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PubMedDate not supplied

Acute pancreatitis in a patient with glutaric acidemia type II.

We describe a two-year-old girl who presented with coma following an upper respiratory tract infection. Nonketotic hypoglycemia, metabolic acidosis and mild hyperammonemia were detected. The urinary organic acid profile was consistent with glutaric aciduria type II. Pancreatitis was diagnosed at autopsy. Although pancreatitis has been described in a number of inborn errors of metabolism including organic acidemias, to the best of our knowledge this is the first report of acute pancreatitis occurring in glutaric acidemia type II. It was stressed, therefore, that this complication should be searched for in organic aciduria patients, and the measurement of plasma amylase and lipase levels should be added to the battery of laboratory investigations in such cases.

Amino Acid Metabolism, Inborn Errors↗
PubMed2007

Enhanced efficiency due to the use of achiral additives in the optical resolution of 1-phenylethylamine by its glutaric acid derivative.

Racemic 1-phenylethylamine was optically resolved by its own derivative formed with glutaric acid namely (+)-(R)-N-(1-phenylethyl)glutaramic acid. The amide acid resolving agent was synthesized from (+)-(R)-1-phenylethylamine by N-derivatization. The glutaric acid derivative was the next in a homologous series of dicarboxilic acid derivatized resolving agents of racemic 1-phenylethylamine. Resolution results obtained with the oxalic, malonic, and succinic acid derivatives were previously discussed(1). Each of the above derivative resolving agents could be successfully applied as resolving agents of 1-phenylethylamine. The efficiency of the present optical resolution using (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent was remarkably inferior to the results obtained by its shorter chained homologues(1). Use of achiral additives, like urea, thiourea, N-methylurea, and N,N'-dimethylurea caused large increase in the efficiency of the resolution by (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent. Precipitated salts obtained in the resolutions performed in the presence of the additives were investigated by thermoanalysis, X-ray powder diffraction, and optical microscopy. Based on the analytical data, the improvement of the resolution results was attributed to the influence of the additives on the crystal nucleation processes of the diasteromeric salts.

Journal Article↗
PubMed1994

Purification and characterization of 2-keto-3-deoxy-6-phosphogluconate aldolase from Azotobacter vinelandii: evidence that the enzyme is bifunctional towards 2-keto-4-hydroxy glutarate cleavage.

2-keto-3-deoxy-6-phosphogluconate aldolase (E.C. 4.1.2.14) has been purified in two chromatographic steps to 99% purity in 73% overall yield from Azotobacter vinelandii. The pure enzyme is a 70 kD trimeric Class I aldolase, inhibitable by bromopyruvate or pyruvate plus sodium borohydride, with a specific activity of 625 mumol per min per mg protein and a Km of 38 microM for 2-keto-3-deoxy-6-phosphogluconate. The enzyme also has 2-keto-4-hydroxy glutarate aldolase (E.C. 4.1.3.16) activity, with a specific activity of 4.8 mumol per min per mg protein and a Km of 39 microM. 2-keto-4-hydroxy glutarate inhibits the 2-keto-3-deoxy-6-phosphogluconate aldolase activity of the enzyme with an apparent Ki of 0.17 mM. Slow steps following formation of the Schiff base intermediate between KHG and the enzyme are responsible for both the slower turnover of this substrate and for its inhibitory effect.

Aldehyde-Lyases↗
PubMed1988

Neuropathology in glutaric acidaemia type 1.

The neuropathology in three cases of glutaric acidaemia type 1 is presented. All three showed extensive neuronal loss in the caudate nucleus and the putamen, with only small numbers of large neurons surviving. The globus pallidus showed moderate shrinkage and gliosis but no conspicuous decreases in neurons. Severe spongiform change was seen in many regions, involving predominantly white matter. These features are very similar to some cases described previously in familial striatal degeneration in childhood, but are different from other cases. If found in a brain at autopsy, they should lead to studies to diagnose glutaric acidaemia type 1 retrospectively, so that accurate genetic counselling and prenatal diagnosis in future pregnancies can be offered.

Child↗
PubMed1997

Glutaric aciduria type 1 (glutaryl-CoA-dehydrogenase deficiency): advances and unanswered questions. Report from an international meeting.

