Danique van Vliet1, Vibeke M Bruinenberg2, Priscila N Mazzola1,2, Martijn Hjr van Faassen3, Pim de Blaauw3, Tiziana Pascucci4,5, Stefano Puglisi-Allegra4,5, Ido P Kema3, M Rebecca Heiner-Fokkema3, Eddy A van der Zee2, Francjan J van Spronsen6. 1. University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands. 2. Department of Molecular Neurobiology, University of Groningen, Groningen Institute for Evolutionary Life Sciences, Groningen, Netherlands. 3. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 4. Department of Psychology and Centro "Daniel Bovet," "La Sapienza" University, Fondazione Santa Lucia, Rome, Italy; and. 5. Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. 6. University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands; f.j.van.spronsen@umcg.nl.
Abstract
BACKGROUND: Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. OBJECTIVE: In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. DESIGN: Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. RESULTS: Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. CONCLUSION: The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria.
BACKGROUND:Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. OBJECTIVE: In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. DESIGN:Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuriamice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. RESULTS: Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. CONCLUSION: The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria.
Authors: Denise M Ney; Sangita G Murali; Bridget M Stroup; Nivedita Nair; Emily A Sawin; Fran Rohr; Harvey L Levy Journal: Mol Genet Metab Date: 2017-04-06 Impact factor: 4.797
Authors: Nasser A Elhawary; Imad A AlJahdali; Iman S Abumansour; Ezzeldin N Elhawary; Nagwa Gaboon; Mohammed Dandini; Abdulelah Madkhali; Wafaa Alosaimi; Abdulmajeed Alzahrani; Fawzia Aljohani; Ehab M Melibary; Osama A Kensara Journal: Hum Genomics Date: 2022-07-19 Impact factor: 6.481
Authors: Rianne Jahja; Francjan J van Spronsen; Leo M J de Sonneville; Jaap J van der Meere; Annet M Bosch; Carla E M Hollak; M Estela Rubio-Gozalbo; Martijn C G J Brouwers; Floris C Hofstede; Maaike C de Vries; Mirian C H Janssen; Ans T van der Ploeg; Janneke G Langendonk; Stephan C J Huijbregts Journal: Behav Genet Date: 2017-08-03 Impact factor: 2.805
Authors: Vibeke M Bruinenberg; Marijke C M Gordijn; Anita MacDonald; Francjan J van Spronsen; Eddy A Van der Zee Journal: Front Neurol Date: 2017-04-26 Impact factor: 4.003
Authors: Elena Fiori; Diego Oddi; Rossella Ventura; Marco Colamartino; Alessandro Valzania; Francesca Romana D'Amato; Vibeke Bruinenberg; Eddy van der Zee; Stefano Puglisi-Allegra; Tiziana Pascucci Journal: PLoS One Date: 2017-08-29 Impact factor: 3.240