Background: Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage.
Methods: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I.
Results: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function.
Conclusions: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I.
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http://dx.doi.org/10.1016/j.braindev.2015.05.013 | DOI Listing |
Eur J Pediatr
December 2024
Department of Pediatric Metabolism and Nutrition, Medical Faculty, Ege University, Izmir, 35040, Turkey.
Unlabelled: Glutaric aciduria type 1 (GA1) is a rare metabolic disorder characterized by a deficiency in the enzyme glutaryl-CoA dehydrogenase. This study aims to present the clinical, biochemical, genetic, and neuroimaging findings of GA1 patients, emphasizing the importance of early detection and the potential benefits of incorporating GA1 into NBS programs. The demographic, clinical, and laboratory findings of GA1 patients were reviewed retrospectively.
View Article and Find Full Text PDFNeurochem Int
December 2024
PPG Ciências Biológicas: Bioquímica, Departamento de Bioquímica, ICBS, UFRGS, Porto Alegre, Brazil; Departamento de Medicina Interna, Faculdade de Medicina, UFRGS, Porto Alegre, Brazil; Serviço de Genética Médica, HCPA, Porto Alegre, Brazil. Electronic address:
Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (Gcdh), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated.
View Article and Find Full Text PDFGlutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder, in which deficiency of glutaryl-CoA dehydrogenase leads to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3-HG). Some low excretors may exhibit only slight elevation of urinary 3-HG, with normal urinary GA, yet are at significant risk of severe clinical disease. Accurate quantitation of urinary 3-HG is crucial in diagnostic workup for GA1, but in this context, current gas chromatography-mass spectrometry (GC-MS) methods have inherent analytical challenges.
View Article and Find Full Text PDFChembiochem
December 2024
Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, David De Wied building, Universiteitsweg 99, 3584 CG, Utrecht, NL.
Crotonyl-CoA (cr-CoA) is a metabolite derived directly from the catabolism of lysine (Lys) and tryptophan (Trp) or from the β-oxidation of fatty acids. In glioblastoma stem cells (GSCs), histone H4 crotonylation levels are significantly elevated, which appears to positively correlate with tumor growth. This increase in crotonyl-CoA production is attributed to the overexpression of specific Lys transporters on the cell membrane, leading to higher free lysine levels.
View Article and Find Full Text PDFJ Med Chem
October 2024
University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied.
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