Infants with macrocephaly, young children with acute disease resembling encephalitis, and children with truncal hypotonia, ataxia, or dystonia may be affected by glutaric aciduria type I (GA 1, glutaryl-CoA-dehydrogenase deficiency), a not-so-rare autosomal recessive neurometabolic disease. Well-known features of GA1 are fronto-temporal brain atrophy with macrocephaly and acute encephalopathic episodes with striatal necrosis followed by dystonia, but some patients develop motor disease without overt crises and other biochemically affected individuals remain asymptomatic. Biochemical and molecular characterization is available and allows post- and prenatal diagnosis. The pathogenesis of fronto-temporal atrophy, macrocephaly, and basal ganglia necrosis is still not understood, and there is no close correlation between biochemical parameters and clinical outcome. There is, however, evidence suggesting that carnitine supplementation and anticatabolic treatment of intercurrent illness may arrest or prevent neurological deterioration, while the role of limitation of dietary lysine and tryptophane is not yet clear. Although pathogenetic aspects are poorly understood, the natural course of glutaric aciduria type 1 can be changed by early diagnosis and treatment. Coordinated research is needed to understand the pathogenesis of brain toxicity, to define the role of dietary therapy, and to explore the possibility of neonatal screening.

Brain Diseases↗
PubMedDate not supplied

Morphologic studies of the placenta and autopsy findings in neonatal-onset glutaric acidemia type II.

A case of neonatal-onset glutaric acidemia type II with electron-transfer flavoprotein (ETF) deficiency is presented. The morphological pattern of disease in the male infant included hypospadias, cryptorchidism, bilateral 13 ribs, nuclear cataract, cystic dysplasia of kidneys, lipid accumulation in the liver and renal tubular epithelium, and immature brain with white matter gliosis. The morphologic examination of the placenta revealed features of delayed maturation, including large-for-gestational-age size and abundant immature intermediate villi with cellular syncytiotrophoblast, persistent villous cytotrophoblast, and decreased syncytial knots. In addition, immature intermediate villi showed exaggeration of lacunar interstitial spaces consistent with non-hydropic villous edema. Marked lipid accumulation was seen within extravillous trophoblasts of placental septa and cell islands. Light lipid accumulation was also noted within fibroblasts of stem villi. These findings suggest that in glutaric acidemia type II, fatty acid oxidation could also be affected in the placenta.

Abnormalities, Multiple↗
PubMed1986

2-Oxo-[14C]glutarate is taken up by glutamatergic nerve terminals in the rat striatum.

High affinity uptake of [14C]glutamate into rat striatal synaptosomes was reduced by 33% after bilateral cortical ablation. The lesion had no effect on striatal [14C]GABA uptake, but reduced 2-oxo-[14C]glutarate uptake by 67%. The results demonstrate the existence of a high-affinity uptake site for 2-oxoglutarate on glutamatergic nerve terminals and support the contention that this Krebs cycle intermediate may be used to replenish the neuronal pool of neurotransmitter glutamate. 2-Oxo-[14C]glutarate uptake may serve as a selective marker for glutamatergic neurones.

Animals↗
PubMed2005

Glutaconyl-CoA is the main toxic agent in glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

Despite early diagnosis and treatment, 35% of the patients with glutaric aciduria type I (GA I) develop severe neurologic damage. Glutaric acid and 3-hydroxyglutaric acid have been suspected to cause neurodegeneration. Lately, this has been questioned, however. We postulate that glutaconyl Coenzyme A (glutaconyl-CoA) is responsible for brain damage. Chemically, glutaconyl-CoA is an analogue of acrylyl-CoA, the parent substance of the extremely reactive class of acrylates. It is expected to react spontaneously with sulfhydryl groups, thus modifying membranes, disturbing enzyme functions and trapping glutathione. Enhanced production of glutaconyl-CoA together with lack of glutathione precipitates brain damage. Such a mechanism is supported by three findings. (1) The addition product of glutaconyl-CoA to cysteine is present in small amounts in normal human urine. (2) Reaction of methacrylyl-CoA with free sulfhydryl groups has been reported previously in a patient with 3-hydroxyisobutyryl CoA deacylase deficiency. (3) Glutathione has been found to be decreased in homozygous glutaryl-CoA dehydrogenase-deficient knock-out mice.

Acyl Coenzyme A↗
PubMed1999

Neuroradiologic findings in glutaric aciduria type II.

