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At least 109 records · Page 6Linked to original sources
PubMed1992

Carrier detection in glutaric aciduria type I using interleukin-2-dependent cultured lymphocytes.

Cultured interleukin 2 (IL-2)-dependent leukocytes from 13 patients with glutaric aciduria type I, 12 obligate carriers, 105 family members and 31 normal controls were assayed for glutaryl-CoA dehydrogenase activity. Of the 13 affected patients, 10 (all Ojibway Indian) had residual enzyme activity (2-13% of control) and 3 patients (all non-Indian) had undetectable enzyme activity. There was partial overlap between the distribution of enzyme activity in obligate heterozygotes and in normal controls (mean values +/- SD: 6.29 +/- 0.94 and 10.75 +/- 2.58 nmol/h per mg protein respectively). Using an arbitrary cutoff level of < 7 nmol/h per mg protein as presumptive evidence of carrier status, the observed frequency of carriers did not differ significantly from that expected from their a priori risk of carrier status. Thirteen per cent of the family members had inconclusive status (activity between 7 and 8.5 nmol/h per mg protein). The method appears suitable for carrier detection, although definitive carrier assignment awaits identification of the mutation(s) responsible for glutaric aciduria type I.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Glutaric aciduria: improved MR appearance after aggressive therapy.

Advances in understanding the metabolic abnormalities which cause glutaric aciduria allow biochemical diagnosis on the basis of deficient enzyme and the potential for therapy. Brain abnormalities associated with this inborn error of metabolism have been demonstrated with CT and MR. The findings typically described are atrophy of the fronto-temporal regions with large insular cisterns and diffuse white matter hypodensities. We present a patient with glutaric aciduria, confirmed by enzymatic assay, who had these findings on CT and MR examination. Repeat imaging demonstrated significant improvement after dietary therapy and aggressive prevention of catabolism during febrile illness.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Biochemical studies in a patient with defects in the metabolism of acyl-CoA and sarcosine: another possible case of glutaric aciduria type II.

The clinical and biochemical abnormalities in a neonate, who died in coma accompanied by severe hypoglycaemia at the age of 3 days, are described. The study of the urinary metabolic profiles of organic acids and amino acids revealed that the excretion rates of glutaric acid, isovaleric acid, isovalerylglycine, 3-hydroxyisovaleric acid and isobutyric acid were very high. Increased excretion rates were also found for 2-methylbutyric acid, adipic acid, caproylglycine, 5-hydroxycaproic acid, caproic acid and butyric acid. The amino acid, sarcosine, was excreted in enhanced amounts and the patient had lactic aciduria, whereas the excretion of 3-hydroxybutyric acid was only moderately increased. This abnormal excretion pattern is consistent with a defect in the metabolism of acyl-CoAs and sarcosine. Normal activity of glutaryl-CoA dehydrogenase was found, excluding glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

Acyl Coenzyme A↗
PubMed2000

Inhibition of energy production in vitro by glutaric acid in cerebral cortex of young rats.

The present study investigated the effects of glutaric acid (GA), which predominantly accumulates in glutaric acidemia type I (GA-I), on some in vitro parameters of energy metabolism in cerebral cortex of rats. We first evaluated CO2 production from [U-14C] acetate, as well as ATP levels in brain of young Wistar rats. The effect of the acid on the activities of the respiratory chain complexes were also investigated. GA was tested at final concentrations ranging from 0.5 to 5.0 mM. GA significantly reduced brain CO2 production by 50% at the concentrations of 0.5 to 3.0 mM, ATP levels by 25% at the concentration of 3.0 mM, succinate:cytochrome C oxireductase (complex II plus CoQ plus complex III) by 25% at 5 mM concentration, and NADH:cytochrome C oxireductase (complex I plus CoQ plus complex Ill) by 25% at 2.5 and 5 mM concentrations. The results strongly indicate that GA impairs brain energy production. If these effects also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by GA-I.

Acetates↗
PubMed1999

Glutaric aciduria type I: ultrasonographic demonstration of early signs.

BACKGROUND: Glutaric aciduria type I (GA-I) is a rare inherited metabolic disease with increased excretion of glutaric acid and its metabolites. Diagnosis is often delayed until the onset of irreversible neurological deficits. MATERIAL AND METHODS: We reviewed the clinical and imaging (US, CT and MRI) findings in six patients with proven GA-I and with emphasis on the early US findings. Coronal and sagittal US images of the brain were obtained through the anterior fontanelle in all patients. CT was obtained in three patients and MRI was obtained in two. RESULTS: Macrocephaly was found in all patients, being present in three children at birth or developing rapidly within the first weeks of life. US showed, in all patients, bilateral symmetrical cyst-like dilatation of the sylvian fissures. Progressive fronto-temporal atrophy developed within the first months. CT and MRI demonstrated fronto-temporal atrophy with lack of opercularisation in all cases and basal ganglia or periventricular hypodensities in three patients. CONCLUSIONS: In patients with macrocephaly at birth or rapidly developing within the first weeks of life, US should be performed as the primary imaging modality. Cyst-like bilateral widening of the sylvian fissures is the first sign of GA-I, followed by progressive fronto-temporal and ventricular enlargement. These patients should be screened for GA-I in order to initiate treatment in the asymptomatic stage.

