glutaryl-CoA Dehydrogenase Research Articles

Genetic Screening of Selected Disease-Causing Mutations in Glutaryl-CoA Dehydrogenase Gene among Indian Patients with Glutaric Aciduria Type I.

Glutaric aciduria type I (GA-I) is an organic aciduria caused by glutaryl-CoA dehydrogenase (GCDH) deficiency. There are limited studies on GA-I from India. A total of 48 Indian GA-I patients were screened for selected disease-causing mutations such as R402W, A421V, A293T, R227P, and V400M using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Among these patients, 9 (18.8%) had R402W mutation, and none had A421V, A293T, R227P, or V400M mutation. One low excretor mutation (P286S) and several novel mutations (I152M, Q144P, and E414X) were also found in this study. We conclude that among selected mutations, R402W is the most common mutation found among Indian GA-I patients.

Disease-causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture.

The neurometabolic disorder glutaric aciduria type 1 (GA1) is caused by mutations in the GCDH gene encoding the mitochondrial matrix protein glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes. Twenty percent of all pathogenic mutations affect single amino acid residues on the surface of GCDH resulting in a severe clinical phenotype. We report here on heterologous expression studies of 18 missense mutations identified in GA1 patients affecting surface amino acids. Western blot and pulse chase experiments revealed that the stability of half of the GCDH mutants was significantly reduced. In silico analyses showed that none of the mutations impaired the 3D structure of GCDH. Immunofluorescence co-localisation studies in HeLa cells demonstrated that all GCDH mutants were correctly translocated into mitochondria. Surprisingly, the expression of p.Arg88Cys GCDH as well as further substitutions by alanine, lysine, or methionine but not histidine or leucine resulted in the disruption of mitochondrial architecture forming longitudinal structures composed of stacks of cristae and partial loss of the outer mitochondrial membrane. The expression of mitochondrial fusion or fission proteins was not affected in these cells. Bioluminescence resonance energy transfer analyses revealed that all GCDH mutants exhibit an increased binding affinity to electron transfer flavoprotein beta, whereas only p.Tyr155His GCDH showed a reduced interaction with dihydrolipoamide succinyl transferase. Our data underscore the impact of GCDH protein interactions mediated by amino acid residues on the surface of GCDH required for proper enzymatic activity.

Glutaric AciduriaType 1: Clinical and Molecular Study in Iranian Patients, 3 Novel Mutations.

Glutaricaciduria type 1 (GA1), is a rare, treatable neuro metabolic disease, due to glutaryl- CoA dehydrogenase (GCDH) gene mutation.In regions without neonatal blood screening (NBS), patients are diagnosed in symptomatic period. This study was carried out to assess patients with GA1 for clinical, biochemical, neuroimaging findings and GCDH gene mutations analysis. In this cross-sectional study, clinical manifestation, neuroimaging and metabolic findings of eleven Iranian GA1 patients of MofidChildren's Hospital, Tehran, Iranbetween 2001 and 2011,were evaluated.Mutational analysis of the GCDH gene was performed on genomic DNA. Genomic DNA was extracted from peripheral lymphocytes using QIAamp DNA Micro Kit (Qiagen). All 11 exons and flanking intronic regions of the GCDH gene were amplified by polymerase chain reaction (PCR). All patients were diagnosed before 32 months old. Clinical presentations of GA1 include acute encephalopathic crisis and/or developmental delay and macrocephaly. Seven GCDH gene mutations were detected in our patients. The most frequent GCDH mutations occurred in exon7 then exon8, 10 and11. G244 C in exon7, R294 Q in exon8 and N373 S in exon 10 were three novel mutations. There was no correlation between of genotype and phenotype in our patients. Physician must remember GA1 in differential diagnosis of acute encephalopathic crisis, macrocephaly, developmental delay, movement disorders such as dystonia and dyskinesia. Early detection, proper treatment and selective screening of patients' siblings can prevent neurologic disabilities.

Glutaric Acidemia Type 1: A Case of Infantile Stroke.

