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Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia
OBJECTIVE: Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed. METHODS: We revie...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767401/ https://www.ncbi.nlm.nih.gov/pubmed/26179960 http://dx.doi.org/10.1002/ana.24485 |
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author | Swanson, Michael A. Coughlin, Curtis R. Scharer, Gunter H. Szerlong, Heather J. Bjoraker, Kendra J. Spector, Elaine B. Creadon‐Swindell, Geralyn Mahieu, Vincent Matthijs, Gert Hennermann, Julia B. Applegarth, Derek A. Toone, Jennifer R. Tong, Suhong Williams, Kristina Van Hove, Johan L. K. |
author_facet | Swanson, Michael A. Coughlin, Curtis R. Scharer, Gunter H. Szerlong, Heather J. Bjoraker, Kendra J. Spector, Elaine B. Creadon‐Swindell, Geralyn Mahieu, Vincent Matthijs, Gert Hennermann, Julia B. Applegarth, Derek A. Toone, Jennifer R. Tong, Suhong Williams, Kristina Van Hove, Johan L. K. |
author_sort | Swanson, Michael A. |
collection | PubMed |
description | OBJECTIVE: Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed. METHODS: We reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay. RESULTS: Patients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P‐protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors. INTERPRETATION: Accurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity. Ann Neurol 2015;78:606–618 |
format | Online Article Text |
id | pubmed-4767401 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-47674012016-09-20 Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia Swanson, Michael A. Coughlin, Curtis R. Scharer, Gunter H. Szerlong, Heather J. Bjoraker, Kendra J. Spector, Elaine B. Creadon‐Swindell, Geralyn Mahieu, Vincent Matthijs, Gert Hennermann, Julia B. Applegarth, Derek A. Toone, Jennifer R. Tong, Suhong Williams, Kristina Van Hove, Johan L. K. Ann Neurol Research Articles OBJECTIVE: Nonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed. METHODS: We reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay. RESULTS: Patients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P‐protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors. INTERPRETATION: Accurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity. Ann Neurol 2015;78:606–618 John Wiley and Sons Inc. 2015-08-10 2015-10 /pmc/articles/PMC4767401/ /pubmed/26179960 http://dx.doi.org/10.1002/ana.24485 Text en © 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Articles Swanson, Michael A. Coughlin, Curtis R. Scharer, Gunter H. Szerlong, Heather J. Bjoraker, Kendra J. Spector, Elaine B. Creadon‐Swindell, Geralyn Mahieu, Vincent Matthijs, Gert Hennermann, Julia B. Applegarth, Derek A. Toone, Jennifer R. Tong, Suhong Williams, Kristina Van Hove, Johan L. K. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title | Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title_full | Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title_fullStr | Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title_full_unstemmed | Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title_short | Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
title_sort | biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767401/ https://www.ncbi.nlm.nih.gov/pubmed/26179960 http://dx.doi.org/10.1002/ana.24485 |
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