The authors report a 3-year-old male with glutaric aciduria type II, whose magnetic resonance imaging studies revealed agenesis of the cerebellar vermis and hypoplastic temporal lobes. Proton magnetic resonance spectroscopy in the parietal white matter revealed a markedly increased choline/creatine ratio, suggesting a demyelinating process. Gas chromatographic analysis of urinary organic acids should be studied in any patient with agenesis of the cerebellar vermis and cystic renal disease to exclude glutaric aciduria type II.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Reactions of glutaric acid on the TiO2(001) single crystal. Effect of surface reduction on the reaction pathway.

The detailed reaction of glutaric acid (a C(5) dicarboxylic acid) has been studied by temperature programmed desorption (TPD) and X-ray photoelectron spectroscopy (XPS). Upon adsorption at 300 K, both carboxylic acid functions are deprotonated to give adsorbed glutarate species. The reaction of these species differs significantly on the oxidized surface from that on the reduced surface. On the oxidized surface, two competing reactions are seen: (i) decomposition to two molecules of CO and one molecule of propene and (ii) dehydration to ketene. Upon sputtering with hydrogen ions (reducing the surface states of Ti ions and implanting hydrogen atoms in the lattice), the main observed reaction is reduction to the dialdehyde and the dialcohol. The yield of these two products, not seen on the oxidized surface, reaches 80% on the highly reduced surface. Another compound is seen on the reduced surface with m/z = 70. The analysis of its fragmentation pattern tends to assign it to cyclopentane that is formed by an intramolecular reductive coupling reaction on the O-defect sites.

Journal Article↗
PubMed2004

A polynuclear coordination glutarate of lanthanum(III) with an uncommon cage feature.

The title compound, triaquatris(glutarato)dilanthanum(III) dihydrate, [[La2(C5H6O4)3(H2O)3] x 2H2O]n, is the first reported glutarate coordination polymer of lanthanum(III) without a protonated ligand. The noteworthy features in the structure are, firstly, the unusual binuclear lanthanum cage formed by three bridging bonds through O atoms involved in different coordination modes and, secondly, the very rare 'malonate' mode exhibited by a dicarboxylate ligand with an alkyl chain of five C atoms. To our knowledge, this eta7 chelation for the glutarate ligand has not been reported and was thought to be forbidden for steric reasons. The gauche-gauche conformation of the corresponding ligand favours cage formation, but trans geometries created along the ligating O atoms prevent cluster packing. The two independent La atoms are nine- and tenfold coordinated, leading to distorted one-face-sharing LaO7(H2O)2 and LaO9(H2O) polyhedra, respectively. In the three-dimensional framework, these asymmetric subunits are linked in a zigzag manner via one-edge-sharing LaO9(H2O) polyhedra and are connected by the carbon backbone chains of the ligands. The structure is very compact and, unlike many other reported dicarboxylate lanthanides, connectivity between the two metal atoms and the three ligands yields a crystal packing with cavities accommodating two guest water molecules but without an open framework.

Journal Article↗
PubMed1997

Early clinical manifestation of glutaric aciduria type I and nephrotic syndrome during the first months of life.

We describe a male patient with glutaric aciduria type I which had already presented during the neonatal period with therapy-resistant seizures. In the course of the disease, he also developed choreoathetosis and dystonia. The disease was associated with nephrotic syndrome. Renal histology showed signs of a glomerular disorder with shrinking of glomerular tufts, increase in mesangial matrix, proliferation of extracapillary epithelial cells and formation of larger epithelial crescents. The child died at 22 weeks of age due to end-stage renal failure. This report illustrates an unusual and early clinical manifestation of glutaric aciduria type I and a hitherto unknown association with nephrotic syndrome in early childhood.

Fatal Outcome↗
PubMed1974

Transformation of 1-Menthene by a Cladosporium: Accumulation of beta-Isopropyl Glutaric Acid in the Growth Medium.

An organism isolated from soil samples collected near a terpene plant grew in the presence of 1-menthene, with no other major source of carbon and energy. The organism was tentatively identified as a member of the genus Cladosporium. When this organism was grown in the presence of 1-menthene, with no other major source of carbon, substantial quantities of beta-isopropyl glutaric acid accumulated in the fermentation medium. beta-Isopropyl glutaric acid is probably an end product of the degradation of 1-menthene by the organism.

