Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels
Abstract 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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-022-02581-6 |
| _version_ | 1797863551558221824 |
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| author | Emily Shelkowitz Russell P. Saneto Walla Al-Hertani Charlotte M. A. Lubout Nicholas V. Stence Mark S. Brown Patrick Long Diana Walleigh Julie A. Nelson Francisco E. Perez Dennis W. W. Shaw Emma J. Michl Johan L. K. Van Hove |
| author_facet | Emily Shelkowitz Russell P. Saneto Walla Al-Hertani Charlotte M. A. Lubout Nicholas V. Stence Mark S. Brown Patrick Long Diana Walleigh Julie A. Nelson Francisco E. Perez Dennis W. W. Shaw Emma J. Michl Johan L. K. Van Hove |
| author_sort | Emily Shelkowitz |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-09T22:38:25Z |
| format | Article |
| id | doaj.art-9af194b7d7c7450f938a5780e5345a8f |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-04-09T22:38:25Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-9af194b7d7c7450f938a5780e5345a8f2023-03-22T12:22:07ZengBMCOrphanet Journal of Rare Diseases1750-11722022-12-0117111410.1186/s13023-022-02581-6Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levelsEmily Shelkowitz0Russell P. Saneto1Walla Al-Hertani2Charlotte M. A. Lubout3Nicholas V. Stence4Mark S. Brown5Patrick Long6Diana Walleigh7Julie A. Nelson8Francisco E. Perez9Dennis W. W. Shaw10Emma J. Michl11Johan L. K. Van Hove12Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoDivision of Pediatric Neurology, Department of Neurology, Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle Children’s HospitalDivision of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical SchoolSection of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center, GroningenDepartment of Radiology, University of ColoradoDepartment of Radiology, University of ColoradoSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoSection of Child Neurology, Department of Pediatrics, University of ColoradoSection of Child Neurology, Department of Pediatrics, University of ColoradoDepartment of Radiology, Seattle Children’s Hospital, University of WashingtonDepartment of Radiology, Seattle Children’s Hospital, University of WashingtonDivision of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical SchoolSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoAbstract 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.https://doi.org/10.1186/s13023-022-02581-6Nonketotic hyperglycinemiaBenzoateKetogenic dietMagnetic resonance spectroscopyGlycineEpilepsy |
| spellingShingle | Emily Shelkowitz Russell P. Saneto Walla Al-Hertani Charlotte M. A. Lubout Nicholas V. Stence Mark S. Brown Patrick Long Diana Walleigh Julie A. Nelson Francisco E. Perez Dennis W. W. Shaw Emma J. Michl Johan L. K. Van Hove Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels Orphanet Journal of Rare Diseases Nonketotic hyperglycinemia Benzoate Ketogenic diet Magnetic resonance spectroscopy Glycine Epilepsy |
| 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 | Nonketotic hyperglycinemia Benzoate Ketogenic diet Magnetic resonance spectroscopy Glycine Epilepsy |
| url | https://doi.org/10.1186/s13023-022-02581-6 |
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