Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria
Corresponding Author
Andrea Pilotto
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
Parkinson's Disease Rehabilitation Centre, FERB ONLUS S. Isidoro Hospital, Trescore Balneario, Italy
Correspondence
Andrea Pilotto, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe Seyler-Strasse 3 72076 Tübingen, Germany.
Email: [email protected]
Search for more papers by this authorNenad Blau
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorEdytha Leks
Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
Search for more papers by this authorClaudia Schulte
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Search for more papers by this authorChristian Deuschl
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Search for more papers by this authorCarl Zipser
Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Search for more papers by this authorDavid Piel
Department of Endocrinology, Internal Medicine I, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Freisinger
Pediatrics, Reutlingen Hospital, Reutlingen, Germany
Search for more papers by this authorGwendolyn Gramer
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorStefan Kölker
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDorothea Haas
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Burgard
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Nawroth
Department of Endocrinology, Internal Medicine I, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorHoffmann Georg
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorKlaus Scheffler
Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
Magnetic Resonance Centre, Max-Planck-Institute for Biological Cybernetics, Tübingen, Germany
Search for more papers by this authorDaniela Berg
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Department of Neurology, University-Hospital-Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorFriedrich Trefz
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Andrea Pilotto
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
Parkinson's Disease Rehabilitation Centre, FERB ONLUS S. Isidoro Hospital, Trescore Balneario, Italy
Correspondence
Andrea Pilotto, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe Seyler-Strasse 3 72076 Tübingen, Germany.
Email: [email protected]
Search for more papers by this authorNenad Blau
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorEdytha Leks
Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
Search for more papers by this authorClaudia Schulte
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Search for more papers by this authorChristian Deuschl
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Search for more papers by this authorCarl Zipser
Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Search for more papers by this authorDavid Piel
Department of Endocrinology, Internal Medicine I, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Freisinger
Pediatrics, Reutlingen Hospital, Reutlingen, Germany
Search for more papers by this authorGwendolyn Gramer
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorStefan Kölker
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDorothea Haas
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Burgard
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter Nawroth
Department of Endocrinology, Internal Medicine I, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorHoffmann Georg
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorKlaus Scheffler
Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
Magnetic Resonance Centre, Max-Planck-Institute for Biological Cybernetics, Tübingen, Germany
Search for more papers by this authorDaniela Berg
Department of Neurodegeneration, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases, Department of Neurodegeneration, Tübingen, Germany
Department of Neurology, University-Hospital-Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorFriedrich Trefz
Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorFunding information Vitaflo Germany
Abstract
Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.
CONFLICTS OF INTEREST
A.P. received speaker honoraria from BioMarin, Chiesi, Nutricia, UCB, and Zambon Pharmaceuticals. He received travel grants from AbbVie, BioMarin, Nutricia, and Zambon Pharmaceuticals and research support from Vitaflo Germany and Zambon Italy. N.B. is a member of Merck-Serono and Biomarin Scientific Advisory Board for PKU and has received grants and honorarium from Merck-Serono and BioMarin. E.L., C.S., C.D., D.P., P.F., G.G., S.K., D.H., P.B., P.N., G.H., and K.S. report no disclosures. D.B. reports grants from Michael J. Fox Foundation, Janssen Pharmaceutica N.V., German Parkinson's Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, and Lundbeck. She received personal fees from Advisory board of UCB Pharma GmbH, Lundbeck, Prexton Therapeutics, and GE-Healthcare. She received Honoraria from UCB Pharma GmbH, Lundbeck, BIAL, and Bayer, outside the submitted work. F.T. reports grants from Vitaflo Germany and received Honoraria as a speaker from Merck-Serono SA.
Supporting Information
| Filename | Description |
|---|---|
| jimd12049-sup-0001-TableS1.docxWord 2007 document , 81.8 KB | Table S1. Correlation between Phe, bioaminergic neurotransmitter and area-specific MRI changes. The analyses were performed by using statistical nonparametric mapping (SnPM 13). Negative (Phe levels) and positive (5-HIAA, 5-HTP, HVA CSF levels) correlations adjusted for the effect of age are reported, threshold set at P < 0.001 uncorrected, with a minimum cluster size 100 voxels. Abbreviations: PKU, phenylketonuria; HC, healthy controls; Phe, phenylalanine levels. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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