Glutaric acidemia Type 1 (GA-1) is an autosomal recessively inherited metabolic disorder which is associated with GCDH gene mutations which alters the glutaryl-CoA dehydrogenase, an enzyme playing role in the catabolic pathways of the amino acids lysine, hydroxylysine, and tryptophan. Clinical findings are often encephalopathic crises, dystonia, and extrapyramidal symptoms. A 9-month-old male infant referred to our department with focal tonic-clonic seizures during rotavirus infection and acute infarcts in MRI. Clinical manifestation, MRI findings, and metabolic investigations directed thoughts towards GA-I. Molecular genetic testing revealed a homozygous c.572T>C (p.M191T) mutation in GCDH gene which confirmed the diagnosis. Application of protein restricted diet, carnitine and riboflavin supplementations prevented the progression of Magnetic Resonance Imaging (MRI) and clinical pathologic findings during the 1 year of follow-up period. This case is of great importance since it shows possibility of infantile stroke in GA-1, significance of early diagnosis and phenotypic variability of disease.

Glutaric Aciduria Type 1 and Acute Renal Failure: Case Report and Suggested Pathomechanisms.

Glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. During catabolic crises, GA1 patients are prone to the development of striatal necrosis and a subsequent irreversible movement disorder during a time window of vulnerability in early infancy. Thus, GA1 had been considered a pure "cerebral organic aciduria" in the past. Single case reports have indicated the occurrence of acute renal dysfunction in children affected by GA1. In addition, growing evidence arises that GA1 patients may develop chronic renal failure during adulthood independent of the previous occurrence of encephalopathic crises. The underlying mechanisms are yet unknown. Here we report on a 3-year-old GA1 patient who died following the development of acute renal failure most likely due to haemolytic uraemic syndrome associated with a pneumococcal infection. We hypothesise that known GA1 pathomechanisms, namely the endothelial dysfunction mediated by 3OHGA, as well as the transporter mechanisms for the urinary excretion of GA and 3OHGA, are involved in the development of glomerular and tubular dysfunction, respectively, and may contribute to a pre-disposition of GA1 patients to renal disease. We recommend careful differential monitoring of glomerular and tubular renal function in GA1 patients.

Early Diagnosed and Treated Glutaric Acidemia Type 1 Female Presenting with Subependymal Nodules in Adulthood.

Glutaric acidemia type 1 (GA-1, OMIM no. 231670) is an autosomal recessive disorder caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH). The subsequent accumulation of the amino acids lysine, hydroxylysine, and tryptophan and their breakdown intermediates can be neurotoxic and particularly cause injury to the basal ganglia.Roughly 1 of 100,000 infants is affected with GA-1, and a common feature at birth is macrocephaly. Stress, such as in febrile illnesses, can precipitate encephalopathic crises in children generally less than 2years with variable recovery. Many infants develop dystonia with complex movement disorders and subtle cognitive and fine motor deficits. Common neuroradiologic findings include hypoplasia of temporal and frontal lobes, striatal lesions, white matter changes, and subdural effusions.There are three previous reports of subependymal nodules found on neuroimaging in GA-1 patients who were diagnosed as adults and untreated for GA-1. We present a unique case of an adult female who was diagnosed at age 2months and managed prior to any metabolic decompensation. Her initial diagnosis was made based on biochemical and enzymatic analysis, and then later confirmed with genetic sequencing. She started experiencing frequent headaches at age 12years. Neuroimaging in adulthood revealed common features seen in GA-1 in addition to the finding of subependymal nodules.This case may provide some insight into the natural progression of the disease despite early treatment. Though subependymal nodules are typically seen in tuberous sclerosis, the significance of these lesions in GA-1 is not well understood. Disease courses of more early diagnosed and treated patients with GA-1 need to be documented.

A novel variant of the GCDH gene causes glutaric aciduria type 1 in a Sudanese family: a case report

Background: Glutaric aciduria type 1 (GA1) is a rare autosomal recessive neurometabolic disorder caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH). If left untreated, it leads to accumulation of neurotoxic metabolites leading to poor neurological outcomes characterized by encephalopathic crises, subdural effusions and extrapyramidal features. Case presentation: We hereby report a consanguineous Sudanese family in which the father and two children were affected whilst the mother was an asymptomatic carrier. All had a novel guanine insertion in position c.1173_1174 (c.1173dupG), resulting in a frameshift and a stop codon downstream (p.Asn392Glufs4X). Conclusion: To our knowledge, this GCDH variant has not been previously reported. Genetic testing should be made widely available in communities where consanguinity is prevalent. This will allow detection of new pathogenic gene variants.

Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases.

The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late-onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis.

Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision.

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.

