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Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess...

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Autores principales: Shelkowitz, Emily, Saneto, Russell P., Al-Hertani, Walla, Lubout, Charlotte M. A., Stence, Nicholas V., Brown, Mark S., Long, Patrick, Walleigh, Diana, Nelson, Julie A., Perez, Francisco E., Shaw, Dennis W. W., Michl, Emma J., Van Hove, Johan L. K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720968/
https://www.ncbi.nlm.nih.gov/pubmed/36471344
http://dx.doi.org/10.1186/s13023-022-02581-6
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author Shelkowitz, Emily
Saneto, Russell P.
Al-Hertani, Walla
Lubout, Charlotte M. A.
Stence, Nicholas V.
Brown, Mark S.
Long, Patrick
Walleigh, Diana
Nelson, Julie A.
Perez, Francisco E.
Shaw, Dennis W. W.
Michl, Emma J.
Van Hove, Johan L. K.
author_facet Shelkowitz, Emily
Saneto, Russell P.
Al-Hertani, Walla
Lubout, Charlotte M. A.
Stence, Nicholas V.
Brown, Mark S.
Long, Patrick
Walleigh, Diana
Nelson, Julie A.
Perez, Francisco E.
Shaw, Dennis W. W.
Michl, Emma J.
Van Hove, Johan L. K.
author_sort Shelkowitz, Emily
collection PubMed
description BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.
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spelling pubmed-97209682022-12-06 Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels Shelkowitz, Emily Saneto, Russell P. Al-Hertani, Walla Lubout, Charlotte M. A. Stence, Nicholas V. Brown, Mark S. Long, Patrick Walleigh, Diana Nelson, Julie A. Perez, Francisco E. Shaw, Dennis W. W. Michl, Emma J. Van Hove, Johan L. K. Orphanet J Rare Dis Research BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine. BioMed Central 2022-12-05 /pmc/articles/PMC9720968/ /pubmed/36471344 http://dx.doi.org/10.1186/s13023-022-02581-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Shelkowitz, Emily
Saneto, Russell P.
Al-Hertani, Walla
Lubout, Charlotte M. A.
Stence, Nicholas V.
Brown, Mark S.
Long, Patrick
Walleigh, Diana
Nelson, Julie A.
Perez, Francisco E.
Shaw, Dennis W. W.
Michl, Emma J.
Van Hove, Johan L. K.
Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title_full Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title_fullStr Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title_full_unstemmed Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title_short Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
title_sort ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720968/
https://www.ncbi.nlm.nih.gov/pubmed/36471344
http://dx.doi.org/10.1186/s13023-022-02581-6
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