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PubMed2001

IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric acid toxicity in striatal cultures.

Glutaric acid (GA) and 3-hydroxyglutaric acid (3GA) are thought to contribute to the degeneration of the caudate and putamen that is seen in some children with glutaric acidaemia type I, a metabolic disorder caused by a glutaryl-CoA dehydrogenase deficiency. This study assessed the neurotoxicity of GA and 3GA (0-50 mmol/L) compared to quinolinic acid (QUIN) in striatal and cortical cultures. All three acids were neurotoxic in a dose-dependent manner; however, GA and 3GA were both more toxic than QUIN. The neurotoxic effects of low concentrations of GA or 3GA were additive to QUIN toxicity. A series of hormones and growth factors were tested for protection against GA and 3GA toxicity. Insulin (5-500 microU /ml), basic fibroblast growth factor (bFGF; 10 ng/ml), insulin-like growth factor (IGF-1; 50 ng/ml), brain-derived neurotrophic factor (BDNF; 10 ng/ml), glial-derived neurotrophic factor (GDNF; 10 ng/ml), and two glutamate antagonists were evaluated in brain cultures to which 7 mmol/L GA or 3GA were added. GA and 3GA neurotoxicities were prevented by bFGF. Attenuation of 3GA-induced neurotoxicity was seen with insulin (5 microU/ml) and IGF-1. BDNF and GDNF had no effects on neuronal survival. Glutamate antagonists MK801 (10 micromol/L) and NBQX (10 micromol/L) failed to prevent GA or 3GA neurotoxicity. We conclude that GA and 3GA are neurotoxic in cultures of embryonic rat striatum and cortex. Striatal neurons were rescued from death by bFGF and IGF-1 but not by glutamate antagonist, suggesting that toxicity in this embryonic system is not necessarily mediated by glutamate receptors.

Animals↗
PubMed2004

Preliminary attempts to establish a rat model of striatal injury in glutaric acidaemia type I.

Glutaric acidaemia type I (GA I) is caused by the deficiency of glutaryl-CoA dehydrogenase, resulting in accumulation of glutaric acid (GA) and 3- hydroxyglutaric acid (3-OH-GA) in blood and cerebrospinal fluid (CSF). Neuropathological changes with onset in childhood consist of severe neuronal loss in the caudate and putamen. An animal model is necessary to test possible intervention strategies, and prior reports suggested that GA or 3-OH-GA could be used to create specific neuron loss in adult rats. Adult, 3-week-old and 2-week-old rats received intrastriatal injections of GA and 3-OH-GA at a range of doses. High concentrations caused necrotic lesions in striatum. Low concentrations caused white-matter axonal damage and small areas of neuron loss. Injection of lipopolysaccharide prior to administration of 3-OH-GA was not associated with enhanced neuronal loss. Our findings contradict prior claims and we conclude that the simple model of a single GA or 3-OH-GA injection into rat brain does not replicate the neuropathological findings in humans.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I.

The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Glutaric aciduria type I and kynurenine pathway metabolites: a modified hypothesis.

Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3-hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl-CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3-dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N-methyl-D-aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3-hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Two-dimensional carboxylate bridged network of europium(III)-transition metal(II) glutarate compounds.

Four new heterometallic glutarate coordination polymers, [Eu2M(H2O)4][O2C(CH2)3CO2]4.2H2O (M = Mn (1), Fe (2), Co (3) and Ni (4)) have been obtained under hydrothermal synthesis. The single-crystal X-ray diffraction analyses showed that they have two-dimensional frameworks based on the linear polyhedral chains consisting of two nine-coordinated Eu(III)O9 and a six-coordinated M(II)O6. These 1-D MO6-Eu2O16 chains are cross-linked by glutarate ligands as an interchain pillared architecture, whose conformations vary depending upon the transition metals. The magnetic behavior of the compounds show a weak antiferromagnetic interaction, in which shielding of the 4f electrons by the outer shell electrons effectively precludes significant coupling interactions between the Eu-4f electrons and transition metal (M)-3d electrons.