Abnormalities, Multiple↗
PubMed2005

Glutaric acid administration impairs energy metabolism in midbrain and skeletal muscle of young rats.

A genetic mice model of glutaric acidemia type I (GAI) has recently been developed, however affected animals do not develop the striatal damage characteristic of patients with this disorder. Therefore, the initial aim of the present work was to induce high glutaric acid (GA) concentrations in rat brain similar to those found in GAI patients through subcutaneous injection of GA. High brain GA concentrations (up to 0.60 micromol/g congruent with 0.60mM) were achieved by a single subcutaneous injection of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 7-22 days of life. GA brain levels were about 10-fold lower than in plasma and 5-fold lower than in skeletal and cardiac muscles, indicating that the permeability of the blood brain barrier to GA is low. We also aimed to use this model to investigate neurochemical parameters in the animals. Thus, we evaluated the effect of this model on energy metabolism parameters in midbrain, in which the striatum is localized, as well as in peripheral tissues (skeletal and cardiac muscles) of 22-day-old rats. Control rats were treated with saline in the same volumes. We verified that CO2 production from glucose was not altered in midbrain of rats treated with GA, indicating a normal functioning of the tricarboxylic acid cycle. Creatine kinase activity was also not changed in midbrain, skeletal and cardiac muscles. In contrast, complex I-III activity of the respiratory chain was inhibited in midbrain (25%), while complexes I-III (25%) and II-III (15%) activities were reduced in skeletal muscle, with no alterations found in cardiac muscle. These data indicate that GA administration moderately impairs cellular energy metabolism in midbrain and skeletal muscle of young rats.

Animals↗
PubMed2006

Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API.

PURPOSE: The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization. METHODS: A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API. RESULTS: A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels. CONCLUSIONS: APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.

Animals↗
PubMed1978

Studies on glutaryl-CoA dehydrogenase in leucocytes, fibroblasts and amniotic fluid cells. The normal enzyme and the mutant form in patients with glutaric aciduria.

Three patients with glutaric aciduria have been shown to possess a partial but severe defect of the enzyme glutaryl-CoA dehydrogenase in isolated leucocytes and cultured skin fibroblasts. They could readily be distinguished from heterozygotes by measuring the activity of this enzyme, as shown in a study of the two families involved. The activity of glutaryl-CoA dehydrogenase in normal cultured amniotic fluid cells was comparable to the activity in normal cultured skin fibroblasts indicating the possibility of prenatal diagnosis. Without flavin adenine dinucleotide added to the assay mixture, the activity of glutaryl-CoA dehydrogenase in fibroblasts from normal individuals was very much reduced and similar to the activity in the patients, but after addition of flavin adenine dinucleotide to saturation the activity increased 20-fold in normal subjects while only a very slight increase could be demonstrated in the patients. The Michaelis constant for the substrate glutaryl-CoA was similar for both normal and patient cell lines. The optimum assay conditions for the enzyme in cultured fibroblasts from normal individuals have been established. In contrast to our patients, we found no activity in a fibroblast cell line from a patient with glutaric aciduria diagnosed elsewhere.

Amniotic Fluid↗
PubMed1995

Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy.

The clinical phenotype of multiple acyl-CoA dehydrogenase deficiency in infancy is characterized by recurrent episodes of hypoketotic hypoglycemia and lipid storage myopathy. Brain damage has been described only as a consequence of severe and protracted hypoglycemia. We describe a child who experienced normal physical and psychomotor development until the age of 3 years, who then developed progressive intention tremors, dysarthria, ataxia, and spastic tetraparesis. Episodes of acute metabolic distress were never observed. Magnetic resonance imaging disclosed abnormal signals within the white matter of the brain and cerebellum, suggesting leukodystrophy. Gas chromatography/mass spectrometry analysis revealed abnormally high levels of glutaric acid, dicarboxylic acids, and glycine derivatives in urine. Riboflavin therapy was initiated at 4 years of age, when the patient had already lost control of trunk and head posture. Consistent improvement rapidly occurred after riboflavin supplementation. Glutaric aciduria type II may cause brain damage, in spite of the absence of acute metabolic distress, and should be considered in the differential diagnosis of leukodystrophies.

