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PubMed1998

Recurrent fetal polycystic kidneys associated with glutaric aciduria type II.

A woman had two pregnancies terminated in the 20th and 21st weeks of gestation after ultrasonographic detection of enlarged hyperechoic kidneys in both fetuses. The combination of polycystic kidneys and steatotic liver found at autopsy suggested glutaric aciduria type II (GA II), which was confirmed by biochemical investigation. GA II or multiple acyl-CoA dehydrogenase deficiency is an autosomal recessively inherited defect of mitochondrial energy metabolism, which usually results in neonatal death. When pregnancy is terminated because of enlarged hyperechoic kidneys in the fetus, autopsy is crucial for establishing the correct diagnosis. The combination of polycystic kidneys and steatotic liver should bring GA II to mind, and prompt appropriate biochemical investigations so that genetic counselling and first trimester diagnosis can be offered in future pregnancies.

Acyl-CoA Dehydrogenases↗
PubMed2005

Validation and diagnostic efficacy of a lipase assay using the substrate 1,2-o-dilauryl-rac-glycero glutaric acid-(6' methyl resorufin)-ester for the diagnosis of acute pancreatitis in dogs.

BACKGROUND: Increased serum lipase activity has been used historically to support the diagnosis of acute pancreatitis, a common disease in dogs. Most of the lipase assays that are currently in use lack optimum sensitivity and specificity. OBJECTIVE: The objectives of this study were to 1) validate the 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) assay for determination of lipase activity in canine serum and 2) compare results, reference intervals, sensitivity, and specificity of the DGGR assay with a standard 1,2-diglyceride (1,2 DiG) assay for diagnosing acute pancreatitis in dogs. METHODS: Precision, linearity, and interference studies were performed for method validation on a Hitachi 911 analyzer. Lipase results from the DGGR and 1,2 DiG assays were compared by linear regression analysis. Sensitivity, specificity, and diagnostic efficacy were determined for both assays on a population of 30 dogs, 15 of which had acute pancreatitis based on history, clinical signs, and ultrasound findings. RESULTS: Within-run and within-day coefficients of variation (CVs) were low (<3%), with higher day-to-day CVs (< or =14 %). The assay was linear between 8 and 2792 U/L. No significant interference by hemolysis and lipemia was found. Poor correlation was found between the assays (r(s)=0.84). The lipase reference interval was 8-120 U/L for the DGGR assay and 30-699 U/L for the 1,2 DiG assay. Sensitivity and specificity for the diagnosis of pancreatitis were 93% and 53%, respectively, for the DGGR assay and 60% and 73% for the 1,2 DiG assay. Receiver operating characteristic curve analysis showed similar areas under the curve. CONCLUSIONS: On the basis of this study, the DGGR method is considered adequate for assaying serum lipase activity in dogs. The high sensitivity of the DGGR assay suggests it may be a useful screening test for canine pancreatitis.

Animals↗
PubMed1984

Inactivation of rhinovirus on human fingers by virucidal activity of glutaric acid.

Hand lotion containing 2% glutaric acid was significantly more effective than placebo in inactivating rhinovirus serotype 2 on the fingers of human volunteers. It may be possible to develop safe, cosmetically acceptable hand lotions which have durable virucidal activity and can interrupt the hand-to-hand transmission of rhinovirus colds.

Adolescent↗
PubMed2000

Prevention of cerebral palsy in glutaric aciduria type 1 by dietary management.

AIMS: To study retrospectively the effects of treatment and the clinical outcome in 12 patients with glutaric aciduria type 1; and to compare the outcome in 6 patients diagnosed as a result of family screening with 6 patients who were diagnosed late after symptomatic presentation. SETTING: The National Centre for Inherited Metabolic Disorders, The Children's Hospital, Dublin, Ireland. RESULT: Four of the 6 children detected on screening are developmentally normal, 1 died, and the remaining 1 has mild mental handicap. All 6 of the late diagnosed symptomatic group suffered dyskinetic cerebral palsy and 5 have died. CONCLUSION: Experience of 50 patient treatment years has shown that early intensive management can alter the natural history of this rare disorder.

