Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia

Bjoraker, Kendra; Swanson, Michael A.; Coughlin, Curtis R.; Christodoulou, John; Tan, Ee Shien; Fergeson, Mark; Dyack, Sarah; Ahmad, Ayesha; Friederich, Marisa W.; Spector, Elaine; Creadon‐Swindell, Geralyn; Redoblado-Hodge, Marie Antoinette; Gaughan, Sommer; Burns, Casey; Hove, Johan L.K. Van

doi:10.1016/j.jpeds.2015.12.027

Cited by 64 publications

(66 citation statements)

References 26 publications

(44 reference statements)

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“…This compendium of new 19 GLDC missense mutations analyzed in the context of a genotype–phenotype correlation will be helpful for clinicians when evaluating the benefit of specific interventions during the neonatal period. Patients who have at least one mutation that allows for residual enzyme activity, many of them described here, have the potential to develop attenuated NKH, and data from a sibling study indicate that early treatment improves outcome (Bjoraker et al., ; Swanson et al., ). This extended study of expressed mutations helps clinicians identify more patients with residual activity that best benefit from early treatment.…”

Section: Discussionmentioning

confidence: 92%

“…Distinguishing different NKH forms is important for prognosis and stratification of patients for treatment. Treatment usually involves sodium benzoate to reduce plasma glycine levels, and dextromethorphan to decrease the excessive stimulating activity of glycine on N-methyl-D-aspartate receptors (Bjoraker et al, 2016;Hamosh, Maher, Bellus, Rasmussen, & Johnston, 1998;Van Hove et al, 2005). Biochemical parameters such as the CSF/plasma glycine ratio can be helpful in this classification.…”

Section: Introductionmentioning

confidence: 99%

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Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

et al. 2017

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The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

et al. 2017

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“…xii. Residue is at the known dimerization interface (because dimerization may be 522 genotype was known and the patient had at least one missense mutation [13,14,29,[46][47][48][49][50][51][52][53][54][55][56]. A 540 comprehensive list of NKH symptoms in the clinical data was created ( Table 2), and we developed 541 a clinical outcome scoring scale based on the four major symptomatic domains of 1) seizures, 2) 542 cognitive disorders, 3) muscle/movement control and 4) brain malformations ( Table 3).…”

Section: Conservation Of Amino Acid Substitution (Based On Blosum62 Mmentioning

confidence: 99%

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity

Farris

Calhoun

Alam

et al. 2019

Preprint

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16Monogenetic diseases provide unique opportunity for studying complex, clinical states that 17 underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact 18 neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-19 metabolic disorder lacking quantitative predictors of disease states. It is characterized by 20 elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer 21 neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated 22 disease. A major challenge has been that there are 255 unique disease-causing missense 23 mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a 24Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, 25 evolutionary conservation and protein interaction models and suitable to assess 251 of 255 26 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of 27 four major disease domains (seizure, cognitive failure, muscular and motor control and brain-28 malformation) to comprehensively score patient symptoms identified in 131 clinical reports 29 published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were 30 used to optimize the MMS for biological and clinical relevance and yield a patient Weighted 31Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological 32 disease (p < 3.5e-5). Our study provides understanding for developing quantitative tools to predict 33 clinical severity of neurological disease and a clinical scale that advances monitoring disease 34 progression needed to evaluate new treatments for NKH. 35 lack of mutation-based predictors of disease progression and a quantitative scale of disease 61 severity scale impedes both management of NKH as well as development of therapies to treat 62 and cure the disease. 63 64In this study, we developed a multi-parametric mutation scale applicable to all but 4 of 255 65 missense NKH mutations across the GLDC gene and thereby assigned a multi-parametric 66 mutation score (MMS) to 251 patient mutations. The MMS was further optimized against a newly 67 developed patient-based clinical outcomes score that was based on major symptomatic domains 68 extracted from a comprehensive review of clinical cases reported in the literature. Our findings 69 yield a quantitative tool with high predictive value to support disease management and emerging 70 treatments associated with >95% of known clinical NKH mutations. 71 72 Results 73Positional distribution of NKH Missense Mutations. 74The most recently published comprehensive list of NKH missense mutations lists 171 unique 75 mutations across the length of GLDC [8]. To this, we added 85 missense mutations based on 76 additional literature and the Clinvar database. This yielded a list of 256 mutations ascribed to 213 77 unique residues (Table S1, Fig 1A). NKH missense mutations were found in the C-te...

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“…Doses required for plasma normalization of L-glycine differ in severe and attenuated forms. If started during the newborn period, sodium benzoate in combination with dextromethorphan, a non-competitive NMDA receptor antagonist, can improve the clinical outcome of children with attenuated GE (Bjoraker et al 2016). Strychnine improves respiration during the neonatal period, but does not fundamentally alter the disease course and should not be considered for long-term treatment because of its severe adverse effects (McDermot et al 1980).…”

Section: Glycine Encephalopathymentioning

confidence: 99%

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

Kölker

2018

J of Inher Metab Disea

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Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABA and GABA receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

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Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia

Abstract: Early treatment with dextromethorphan and sodium benzoate sufficient to normalize plasma glycine levels is effective at improving outcome if used in children with attenuated disease with mutations providing residual activity and when started from the neonatal period.

Cited by 64 publications

References 26 publications

Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

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