Child, Preschool↗
PubMed2006

Zero-order release of aspirin, theophylline and atenolol in water from novel methylcellulose glutarate matrix tablets.

A novel hydrocolloidal polymer, methylcellulose glutarate (MC-GA), was prepared by esterifying methylcellulose with glutaric anhydride. The formation of ester was confirmed by FTIR and NMR spectroscopy, DSC and elemental analysis. The physicochemical properties such as, rate of swelling in water, viscosity and hygroscopicity of MC-GA were determined and compared with those of methycellulose A (MC). Aspirin, theophylline and atenolol tablets were compacted on a Carver press using the wet granulation method. Each tablet contained: 200 mg active, 80 mg anhydrous lactose, 8 mg povidone, 4 mg magnesium stearate, 4 mg talc, 50mg MC or MC-GA (drug-to-polymer ratio, 4:1). Contrary to the first-order release profile of all the drugs from the MC matrix tablets, a zero-order release was obtained from the MC-GA matrix tablets in water.

Adrenergic beta-Antagonists↗
PubMed2006

GM1 ganglioside prevents seizures, Na+,K+-ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole.

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.

Animals↗
PubMed2004

Glutaric acid stimulates glutamate binding and astrocytic uptake and inhibits vesicular glutamate uptake in forebrain from young rats.

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by glutaryl-CoA dehydrogenase deficiency, which leads to accumulation in body fluids and in brain of predominantly glutaric acid (GA), and to a lesser extent of 3-hydroxyglutaric and glutaconic acids. Neurological presentation is common in patients with GA I. Although the mechanisms underlying brain damage in this disorder are not yet well established, there is growing evidence that excitotoxicity may play a central role in the neuropathogenesis of this disease. In the present study, preparations of synaptosomes, synaptic plasma membranes and synaptic vesicles, as well as cultured astrocytes from rat forebrain were exposed to various concentrations of GA for the determination of the basal and potassium-induced release of [(3)H]glutamate by synaptosomes, Na(+)-independent glutamate binding to synaptic membranes and vesicular glutamate uptake and Na(+)-dependent glutamate uptake into astrocytes, respectively. GA (1-100 nM) significantly stimulated [(3)H]glutamate binding to brain plasma membranes (40-70%) in the absence of extracellular Na(+) concentrations, reflecting glutamate binding to receptors. Furthermore, this stimulatory effect was totally abolished by the metabotropic glutamate ligands DHPG, DCG-IV and l-AP4, attenuated by the ionotropic non-NMDA glutamate receptor agonist AMPA and had no interference of the NMDA receptor antagonist MK-801. Moreover, [(3)H]glutamate uptake into synaptic vesicles was inhibited by approximately 50% by 10 and 100 nM GA and Na(+)-dependent [(3)H]glutamate uptake by astrocytes was significantly increased (up to 50%) in a dose-dependent manner (maximal stimulation at 100 microM GA). In contrast, synaptosomal glutamate release was not affected by the acid at concentrations as high as 1 mM. These results indicate that the inhibition of glutamate uptake into synaptic vesicles by low concentrations GA may result in elevated concentrations of the excitatory neurotransmitter in the cytosol and the stimulatory effect of this organic acid on glutamate binding may potentially cause excitotoxicity to neural cells. Finally, taken together these results and previous findings showing that GA markedly decreases synaptosomal glutamate uptake, it is possible that the stimulatory effect of GA on astrocyte glutamate uptake might indicate that astrocytes may protect neurons from excitotoxic damage caused by GA by increasing glutamate uptake and therefore reducing the concentration of this excitatory neurotransmitter in the synaptic cleft.

Animals↗
PubMed1979

Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue.

The autosomal recessive inherited disorder glutaryl-CoA dehydrogenase deficiency (glutaric aciduria) runs a progressive course with severe choreoathetosis and dystonia, eventually leading to total helplessness and early death. Theree patients were observed during therapeutic trials with a protein-low diet, riboflavin and GABA analogue. Diet and riboflavin had a slight-to-moderate effect on the clinical symptoms; the excretion of glutaric acid and 2-amino-adipic acid decreased considerably during treatment. Regression of neurologic symptoms was observed during treatment with GABA analogue. It is concluded that the patients should be treated as early as possible with protein-low diet, riboflavin, and GABA analogue.

2-Aminoadipic Acid↗
PubMed1980

Glutaric aciduria Type II.

Two infants have been studied with glutaric aciduria Type II. The clinical presentation was of an overwhelming illness very early in life; both infants died in the neonatal period. One had dysmorphic features. An acrid odor may be a clue to the diagnosis. Neonatal acidosis, hypoglycemia, and hyperammonemia are characteristic. Organic acid analysis revealed massive lactic aciduria and glutaric aciduria. A variety of other dicarboxylic acids and hydroxy acids and amino acids were found in elevated amounts in body fluids, along with elevated concentrations of butyric, isobutyric, 2-methylbutyric, and isovaleric acids. The pattern of metabolites accumulated is consistent with deficient activity of a number of acyl-CoA dehydrogenases.