Immunolocalization of glutaryl-CoA dehydrogenase (GCDH) in adult and embryonic rat brain and peripheral tissues

Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme that is involved in the degradation of tryptophan, lysine and hydroxylysine. Deficient enzyme activity leads to glutaric aciduria type-I (GA-I). This neurometabolic disease usually manifests with acute encephalopathic crises and striatal neuronal death in early childhood leading to an irreversible dystonic-dyskinetic movement disorder. Fronto-temporal atrophy and white matter changes are already present in the pre-symptomatic period. No detailed information on GCDH expression during embryonic development and in adulthood was available so far.Using immunofluorescence microscopy and cell-type-specific markers to localize GCDH in different tissues, we describe the differential cellular localization of GCDH in adult rat brain and peripheral organs as well as its spatiotemporal expression pattern.During embryonic development GCDH was predominantly expressed in neurons of the central and peripheral nervous system. Significant expression levels were found in epithelial cells (skin, intestinal and nasal mucosa) of rat embryos at different developmental stages. Besides the expected strong expression in liver, GCDH was found to be significantly expressed in neurons of different brain regions, renal proximal tubules, intestinal mucosa and peripheral nerves of adult rats.GCDH was found widely expressed in embryonic and adult rat tissues. In rat embryos GCDH is predominantly expressed in brain implying an important role for brain development. Interestingly, GCDH was found to be significantly expressed in different other organs (e.g. kidney, gut) in adult rats probably explaining the evolving phenotype in GA-I patients.

Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excretors.

Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.

Molecular characterization of lysR-lysXE, gcdR-gcdHG and amaR-amaAB operons for lysine export and catabolism: a comprehensive lysine catabolic network in Pseudomonas aeruginosa PAO1.

Among multiple interconnected pathways for l-Lysine catabolism in pseudomonads, it has been reported that Pseudomonas aeruginosa PAO1 employs the decarboxylase and the transaminase pathways. However, up until now, knowledge of several genes involved in operation and regulation of these pathways was still missing. Transcriptome analyses coupled with promoter activity measurements and growth phenotype analyses led us to identify new members in l-Lys and d-Lys catabolism and regulation, including gcdR-gcdHG for glutarate utilization, dpkA, amaR-amaAB and PA2035 for d-Lys catabolism, lysR-lysXE for putative l-Lys efflux and lysP for putative l-Lys uptake. The gcdHG operon encodes an acyl-CoA transferase (gcdG) and glutaryl-CoA dehydrogenase (gcdH) and is under the control of the transcriptional activator GcdR. Growth on l-Lys was enhanced in the mutants of lysX and lysE, supporting the operation of l-Lys efflux. The transcriptional activator LysR is responsible for l-Lys specific induction of lysXE and the PA4181-82 operon of unknown function. The putative operator sites of GcdR and LysR were deduced from serial deletions and comparative genomic sequence analyses, and the formation of nucleoprotein complexes was demonstrated with purified His-tagged GcdR and LysR. The amaAB operon encodes two enzymes to convert pipecolate to 2-aminoadipate. Induction of the amaAB operon by l-Lys, d-Lys and pipecolate requires a functional AmaR, supporting convergence of Lys catabolic pathways to pipecolate. Growth on pipecolate was retarded in the gcdG and gcdH mutants, suggesting the importance of glutarate in pipecolate and 2-aminoadipate utilization. Furthermore, this study indicated links in the control of interconnected networks of lysine and arginine catabolism in P. aeruginosa.

Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1.

Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome.

A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I

BackgroundGlutaric aciduria type I (GA-I) is an inherited metabolic disease due to deficiency of glutaryl-CoA dehydrogenase (GCDH). Cognitive functions are generally thought to be spared, but have not yet been studied in detail.MethodsThirty patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model.ResultsBADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients did not differ from controls, except showing significantly better results in Tracking and a trend for slower reactions in visual search. Data across all age groups of patients and controls fitted well to a model of negative exponential development.ConclusionsDystonic patients predominantly showed motor speed impairment, whereas performance improved with higher cognitive load. Patients without motor symptoms did not differ from controls. Developmental functions of cognitive performances were similar in patients and controls. Performance in tests with higher cognitive demand might be preserved in GA-I, even in patients with striatal degeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0379-6) contains supplementary material, which is available to authorized users.