Adolescent↗
PubMed1983

Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.

Using cultured skin fibroblasts, we studied the heterogeneity of inborn errors of leucine metabolism such as isovaleric acidemia (IVA), glutaric aciduria type II (GA II), and multiple carboxylase deficiency (MC). We first developed a simple macromolecular-labeling test to measure the ability of cells to oxidize [1-14C]isovaleric acid in situ in culture. Cells from two different lines were fused using polyethylene glycol, and the ability of the heterokaryons to oxidize [1-14C]isovaleric acid was tested by the macromolecular-labeling test. The MC line complemented with all 10 IVA lines tested; heterokaryons showed 99 +/- 68% more activity than the unfused mixture of component cells. GA II/IVA heterokaryons exhibited poor growth, but when the culture remained confluent, the GA II cells complemented with all six IVA lines tested, showing a 71 +/- 41% increase in activity. The relatively large standard deviations are due to a few experiments in which significant enhancement of macromolecular-labeling test activity was not observed upon fusion, but significant complementation was clearly observed in repeats of the same combinations. These results are consistent with our previous findings, which indicated that the decreased ability of GA II cells to oxidize isovaleryl-CoA involves a defective electron-transporting system rather than a defective isovaleryl-CoA dehydrogenase. IVA/IVA heterokaryons showed no complementation in any combination tested, indicating no detectable heterogeneity in isovaleric acidemia. This finding indicates that the same gene is mutated in all IVA lines. Previous results indicated that this gene codes for isovaleryl-CoA dehydrogenase.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Biosynthesis of electron transfer flavoprotein in a cell-free system and in cultured human fibroblasts. Defect in the alpha subunit synthesis is a primary lesion in glutaric aciduria type II.

We investigated the biosynthesis of electron transfer flavoprotein (ETF) in a cell-free system. Both alpha-(alpha-ETF, 32,000 molecular weight [mol wt]) and beta-subunits (beta-ETF, 27,000 mol wt) were nuclear-coded, and synthesized in the cytosol. alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. The newly synthesized beta-ETF was the same as the mature beta-ETF. Using [35S]methionine labeling, we also studied the biosynthesis in cultured normal human fibroblasts. p alpha-ETF was detected when the cells were labeled in the presence of dinitrophenol or rhodamine 6G. Among six glutaric aciduria type II (GAII) and two ethylmalonic-adipic aciduria cell lines, defective p alpha-ETF synthesis was observed in three GAII cell lines, and beta-ETF synthesis was normal. In one of them, no p alpha-ETF was synthesized at all, while in another, a faint p alpha-ETF band of normal size was detected, and was efficiently processed. In the third line, alpha-EFT was 1,000 mol wt smaller than the normal counterpart, both as the precursor and as the mature form.

Adipates↗
PubMed1992

Glutaric acidemia type II. Heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha subunit of electron transfer flavoprotein in eight patients.

We studied metabolic, polypeptide and genetic variation in eight glutaric acidemia type II (GA II) patients with electron transfer flavoprotein (ETF) deficiency. As measured by 3H-fatty acid oxidations in fibroblasts, beta-oxidation pathway flux correlated well with clinical phenotypes. In six patients with severe neonatal onset GA II, oxidation of [9,10(n)-3H]-palmitate ranged from 2% to 22% of control and of [9,10(n)-3H]myristate, from 2% to 26% of control. Of two patients with late onset GA II, one had intermediate residual activities with these substrates and the other normal activities. Radiolabeling and immunoprecipitation studies revealed that three of the six neonatal onset GA II patients had greatly diminished or absent alpha- and beta-ETF subunits, consistent with a failure to assemble a stable heterodimer. Another neonatal onset patient showed normal synthesis of beta-ETF but decreased synthesis of alpha-ETF. Two neonatal onset and two late onset GA II patients showed normal synthesis of both subunits. Analysis of the pre-alpha-ETF coding sequence revealed seven different mutations in the six patients with neonatal onset GA II. The most common mutation was a methionine for threonine substitution at codon 266 found in four unrelated patients, while all the other mutations were seen in single patients. No mutations were detected in the two patients with late onset GA II.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Glutaric aciduria type II: a case report.

