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Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation

BACKGROUND: Phenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, mic...

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Autores principales: Cannet, Claire, Pilotto, Andrea, Rocha, Júlio César, Schäfer, Hartmut, Spraul, Manfred, Berg, Daniela, Nawroth, Peter, Kasperk, Christian, Gramer, Gwendolyn, Haas, Dorothea, Piel, David, Kölker, Stefan, Hoffmann, Georg, Freisinger, Peter, Trefz, Friedrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047385/
https://www.ncbi.nlm.nih.gov/pubmed/32106880
http://dx.doi.org/10.1186/s13023-020-1329-5
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author Cannet, Claire
Pilotto, Andrea
Rocha, Júlio César
Schäfer, Hartmut
Spraul, Manfred
Berg, Daniela
Nawroth, Peter
Kasperk, Christian
Gramer, Gwendolyn
Haas, Dorothea
Piel, David
Kölker, Stefan
Hoffmann, Georg
Freisinger, Peter
Trefz, Friedrich
author_facet Cannet, Claire
Pilotto, Andrea
Rocha, Júlio César
Schäfer, Hartmut
Spraul, Manfred
Berg, Daniela
Nawroth, Peter
Kasperk, Christian
Gramer, Gwendolyn
Haas, Dorothea
Piel, David
Kölker, Stefan
Hoffmann, Georg
Freisinger, Peter
Trefz, Friedrich
author_sort Cannet, Claire
collection PubMed
description BACKGROUND: Phenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described. RESULTS: Concurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50–1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher. CONCLUSIONS: Using NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.
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spelling pubmed-70473852020-03-03 Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation Cannet, Claire Pilotto, Andrea Rocha, Júlio César Schäfer, Hartmut Spraul, Manfred Berg, Daniela Nawroth, Peter Kasperk, Christian Gramer, Gwendolyn Haas, Dorothea Piel, David Kölker, Stefan Hoffmann, Georg Freisinger, Peter Trefz, Friedrich Orphanet J Rare Dis Research BACKGROUND: Phenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described. RESULTS: Concurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50–1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher. CONCLUSIONS: Using NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins. BioMed Central 2020-02-27 /pmc/articles/PMC7047385/ /pubmed/32106880 http://dx.doi.org/10.1186/s13023-020-1329-5 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Cannet, Claire
Pilotto, Andrea
Rocha, Júlio César
Schäfer, Hartmut
Spraul, Manfred
Berg, Daniela
Nawroth, Peter
Kasperk, Christian
Gramer, Gwendolyn
Haas, Dorothea
Piel, David
Kölker, Stefan
Hoffmann, Georg
Freisinger, Peter
Trefz, Friedrich
Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title_full Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title_fullStr Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title_full_unstemmed Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title_short Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation
title_sort lower plasma cholesterol, ldl-cholesterol and ldl-lipoprotein subclasses in adult phenylketonuria (pku) patients compared to healthy controls: results of nmr metabolomics investigation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047385/
https://www.ncbi.nlm.nih.gov/pubmed/32106880
http://dx.doi.org/10.1186/s13023-020-1329-5
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