Carboxylic Acids↗
PubMed1977

The allosteric mechanism of bovine liver glutamate dehydrogenase. Evidence from circular-dichroism studies for a conformational change in the ternary complex enzyme-(oxidized nicotinamide-adenine dinucleotide)-glutarate.

1. Computer averaging of multiple scans was used to refine the circular dichroism spectrum of bovine liver glutamate dehydrogenase, revealing well-defined structure in the aromatic region. 2. The circular dichroism of NAD+ bound to glutamate dehydrogenase is strongly negative at 260nm, probably owing to immobilization of the adenosine moiety. Loss of the characteristic adenine-nicotinamide interaction suggests that the coenzyme is bound in an unstacked conformation. 3. Glutarate and succinate, substrate analogues that are both inhibitors competitive with glutamate, do not significantly perturb the circular-dichroism spectrum of the enzyme in the absence of NAD+. 4. In the presence of NAD+, 150nM-succinate decreases the negative circular dichroism corresponding to bound coenzyme, but does not affect the protein circular dichroism. However, ISOmM-glutarate causes profound alternations of the circular-dichroism spectra of the bound NAD+ and of the enzyme, indicative of a protein conformational change. This direct evidence of conformational change specifically promoted by C5 dicarboxylates confirms the previous inference from protection studies. 5. The conformational change is discussed in relation to the allosteric mechanism of glutamate dehydrogenase.

Allosteric Regulation↗
PubMed2000

Atypical and variable clinical presentation of glutaric aciduria type I.

We report atypical and variable clinical presentation of glutaric aciduria type I (GA I) in four children from two Greek families. In one family, a boy with typical biochemical and neuroradiological features of GA I suffered a metabolic crisis at 16 months of age resulting in a severe movement disorder. His sister, two years older and showing identical biochemical features, has remained neurologically normal throughout childhood and at six years of age is attending normal primary school. Both children are homozygous for P217 L, a novel mis-sense mutation in exon 7 of the glutaryl-CoA dehydrogenase (GCDH) gene. In the other family, monozygotic twins presented at 6 years of age with mild developmental delay and a single episode of hypoglycaemia. Cranial magnetic resonance imaging (MRI) scans in both twins revealed almost identical high-signal alterations in the periventricular white matter and in the centrum semiovale. Biochemical analyses showed massive urinary excretion of glutaric and 3-hydroxyglutaric acids and carnitine depletion. Molecular studies showed compound heterozygosity for two novel putative null mutations, IVS6-1 G > A and Y413 X, in the GCDH gene. The milder clinical course of GA I in three of the four Greek patients demonstrates the phenotypic heterogeneity of the disease even within families. Asymptomatic siblings of GA I patients should always be investigated, and molecular studies may be useful for confirming the diagnosis, particularly when the presentation is atypical.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

[Development of brain atrophy, therapy and therapy monitoring in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency)].

Serial trans-fontanellar sonographic examination in a patient with glutaric aciduria type I (GA I) demonstrated that the typical frontotemporal cerebral atrophy developed postnatally within three months paralleling the onset of dystonic symptoms. Pathogenesis of the accompanying macrocephaly remains unclear and can form a diagnostic pitfall. Diet low in lysine and tryptophan led to a dramatic fall in urinary glutaric acid (GA) excretion but as in other patients with GA I did not substantially influence clinical symptoms and course. We determined unchanged levels of GA in plasma and cerebrospinal fluid resulting from variable renal tubular secretion and reabsorption of GA. Monitoring urinary excretion of GA appears inappropriate to control dietary treatment in GA I. Substitutive correction of secondary carnitine depletion seems to protect from deleterious metabolic crises. Treatment with valproic acid resulted in a rise of GABA-concentration in cerebrospinal fluid but did not ameliorate clinical symptoms. This finding is in contrast with the hypothesis that inhibition of cerebral GABA-synthesis by GA is responsible for the development of dystonia in GA 1. Although we observed impressing fluctuation of dystonic symptoms, levodopa did not show therapeutic effects. The extreme variability in the severity of neurologic disease in metabolically identical individuals leads to a "two-hit"-hypothesis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

[Ultrasound, computed tomography and magnetic resonance tomography in a child with macrocephaly and glutaric aciduria type I].