Oxidative Stress, Disrupted Energy Metabolism, and Altered Signaling Pathways in Glutaryl-CoA Dehydrogenase Knockout Mice: Potential Implications of Quinolinic Acid Toxicity in the Neuropathology of Glutaric Acidemia Type I.

We investigated the effects of an acute intrastriatal QUIN administration on cellular redox and bioenergetics homeostasis, as well as on important signaling pathways in the striatum of wild-type (Gcdh +/+ , WT) and knockout mice for glutaryl-CoA dehydrogenase (Gcdh -/- ) fed a high lysine (Lys, 4.7%) chow. QUIN increased lactate release in both Gcdh +/+ and Gcdh -/- mice and reduced the activities of complex IV and creatine kinase only in the striatum of Gcdh -/- mice. QUIN also induced lipid and protein oxidative damage and increased the generation of reactive nitrogen species, as well as the activities of the antioxidant enzymes glutathione peroxidase, superoxide dismutase 2, and glutathione-S-transferase in WT and Gcdh -/- animals. Furthermore, QUIN induced DCFH oxidation (reactive oxygen species production) and reduced GSH concentrations (antioxidant defenses) in Gcdh -/- . An early increase of Akt and phospho-Erk 1/2 in the cytosol and Nrf2 in the nucleus was also observed, as well as a decrease of cytosolic Keap1caused by QUIN, indicating activation of the Nrf2 pathway mediated by Akt and phospho-Erk 1/2, possibly as a compensatory protective mechanism against the ongoing QUIN-induced toxicity. Finally, QUIN increased NF-κB and diminished IκBα expression, evidencing a pro-inflammatory response. Our data show a disruption of energy and redox homeostasis associated to inflammation induced by QUIN in the striatum of Gcdh -/- mice submitted to a high Lys diet. Therefore, it is presumed that QUIN may possibly contribute to the pathophysiology of striatal degeneration in children with glutaric aciduria type I during inflammatory processes triggered by infections or vaccinations.

Glutaric aciduria type 1 as a cause of dystonic cerebral palsy.

Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). Here, we report a 14-month-old Saudi boy with GA1 who presented with severe dystonia and was mis-diagnosed as cerebral palsy (CP). He presented to our institute with encephalopathy following an episode of gastroenteritis. His physical examination showed dystonia and spastic quadriplegia. His investigations revealed elevated both urinary 3-hydroxy glutaric acid, and serum glutarylcarnitine. The DNA analysis confirmed homozygosity for a mutation in the GCDH-coding gene (c.482G>A;p.R161Q). This case alerts pediatricians to consider GA1 as a differential diagnosis of children presenting with dystonic CP.

Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: A potential role for glutamatergic-induced excitotoxicity in GA I neuropathology

Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh+/+) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh−/−) mice fed a baseline chow. Oxidative stress parameters were also measured after acute lysine overload. Finally, mRNA expression of NMDA subunits and GLT1 transporter was determined in cerebral cortex and striatum of these animals fed a baseline or high lysine (4.7%) chow. No significant alterations of bioenergetics or redox status were observed in these mice. In contrast, mRNA expression of the NR2B glutamate receptor subunit and of the GLT1 glutamate transporter was higher in cerebral cortex of Gcdh−/− mice. Furthermore, NR2B expression was markedly elevated in striatum of Gcdh−/− animals receiving chronic Lys overload. These data indicate higher susceptibility of Gcdh−/− mice to excitotoxic damage, implying that this pathomechanism may contribute to the cortical and striatum alterations observed in GA I patients.

AB120. Correlation of genotype with biochemical profile in patients with Glutaric Acidemia type I: a study from India

Background and objective Mutations in glutaryl-CoA dehydrogenase gene causes Glutaric Acidemia type I (GA-I), an autosomal recessive, metabolic disorder which leads to accumulation of Glutaric Acid, 3-Hydroxyglutaric acid, Glutaconic Acid and Glutarylcarnitine (C5DC). There are no studies that correlate the genotype with biochemical profile in patients with GA-I from India. The objective of this study was to screen Indian patients with GA-I, for common mutations such as R402W, A421V, A293T, R227P and V400M and to correlate the genotype profile of the patients with C5DC levels.

Spectrum of mutations in Glutaryl-CoA dehydrogenase gene in glutaric aciduria type I – Study from South India

BackgroundGlutaric 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. MethodsThe 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. ResultsWe 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. ConclusionsThe 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.