Pediatric Neurotransmitter Disorders

2017 ◽  
Author(s):  
Phillip L. Pearl ◽  
William P. Welch
Keyword(s):  
Elevated Serum ◽  
Serum Levels ◽  
Acid Decarboxylase ◽  
Succinic Semialdehyde ◽  
Monoamine Synthesis ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Amino Acid Decarboxylase ◽  
Semialdehyde Dehydrogenase ◽  
Glycine Encephalopathy ◽  
Heterozygous Form

The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by inherited abnormalities of neurotransmitter synthesis, metabolism, and transport. Disorders involving monoamine synthesis include guanosine triphosphate cyclohydrolase deficiency (Segawa disease or classical Dopa-responsive dystonia as the heterozygous form), aromatic amino acid decarboxylase deficiency, tyrosine hydrolase deficiency, sepiapterin reductase deficiency, and disorders of tetrahydrobiopterin synthesis. These disorders can be classified according to whether they feature elevated serum levels of phenylalanine. Disorders of γ-amino butyric acid (GABA) metabolism include succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency. Glycine encephalopathy is typically manifested by refractory neonatal seizures due to a defect in the glycine degradative pathway. Pyridoxine-responsive seizures have now been associated with deficiency of α-aminoadipic semialdehyde dehydrogenase as well as a variants requiring therapy with pyridoxal-5-phosphate and folinic acid.

scholarly journals Outcome of Patients With Inherited Neurotransmitter Disorders

2018 ◽  
Vol 45 (5) ◽  
pp. 571-576 ◽  
Author(s):  
Dawn Cordeiro ◽  
Garrett Bullivant ◽  
Ronald D. Cohn ◽  
Julian Raiman ◽  
Saadet Mercimek-Andrews
Keyword(s):  
Tyrosine Hydroxylase ◽  
Neurodevelopmental Outcome ◽  
Specific Treatment ◽  
Acid Decarboxylase ◽  
Succinic Semialdehyde ◽  
Dihydropteridine Reductase ◽  
Loading Test ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Amino Acid Decarboxylase ◽  
Semialdehyde Dehydrogenase

AbstractWe report the outcome of 12 patients with inherited neurotransmitter disorders of monoamine, tetrahydrobiopterin and γ amino butyric acid metabolisms from a single Inherited Neurotransmitter Disorder Clinic including tyrosine hydroxylase (n=2), aromatic l-amino acid decarboxylase (n=1), 6-pyruvoyltetrahydropterin synthase, dihydropteridine reductase and succinic semialdehyde dehydrogenase deficiencies. Six patients (with 6-pyruvoyltetrahydropterin synthase, dihydropteridine reductase and tyrosine hydroxylase deficiencies) had normal neurodevelopmental outcome on treatment. Tetrahydrobiopterin loading test in newborns with positive newborn screening for phenylketonuria will identify patients with 6-pyruvoyltetrahydropterin synthase and dihydropteridine reductase deficiencies resulting in abnormal neurotransmitter synthesis in the central nervous system in the neonatal period to initiate disease-specific treatment to improve neurodevelopmental outcome.

An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia

2005 ◽  
Vol 20 (1) ◽  
pp. 45-49 ◽  
Author(s):  
Boyu Zhang ◽  
Yanbo Yuan ◽  
Yanbin Jia ◽  
Xin Yu ◽  
Qi Xu ◽  
...  
Keyword(s):  
Paranoid Schizophrenia ◽  
Northern China ◽  
Acid Decarboxylase ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Gabaergic Neurotransmission ◽  
Semialdehyde Dehydrogenase ◽  
Pcr Product ◽  
Length Polymorphisms ◽  
Polymerase Chain

AbstractDysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the possible involvement of these genes in the development of paranoid schizophrenia, we genotyped 80 paranoid schizophrenics from northern China and 108 matched controls by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) methods or directly sequencing of PCR product. Seven SNPs were found to be polymorphic in the population investigated. No significant differences in the genotype distributions or allele frequencies between patients and controls were found. Therefore, we conclude the polymorphisms studied in the five genes do not play major roles in pathogenesis of paranoid schizophrenia in the population investigated.

scholarly journals Characterization of Genes Involved in γ-Aminobutyric Acid Metabolic Pathways Response to Metabolites Accumulation in Embryos during Barley Germination

2021 ◽  
Vol 25 (04) ◽  
pp. 786-794
Author(s):  
Mengyuan Jin
Keyword(s):  
Gene Expression ◽  
Metabolic Pathways ◽  
Aminobutyric Acid ◽  
Acid Decarboxylase ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Key Enzyme ◽  
Gaba Content ◽  
Gaba Accumulation