The rare case of glutaric aciduria type I (GA Type I) is described. Its characteristics are discussed and compared with cases in the literature. This disease is basically due to a lack of glutaryl-CoA-dehydrogenase with increased excretion of glutaric acid. Most authors describe frontotemporal cerebral atrophy. In the majority of cases macrocephaly is also present. This sign was also seen in our case and was the reason for performing an ultrasound examination, CT and MR. Ultrasound and CT showed a large insular cistern with incomplete formation of the opercula and frontal atrophy. In addition MR revealed hyperintensity of the basal ganglia and the periventricular white matter. To our knowledge this is the first publication of radiological findings in GA Type I in the German language.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

A diet-induced mouse model for glutaric aciduria type I.

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

X-ray studies on crystalline complexes involving amino acids and peptides. XXXVII. Novel aggregation patterns and effect of chirality in the complexes of DL- and L-lysine with glutaric acid.

The complexes of glutaric acid with DL-lysine contain singly positively charged zwitterionic lysinium ions and singly negatively charged semi-glutarate ions. Both the ions exhibit different conformations in the two complexes. The structures contain head-to-tail sequences of amino acids. However, the aggregation patterns in the two complexes are entirely different, demonstrating the effect of chirality on molecular aggregation. These patterns also turn out to be different from those so far observed, in structures containing amino acids. The structures contain characteristic interaction patterns involving linear arrays of alternating amino and carboxylate groups.

Crystallography, X-Ray↗
PubMed1984

Virucidal activity of glutaric acid and evidence for dual mechanism of action.

Rhinoviruses as a group are notably sensitive to inactivation in solutions with a pH of less than 5.3. Glutaric acid appears to possess virucidal activity in addition to the aciduant effect against rhinoviruses. A model system in which rhinovirus type 14 was incubated in the presence of glutaric acid (GA) (pH 4.0) at 0 degrees C was devised to separate intrinsic virucidal activity from the aciduant effect. Under these conditions, virucidal activity against rhinovirus type 14 was directly related to the concentration of GA present and the proportion of the acid in the diprotonated form. The virucidal activities of GA and several other compounds, including GA analogs and other mono- and dicarboxylic acids, were tested under the conditions described. In general, as the alkane bridge separating two carboxylic acid functions was lengthened, virucidal activity decreased. When 26 additional strains of rhinoviruses were tested in the model system, 19 were inactivated slowly enough to be compared. Of these, 63% were more susceptible to GA than to sodium acetate buffer and 26% were more susceptible to sodium acetate buffer. Eleven percent were resistant to both GA and sodium acetate buffer. The virucidal activity of GA for a majority of strains tested appeared to be due to combination of low pH and another mechanism of action presumably unrelated to pH.

Antiviral Agents↗
PubMed2000

Mutation analysis in glutaric aciduria type I.

Glutaric aciduria type 1 (GA1), resulting from the genetic deficiency of glutaryl-CoA dehydrogenase (GDH), is a relatively common cause of acute metabolic brain damage in infants. Encephalopathic crises may be prevented by carnitine supplementation and diet, but diagnosis can be difficult as some patients do not show the typical excretion of large amounts of glutaric and 3-hydroxyglutaric acids in the urine. We present a rapid and efficient denaturing gradient gel electrophoresis (DGGE) method for the identification of mutations in the glutaryl-CoA dehydrogenase (GCDH) gene that may be used for the molecular diagnosis of GA1 in a routine setting. Using this technique, we identified mutations on both alleles in 48 patients with confirmed GDH deficiency, while no mutations were detected in other patients with clinical suspicion of GA1 but normal enzyme studies. There was a total of 38 different mutations; 27 mutations were found in single patients only, and 21 mutations have not been previously reported. Fourteen mutations involved hypermutable CpG sites. The commonest GA1 mutation in Europeans is R402W, which accounts for almost 40% of alleles in patients of German origin. GCDH gene haplotypes were determined through the analysis of polymorphic markers in all families, and three CpG mutations were associated with different haplotypes, possibly reflecting independent recurrence. The high sensitivity of the DGGE method allows the rapid and cost efficient diagnosis of GA1 in instances where enzyme analyses are not available or feasible, despite the marked heterogeneity of the disease.

