The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT

Coughlin, Curtis R.; Swanson, Michael A.; Kronquist, Kathryn E.; Acquaviva, Cécile; Hutchin, Tim; Rodríguez‐Pombo, Pilar; Väisänen, Marja‐Leena; Spector, Elaine; Creadon‐Swindell, Geralyn; Brasgoldberg, Ana Maria; Rahikkala, Elisa; Moilanen, Jukka S.; Mahieu, Vincent; Matthijs, Gert; Bravo-Alonso, Irene; Pérez‐Cerdá, Celia; Ugarte, Magdalena; Vianey‐Saban, Christine; Scharer, Gunter; Hove, Johan L.K. Van

doi:10.1038/gim.2016.74

Cited by 70 publications

(79 citation statements)

References 36 publications

(52 reference statements)

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“…Population incidence of PDE: Previous studies have attempted to utilize population databases, such as the ExAc database, in order to estimate a disease incidence for autosomal recessive and X‐linked recessive disorders. This has been most successful when a large number of pathogenic variants are known a priori . We expanded the limited information on pathogenic variants in ALDH7A1 from the literature of case reports and small case series in this large cohort, but the number of variants identified remains limited in comparison to those identified in the gnomeAD database.…”

Section: Discussionmentioning

confidence: 99%

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

Coughlin

Swanson

Spector

et al. 2019

J of Inher Metab Disea

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Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over‐expressed in an E.coli‐based expression system to measure α‐aminoadipic semialdehyde dehydrogenase activity and production of α‐aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under‐diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.

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Section: Discussionmentioning

confidence: 99%

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

Coughlin

Swanson

Spector

et al. 2019

J of Inher Metab Disea

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“…A mutation in the gene that encodes the glycine cleavage enzyme leads to abnormal metabolism and accumulation of glycine in the brain and other body tissues. The majority (80%) of mutations are in glycine decarboxylase ( GLDC gene); in the remaining cases, the mutations affect the aminomethyltransferase or glycine cleavage system H protein gene 4. The accrual of glycine to toxic levels results in symptoms usually in the neonatal period and presents with a progressive encephalopathy, resulting in coma and death within the first few days to weeks of life.…”

Section: Introductionmentioning

confidence: 99%

Ventilator respiratory graphic diagnosis of hiccupping in non-ketotic hyperglycinaemia

et al. 2017

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A neonate presented with early encephalopathy deteriorated and was intubated and ventilated. Ventilator data were monitored and recorded at 100 Hz for 24 hours.The infant had many sudden deep inspirations during this time which were initially thought to be seizures. These were characterised by short, rapid, large inspirations when the airway pressure was reduced well below the positive end expiratory pressure level. Analysis of the ventilator data showed that these were hiccupping episodes misinterpreted by the ventilator as spontaneous breaths and triggering ventilator inflations. The expired tidal volumes during the hiccupping episodes were more than double the set 4.5 mL/kg. During these episodes, there was no change in the level of consciousness or in the amplitude-integrated electroencephalogram signal. Detailed respiratory recording of pathological hiccups has not been reported.Metabolic screening diagnosed non-ketotic hyperglycinaemia. Hiccups commonly occur in this condition and should not be misinterpreted as seizures, spontaneous breaths or gasps.

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“…As previously described (Coughlin et al., ), mutations affecting residues located near the active‐site pocket, such as p.Arg373Trp, p.Ala624Asp, or p.Gly768Glu, result in stable protein with variable residual activities. At the entrance site of glycine into the catalytic tunnel, the exchange of a polar‐positive amino acid such as Arg373 by the large aliphatic residue Trp modified the predicted interaction pattern between Arg373 and Asp995, although it retained part of these interactions through Van der Waals forces.…”

Section: Resultsmentioning

confidence: 75%

“…Sequencing of the GLDC or AMT genes identified 32 different single‐nucleotide changes (see Table A and B), which were rare or absent in major databases such as the Exome Sequencing Project, dbSNP, or ExAc consortium (Lek et al., ). Most have been included in a previously published survey of mutations in NKH (Coughlin et al., ), and all mutations have been deposited in the LOVD database accessible at http://www.lovd.nl. Most mutations were located in exonic sequence.…”

Section: Resultsmentioning

confidence: 99%

“…Most NKH patients have disease-causing mutations in GLDC (around 80%) or AMT (20%) genes (Coughlin et al, 2017). The reported GLDC and AMT mutation spectrum includes exonic copynumber variants including different deletions involving multiple GLDC exons, and an extensive number of missense mutations, mostly private (Applegarth & Toone, 2001;Conter et al, 2006;Coughlin et al, 2017;Kanno et al, 2007;Kure, 2011;Kure et al, 2004;Kure et al, 2006;Pardal-Fernandez et al, 2009;Suzuki et al, 2010;Swanson et al, 2015). Evidence for an important role of genotype as a predictive factor of outcome has been reported in NKH patients (Swanson et al, 2015).…”

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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The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT

Abstract: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.

Cited by 70 publications

References 36 publications

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

Ventilator respiratory graphic diagnosis of hiccupping in non-ketotic hyperglycinaemia

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

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