Amino Acids↗
PubMed1998

Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in glutaric aciduria type 1: clinical and MRI correlations.

The clinical, PET (positron emission tomography) and MRI (magnetic resonance imaging) findings of brain studies in eight patients, previously diagnosed to have glutaric aciduria type 1, were retrospectively reviewed. The neurological findings typically consisted of variable degrees of dementia and extrapyramidal symptoms (dystonia, choreoathetosis and rigidity). Both MRI and PET showed involvement of the putamina in all the patients. The PET scan demonstrated lesions in the head of the caudate nuclei in all of the patients. Brain atrophy, and in particular the characteristically-enlarged Sylvian fissures, was better demonstrated by MRI. On the other hand, the cerebral cortex and thalamic structures were found to be normal by MRI in all patients, whereas PET scan showed decreased uptake in the cerebral cortex in seven, and in the thalami in three patients. Correlation between imaging and clinical findings was found to be good when both PET scan and MRI findings of the brain were taken into consideration. Therefore, the functional (PET) and structural (MRI) studies of the brain were complementary in the imaging evaluation of glutaric aciduria type 1.

Brain↗
PubMed2003

Glutaric aciduria I: creatine supplementation restores creatinephosphate levels in mixed cortex cells from rat incubated with 3-hydroxyglutarate.

The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still unclear. Some evidence exists for compromised energy generation in the brain of patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH glut) for 24h. In the present study we measured cellular contents of high energy phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a 24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut specifically led to a reduction of CP content in a dose-dependent manner, whereas concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP-concentration could be prevented by preincubation with the non-competitive NMDA-receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor associated ion channels may be opened due to a lack of energy inside the neurons caused by a reduction of CP. This is followed by membrane depolarization which could impair electrogenic creatine transport into the cell.

Adenine Nucleotides↗
PubMed2006

Magnetic resonance spectroscopic characteristics of glutaric aciduria type II.

Magnetic resonance spectroscopy (MRS) of a 12-year-old female patient with glutaric aciduria type II was compared with data obtained from four healthy age- and sex-matched volunteers. In the clinically active phase, conventional magnetic resonance imaging showed mild ventricular dilatation. Frontal lobe choline/creatine (Cho/Cr) ratio (1.98) was higher than the ratios reported for the comparison participants (1.64 [SD 0.21]). The N-acetylaspartate/creatine (NAA/Cr) ratio (1.95) was lower than normal limits (2.66 [SD 0.23]). After successful riboflavin treatment and dietary restriction for proteins, the NAA/Cr ratio was within the normal range (2.44) and Cho/Cr ratio was below the normal range (1.15), suggesting riboflavin-responsive multiple acyl-coA dehydrogenase deficiency. An elevated Cho/Cr ratio and decreased NAA/Cr ratio is consistent with a demyelinating process in the active phase of glutaric aciduria type II. MRS helps to monitor the progress of the disease and the efficacy of treatment by revealing changes in NAA/Cr and Cho/Cr ratios.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Nonpeptide renin inhibitors employing a novel 3-aza(or oxa)-2,4-dialkyl glutaric acid moiety as a P2/P3 amide bond replacement.

A new series of renin inhibitors has been developed. The inhibitors feature a novel replacement for the P2/P3 dipeptide moiety normally associated with renin inhibitors. The dipeptide replacement was a (2S,4S)-3-aza(or oxa)-2,4-dialkylglutaric acid amide. Extensive structure-activity relationship studies determined that optimum potency was achieved when inhibitors employed a benzyl and butyl group at the C(4) and C(2) carbon position, respectively. In addition, maximum in vitro potency was obtained when the N-terminus was functionalized by incorporating a 4-(1,3-dioxabutyl)piperidine amide. SAR data suggested that the 1,3-dioxabutyl group (methoxymethyl ether) interacted by hydrogen bonding to groups in the S4 domain of renin. This hypothesis was strengthened when a 4-butylpiperidine amide was substituted and inhibitor potency decreased dramatically. Inhibitors employing this novel dipeptide mimic were prepared by coupling the glutaric acid amides with either the transition-state mimic (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6- methylheptane (18) or the hydroxyethylene dipeptide isostere. The glutaric acid amides were prepared by two general procedures. The first procedure involved the reductive amination of alpha-amino acid esters with alpha-keto esters. The second procedure involved the displacement reaction of alpha-bromo esters or acids with alpha-amino acid amides.

Amides↗