Brain Diseases, Metabolic, Inborn↗
PubMed2004

Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria.

Glutaric aciduria type 1 is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase. This disorder mainly affects children. The majority of patients develop a dystonic-dyskinetic syndrome. The dystonia is painful and can cause significant disability. This report documents an 18-month-old child, the youngest reported, who underwent pallidotomy for disabling dystonia. The surgery improved dystonic symptoms, especially pain in this child with minor complications related to the procedure. Pallidotomy is a reasonable option for children with dystonic symptoms secondary to glutaric aciduria.

Dystonic Disorders↗
PubMed1984

Specific glutaryl-CoA dehydrogenating activity is deficient in cultured fibroblasts from glutaric aciduria patients.

Patients with glutaric aciduria (GA) have greatly increased urinary excretion of glutarate. Their leukocyte and fibroblast sonicates have deficient ability to produce 14CO2 from [1,5-14C]glutaryl-CoA, an enzymatic process with two sequential reaction steps, dehydrogenation and decarboxylation. In normal individuals, it is not known whether these two reaction steps require one or two enzymes, and currently it is assumed that a single enzyme, glutaryl-CoA dehydrogenase (GDH), carries out these two reactions. Since GA patients also excrete increased amounts of 3-hydroxyglutarate and glutaconate in urine, it was thought that glutaryl-CoA in these patients may be dehydrogenated but not decarboxylated. We developed a new assay specific for glutaryl-CoA dehydrogenation which measures enzyme-catalyzed tritium release from [2,3,4-3H]glutaryl-CoA, and we studied the glutaryl-CoA dehydrogenating activity in cultured normal human fibroblasts and those from patients with GA. The Michaelis constant (Km) of normal human fibroblast GDH for [2,3,4-3H]glutaryl-CoA was 5.9 microM, and activity was severely inhibited by (methylenecyclopropyl)acetyl-CoA at low concentrations. Sonicates from all five GA fibroblast lines examined showed 2-9% of control glutaryl-CoA dehydrogenating activity, corresponding to the deficient 14CO2 releasing activity. These results indicate either that the conversion of glutaryl-CoA to crotonyl-CoA is accomplished by two enzymes, and patients with GA are deficient in the activity of the first component, or alternatively, that this process is carried out by a single enzyme which is deficient in these patients. It is unlikely that urinary glutaconate and 3-hydroxyglutarate in GA patients are produced via GDH.

Acetyl Coenzyme A↗
PubMed1986

The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria. Mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts.

The multiple acyl-coenzyme A (CoA) dehydrogenation disorders (MAD) include severe (S) and mild (M) variants, glutaric aciduria type II (MAD:S) and ethylmalonic-adipic aciduria (MAD:M). Intact MAD:M mitochondria oxidized [1-14C]octanoate, [1-14C]palmityl-CoA, and [1,5-14C]glutarate at 20-46% of control levels; MAD:S mitochondria oxidized these three substrates at 0.4-18% of control levels. In MAD:M mitochondria, acyl-CoA dehydrogenase (ADH) activities were similar to control, whereas MAD:S ADH activities ranged from 38% to 73% of control. Electron transfer flavoprotein (ETF) activities in five MAD:M cell lines ranged from 29 to 51% of control (P less than 0.01); ETF deficiency was the primary enzymatic defect in two MAD:M lines. In four MAD:S patients, ETF activities ranged from 3% to 6% of control (P less than 0.001); flavin adenine dinucleotide addition increased residual ETF activity from 4% to 21% of control in a single MAD:S line (P less than 0.01). Three MAD:S patients had ETF activities ranging from 33 to 53% of control; other investigators found deficient ETF-dehydrogenase activity in these MAD:S and three of our MAD:M cell lines.