Journal Article↗
PubMed2006

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p.

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Adult↗
PubMed2003

Type I glutaric aciduria, part 1: natural history of 77 patients.

Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl-CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Microencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibility. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities.

Brain Diseases, Metabolic, Inborn↗
PubMed1991

Mass spectrometric analysis of metabolite excretion in five Japanese patients with the late-onset form of glutaric aciduria type II.

The variability of clinical and biochemical features in five Japanese patients with the late-onset form of glutaric aciduria type II (GAII) was studied using mass spectrometric procedures. The age at onset ranged from 5 months to five years, presenting acute episodes such as lethargy, hypotonia, hyperammonaemia, hypoglycaemia or Reye's syndrome-like illness, while one of the five cases was asymptomatic at 1 year of age. Organic acid analysis as oxime-trimethylsilyl derivatives by gas chromatography/mass spectrometry revealed the presence of several abnormalities characteristic of GAII in clinically asymptomatic conditions of three patients but not of the two others. Quantitative acylglycine analysis using a stable isotope dilution method and qualitative acylcarnitine analysis by fast atom bombardment mass spectrometry provided diagnostic information in all five patients, regardless of their clinical conditions. However, significant differences in the respective metabolite profiles as well as in their clinical pictures were noted. Although an increased excretion of both isovalerylglycine and isovalerylcarnitine was found in four patients, the fifth showed normal isovalerylglycine excretion during both the acute stage and in remission, despite the increased amount of isovalerylcarnitine in urine. From these results, it was suggested that the variations in clinical severity and metabolite excretion among GAII patients may be attributed not only to the residual enzyme activity at the defective site but also to differences in the capability to conjugate accumulated acyl-coenzyme A.

Acids↗
PubMed2002

Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons.

Glutaryl-CoA dehydrogenase deficiency (GDD) is characterized biochemically by an accumulation of glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids and clinically by the development of acute striatal degeneration. 3-OH-GA was recently shown to induce neuronal damage via N-methyl-D-aspartate (NMDA) receptors. The pathogenetic role of GA, however, remains unclear. We demonstrate that GA exerts a dual action in cultured chick embryo neurons. Short-term incubation with millimolar concentrations of GA induces a weak neuronal damage, adding to 3-OH-GA neurotoxicity. In contrast, chronic treatment with subtoxic, micromolar concentrations of GA results in partial tolerance to 3-OH-GA- and NMDA-induced cell damage. A downregulation of NMDA receptors, in particular of the NR2B subunit, is critically involved in this GA-induced effect, resulting in a reduced Ca(2+) increase and generation of reactive oxygen species after acute exposure to NMDA or 3-OH-GA. Furthermore, GA decreases Na(+)/K(+)-ATPase activity, which is prevented by glutathione, suggesting a modulation of NMDA receptor function via resting membrane potential and Na(+)-dependent glutamate transport. In contrast, GA does not inhibit mitochondrial respiratory chain and beta-oxidation of fatty acids, virtually excluding an activation of NMDA receptors secondary to ATP depletion. These results strongly suggest that GA modulates the NMDA receptor-mediated neurotoxicity of 3-OH-GA, providing an explanatory basis for the non-linear relationship between organic acid concentrations and disease progression in GDD patients. Furthermore, GA-induced downregulation of NMDA receptors might be involved in the delayed cerebral maturation of GDD patients, resulting in frontotemporal atrophy and a reduced opercularization, which are common neuroradiological findings in GDD patients.

Animals↗
PubMed1976

Hypocholesterolemic agents IV: inhibition of beta-hydroxy-beta-methyglutaryl coenzyme A reductase by arylalkenyl and arylepoxy hydrogen succinates and glutarates.

Two series of half acid esters of succinic and glutaric acids were synthesized and assayed for inhibition of rat liver beta-hydroxy-beta-methylglutaryl coenzyme A reductase. Irreversible inhibition was studied by incorporation of a potential alkylating group (the epoxide function) into the side chain of the alcohol portion of the half acid esters. Incorporation of a terminal olefin function into the side chain of the alcohol portion of the half acid esters provided a group that could form a charge-transfer complex. Neither irreversible inhibition nor formation of a charge-transfer complex was indicated from these studies; however, the two series of half acid esters exhibited reversible inhibition.

Alcohol Oxidoreductases↗