Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria.

Andrea Pilotto, Nenad Blau, Edytha Leks, Claudia Schulte, Christian Deuschl, Carl Zipser, David Piel, Peter Freisinger, Gwendolyn Gramer, Stefan Kölker, Dorothea Haas, Peter Burgard, Peter Nawroth, Hoffmann Georg, Klaus Scheffler, Daniela Berg, Friedrich Trefz

Journal: Journal of inherited metabolic disease 2020;42(3):398-406

PMID: 30706953

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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.

Address: 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.; Department of Pediatrics, Division for Neuropediatrics and Metabolic Medicine, University of Heidelberg, Heidelberg, Germany.; Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany.; 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 and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Department of Endocrinology, Internal Medicine I, University of Heidelberg, Heidelberg, Germany.; Pediatrics, Reutlingen Hospital, Reutlingen, Germany.; Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany.; Magnetic Resonance Centre, Max-Planck-Institute for Biological Cybernetics, Tübingen, Germany.; 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.

DOI: 10.1002/jimd.12049

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MeSH Terms: Adult, Atrophy, Biogenic Amines, Case-Control Studies, Female, Gray Matter, Homovanillic Acid, Humans, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Phenylketonurias