Treatment from birth of nonketotic hyperglycinemia due to a novel <i>GLDC</i> mutation

Korman, Stanley H.; Wexler, Isaiah D.; Gutman, Alisa; Rolland, M. O.; Kanno, Junko; Kure, Shigeo

doi:10.1002/ana.20759

Cited by 44 publications

(45 citation statements)

References 18 publications

(14 reference statements)

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“…Prediction of severe outcome can help families in considering withdrawal of life-sustaining therapy in the neonatal apneic phase given the current lack of effective therapies in this setting. 15,36 It is also important in the stratification of patients in treatment studies. Different treatment responses may exist between severe and attenuated NKH.…”

Section: Discussionmentioning

confidence: 99%

“…Different treatment responses may exist between severe and attenuated NKH. 30,36 The relation between residual activity and outcome suggests that novel strategies to improve residual activity such as chaperones may have a beneficial clinical effect and should be researched. The complex relationship between genotype and phenotype indicates that additional factors will need to be identified to make such a strategy fully successful.…”

Section: Discussionmentioning

confidence: 99%

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Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia

Swanson

Coughlin

Scharer

et al. 2015

Annals of Neurology

121

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ObjectiveNonketotic 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.MethodsWe 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.ResultsPatients 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.InterpretationAccurate 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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia

Swanson

Coughlin

Scharer

et al. 2015

Annals of Neurology

121

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“…Clinical features of the late-onset variant include spastic paraparesis, optical atrophy, mild development delay or normal cognition, ataxia, and choreoathetoid movements. Early treatment consisting of sodium benzoate and dextromethorphan administration may improve the neurological sequelae of these patients, but are usually not very successful (Korman et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Glycine Provokes Lipid Oxidative Damage and Reduces the Antioxidant Defenses in Brain Cortex of Young Rats

et al. 2008

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Patients affected by nonketotic hyperglycinemia (NKH) usually present severe neurological symptoms and suffer from acute episodes of intractable seizures with leukoencephalopathy. Although excitotoxicity seems to be involved in the brain damage of NKH, the mechanisms underlying the neuropathology of this disease are not fully established. The objective of the present study was to investigate the in vitro effects of glycine (GLY), that accumulate at high concentrations in the brain of patients affected by this disorder, on important parameters of oxidative stress, such as lipid peroxidation (thiobarbituric acid-reactive substances (TBA-RS) and chemiluminescence) and the most important non-enzymatic antioxidant defense reduced glutathione (GSH) in cerebral cortex from 30-day-old rats. GLY significantly increased TBA-RS and chemiluminescence values, indicating that this metabolite provokes lipid oxidative damage. Furthermore, the addition of high doses of the antioxidants melatonin, trolox (soluble vitamin E) and GSH fully prevented GLY-induced increase of lipid peroxidation, indicating that free radicals were involved in this effect. GLY also decreased GSH brain concentrations, which was totally blocked by melatonin treatment. Finally, GLY significantly reduced sulfhydryl group content from a commercial GSH solution, but did not oxidize reduced cytochrome C. Our data indicate that oxidative stress elicited in vitro by GLY may possibly contribute at least in part to the pathophysiology of the neurological dysfunction in NKH.

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“…Although milder, patients affected by the late onset form of the disorder also present neurological abnormalities. Early treatment consisting of sodium benzoate and dextromethorphan administration may improve the neurological sequel of these patients, but is usually not very successful (Korman et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain

et al. 2011

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The data shows that Gly in vivo administration causes lipid peroxidation, probably secondary to NMDA stimulation, induces protein oxidation and modulates the activities of important antioxidant enzymes in the striatum. In case these findings can be extrapolated to the human NKH, it is feasible that oxidative stress may be involved in the pathophysiology of the brain injury observed in patients with this neurometabolic disease.

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Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation

Abstract: Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long-term outcome, suggesting glycine-induced prenatal injury and/or ongoing postnatal damage.

Cited by 44 publications

References 18 publications

Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia

Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia

Glycine Provokes Lipid Oxidative Damage and Reduces the Antioxidant Defenses in Brain Cortex of Young Rats

Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain

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