Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice |
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| Institution: | 1. University of Groningen, University Medical Center Groningen, Beatrix Children''s Hospital, Groningen, the Netherlands;2. University of Groningen, Groningen Institute for Evolutionary Life Sciences (GELIFES), Department of Molecular Neurobiology, Groningen, the Netherlands;3. University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, the Netherlands;1. Department of Pathology, Children''s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States;2. Genomics and Proteomics Core Laboratories, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15260, United States;3. Department of Pediatrics, University of Pittsburgh School of Medicine, Children''s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States;4. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, 4401 Penn Avenue, Pittsburgh, PA 15224, United States;1. Department of Pediatrics in the College of Medicine, University of Florida, Gainesville, FL, USA;2. Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA;3. Pediatrics Genetics Group, Albany Medical Center, Albany, NY, USA;4. Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA;5. BioMarin Pharmaceutical Inc., Novato, CA, USA;6. Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA;1. Dept. of Psychology and Center \"Daniel Bovet\", Sapienza University, 00184 Rome, Italy;2. IRCSS Fondazione Santa Lucia, 00142 Rome, Italy;3. Behavioral Neuroscience PhD Programme, Sapienza University, 00184, Rome, Italy;4. Dept. of Applied and Biotechnological Clinical Sciences, University of L''Aquila, 67100 L''Aquila, Italy;5. Cell Biology and Neurobiology Institute, National Research Council, 00143 Rome, Italy;6. Institut Universitaire en Santé Mentale de Québec, Laval University, Quebec, Canada;1. Department of Medical and Molecular Genetics, Oregon Health & Science University, Mailstop L-103, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA;2. Department of Pediatrics, University of Zurich, Steinweissstrasse 75, Zurich CH-8032, Switzerland;3. Department of Biomedicine, KG Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, 5009 Bergen, Norway;4. Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA;5. Department of Neurology, Division of Neuroscience, ONPRC, Oregon Health & Science University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA;6. Department of Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA;1. Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, the Netherlands;2. Leiden Institute for Brain and Cognition, Leiden University Medical Centre, Leiden, the Netherlands;3. Department of Pediatrics, Emma Children''s Hospital, Academic Medical Center, University of Amsterdam, the Netherlands;4. Beatrix Children''s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;5. Maastricht University Medical Centre, Maastricht, the Netherlands;6. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;7. Wilhelmina Children''s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands;8. Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands;9. Erasmus Medical Center, Rotterdam, the Netherlands;10. Department of Developmental and Clinical Neuropsychology, University of Groningen, Groningen, the Netherlands |
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| Abstract: | Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning. |
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