norman; Hazel Sutherland; Anna M Milan; James A Gallagher; Jonathan C Jarvis; Lakshminarayan R Ranganath Journal: Metabolites Date: 2022-05-25
Authors: Lakshminarayan R Ranganath; Anna M Milan; Andrew T Hughes; Milad Khedr; Brendan P Norman; Mohammed Alsbou; Richard Imrich; Matthew Gornall; Nicolas Sireau; James A Gallagher; Richard Jackson Journal: JIMD Rep Date: 2021-11-11