To reveal the key enzyme genes involved in γ-aminobutyric acid (GABA) metabolic pathways response to elevated metabolite storage in embryos during barley germination, this study investigated the GABA content, cloned GABA metabolic pathway genes and analyzed their expression levels, respectively. In barley embryos, GABA content continued to rise during the soaking process and then decreased after the germination. Three genes including glutamic acid decarboxylase (GAD), GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) involved in the GABA pathway were cloned and characterized from the barley embryos, respectively. Before the germination, the expression of GAD gene was up-regulated, while GABA-T gene expression was down-regulated. After the germination, GAD gene expression was lowered, but GABA-T gene expression was rapidly increased. The SSADH gene expression remained stable after soaking of 4 h, and then down-regulated. There is evidence that the high GABA content in germinating barley seeds is parallel with the upregulation of the GAD gene, and down-regulation of GABA-T gene. These results indicate that the expression level of the genes involved in GABA pathway is a crucial factor in GABA accumulation during soaking and germination. This study is beneficial for the development of GABA-rich barley products by germination. © 2021 Friends Science Publishers

scholarly journals Succinic Semialdehyde Dehydrogenase Deficiency: Review of the Natural History Study

2021 ◽  
pp. 088307382098126
Author(s):  
Phillip L. Pearl ◽  
Melissa L. DiBacco ◽  
Christos Papadelis ◽  
Thomas Opladen ◽  
Ellen Hanson ◽  
...  
Keyword(s):  
Natural History ◽  
Psychiatric Symptoms ◽  
Epileptiform Activity ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Natural History Study ◽  
Semialdehyde Dehydrogenase ◽  
Verbal Score

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity. Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort. Results: At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months–40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls. Conclusions: The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.

scholarly journals Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue

2021 ◽  
pp. 088307382098774
Author(s):  
Dana C. Walters ◽  
Regan Lawrence ◽  
Trevor Kirby ◽  
Jared T. Ahrendsen ◽  
Matthew P. Anderson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dehydrogenase Deficiency ◽  
Metabotropic Glutamate Receptor ◽  
Total Phospholipid ◽  
Null Mouse ◽  
Succinic Semialdehyde ◽  
Long Term Effects ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Succinic Semialdehyde Dehydrogenase Deficiency

This study has extended previous metabolic measures in postmortem tissues (frontal and parietal lobes, pons, cerebellum, hippocampus, and cerebral cortex) obtained from a 37-year-old male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) who expired from SUDEP (sudden unexplained death in epilepsy). Histopathologic characterization of fixed cortex and hippocampus revealed mild to moderate astrogliosis, especially in white matter. Analysis of total phospholipid mass in all sections of the patient revealed a 61% increase in cortex and 51% decrease in hippocampus as compared to (n = 2-4) approximately age-matched controls. Examination of mass and molar composition of major phospholipid classes showed decreases in phospholipids enriched in myelin, such as phosphatidylserine, sphingomyelin, and ethanolamine plasmalogen. Evaluation of gene expression (RT2 Profiler PCR Arrays, GABA, glutamate; Qiagen) revealed dysregulation in 14/15 GABAA receptor subunits in cerebellum, parietal, and frontal lobes with the most significant downregulation in ∊, θ, ρ1, and ρ2 subunits (7.7-9.9-fold). GABAB receptor subunits were largely unaffected, as were ionotropic glutamate receptors. The metabotropic glutamate receptor 6 was consistently downregulated (maximum 5.9-fold) as was the neurotransmitter transporter (GABA), member 13 (maximum 7.3-fold). For other genes, consistent dysregulation was seen for interleukin 1β (maximum downregulation 9.9-fold) and synuclein α (maximal upregulation 6.5-fold). Our data provide unique insight into SSADHD brain function, confirming astrogliosis and lipid abnormalities previously observed in the null mouse model while highlighting long-term effects on GABAergic/glutamatergic gene expression in this disorder.

scholarly journals Magnetic Resonance Imaging (MRI) and Spectroscopy in Succinic Semialdehyde Dehydrogenase Deficiency

2021 ◽  
pp. 088307382199129
Author(s):  
Onur Afacan ◽  
Edward Yang ◽  
Alexander P. Lin ◽  
Eduardo Coello ◽  
Melissa L. DiBacco ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Mr Spectroscopy ◽  
Succinic Semialdehyde ◽  
Resonance Imaging ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Magnetic Resonance Imaging Mri ◽  
Brain Gaba ◽  
Ssadh Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.

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