Acyl Coenzyme A↗
PubMed1980

Multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein.

When amino acids were infused at a rate of 4 g/kg/day, an infant with hypoglycemia, metabolic acidemia and chronic regurgitation showed hypersarcosinemia and excreted abnormal amounts of sarcosine, isovalerylglycine, isobutyrylglycine, alpha-methylbutyrylglycine, and beta-hydroxyisovaleric, glutaric, alpha-hydroxyglutaric, methylsuccinic, and alpha-hydroxyisobutyric acids in urine. On all other occasions, when protein intake was lower and lipid intake higher, urine organic acids were dominated by methylsuccinic, ethylmalonic, and alpha-hydroxyglutaric acids, and hypersarcosinemia was absent. Autopsy showed severe fatty changes in liver, kidneys, and skeletal muscle. A previous female sibling had died with similar autopsy findings at 4 days of age. While activity of glutaryl-CoA dehydrogenase was completely deficient in liver and almost completely so in kidney, it was normal in cultured fibroblasts in the presence of flavin adenine dinucleotide (FAD) and only marginally low in its absence. Incorporation of D-(2-14C) riboflavin into flavin mononucleotides (FMN) and FAD by kidney tissue was normal. The authors conclude that this disorder is not due to generalized deficiency of glutaryl-CoA dehydrogenase or to a defect in FAD synthesis. The amino and organic acid abnormalities noted are most consistent with a defect in the flavoprotein which transfers electrons from the FAD of sarcosine and acyl-CoA dehydrogenases into the respiratory chain, although a defect in intercompartmental transfer of C4--5 acyl CoA esters across cell membranes is not excluded. The variability of the organic aciduria, which possibly reflects changes in protein and fat intake, suggests that a previous name for this disorder, i.e., glutaric aciduria type II, is inappropriate and should be replaced, perhaps by "multiple acyl-CoA dehydrogenase deficiency."

Acids↗
PubMed2005

Glutaric acid and its metabolites cause apoptosis in immature oligodendrocytes: a novel mechanism of white matter degeneration in glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase deficiency is an inherited metabolic disease characterized by elevated concentrations of glutaric acid (GA) and its metabolites glutaconic acid (GC) and 3-hydroxy-glutaric acid (3-OH-GA). Its hallmarks are striatal and cortical degeneration, which have been linked to excitotoxic neuronal cell death. However, magnetic resonance imaging studies have also revealed widespread white matter disease. Correspondingly, we decided to investigate the effects of GA, GC, and 3-OH-GA on the rat immature oligodendroglia cell line, OLN-93. For comparison, we also exposed the neuroblastoma line SH-SY5Y and the microglia line BV-2 to GA, GC, and 3-OH-GA. Cell viability was measured by metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium. Flow cytometry was used to assess apoptosis via annexin-V, anti-active caspase-3 antibody, and propidium iodide staining. GA, GC, and 3-OH-GA reduced OLN-93 oligodendroglia cell viability in a dose-dependent manner. Toxicity of GA, GC, and 3-OH-GA was abrogated by preincubation with the pan-caspase inhibitor z-VAD-fmk. Apoptosis but not necrosis was detected at various stages (early: annexin-V; effector: caspase-3) after 24-48 h of incubation with GA, GC, or 3-OH-GA in OLN-93 but not in neuroblastoma or microglia cells. OLN-93 lacked expression of N-methyl-d-aspartate receptors, making classical glutamatergic excitotoxicity an unlikely explanation for the selective toxicity of GA, GC, and 3-OH-GA for OLN-93 cells. GA, GC, and 3-OH-GA directly initiate the apoptotic cascade in oligodendroglia cells. This mechanism may contribute to the white matter damage observed in glutaryl-CoA dehydrogenase deficiency.

Amino Acid Chloromethyl Ketones↗