We report a case of a newborn with Glutaric aciduria type II. Pregnancy was complicated by polyhidramnios and fetal bradycardia. Cardiomegaly was detected by fetal echocardiography. The baby was admitted to the Neonatal Intensive Care Unit of Chieti with respiratory distress syndrome immediately after delivery. He showed head and neck edema, micrognathia, paucity of movement, pronounced hypotonia, bilateral cryptorchidism, micropenis, small hands, skin hyperelasticity and joint hypermobility. Serum and urine analysis showed a fatty acid beta-oxidation disorder. He died at 7 days of age for cardiac arrest and autopsy showed marked hepatic and cardiac vacuolisation, lipid storage myopathy and glial cells vacuolisation. Based upon these findings, we speculate that this infant may be suffering from inborn metabolic disease.

Echocardiography↗
PubMed1980

Glutaric aciduria type II: in vitro studies on substrate oxidation, acyl-CoA dehydrogenases, and electron-transferring flavoprotein in cultured skin fibroblasts.

The previous biochemical evidence had suggested that glutaric aciduria type II (GA II) is due to deficient dehydrogenation of multiple short-chain acyl coenzyme A's (CoA's), bu the precise biochemical mechanism underlying this disease was unknown. We investigated substrate oxidation and in vitro activities of isovaleryl CoA- and butyryl CoA dehydrogenases as well as that of electron-transferring flavoprotein (ETF) in cultured skin fibroblasts from a patient with GA II. GA II cells have a markedly decreased ability to oxidize [1-14C]butyrate, [2-14C]lysine, and [2,14C]leucine (3, 9, and 9% of control values, respectively). Mitochondrial isovaleryl CoA- and butyryl CoA dehydrogenase activities in GA II cells were determined using a tritium release assay with [2,3-3H] acyl-CoA's as substrate. When an artificial electron acceptor, phenazine methosulfate (PMS) was not added in the assay media, these activities were 108 and 113% of controls, respectively. This represents the normal abilities of the dehydrogenases in GA II cells to bind the substrate and to catalyze tritium exchange between the bound substrate and solvent. When PMS was added to the assay mixture, these activities were 88 and 70% of control values, respectively, indicating that these enzymes can both dehydrogenate their substrates normally and then transfer electrons to an acceptor (PMS). ETF activity in mitochondrial sonic supernatants from GA II cells, as assessed by a newly devised method, was 159% of control values. These observations suggest that the acyl CoA dehydrogenases themselves and ETF are not defective in GA II. Therefore, the deficiency of another common gene product necessary for the function of all the affected acyl CoA dehydrogenases must be sought to explain the etiology of GA II.

Acyl Coenzyme A↗
PubMed1982

Transport of beta-hydroxy-beta-methyl-glutarate and beta-hydroxbutyrate by renal brushborder membrane vesicles.

The uptake of beta-hydroxy-beta-methyl-glutarate (HMG) and beta-hydroxy-butyrate (beta-HB) by renal brushborder membrane vesicles prepared from normal and starved rats was examined. HMG and beta-HB uptake show a Na+ gradient-induced overshoot, suggesting luminal cotransport of these organic acids. Kinetic analysis of HMG and beta-HB uptake revealed a single component carrier system and a diffusional component for each compound. Vesicles from starved rats exhibit the same transport characteristics as those from normal rats. The transport interactions of other organic acids with HMG were examined and revealed that citrate is a competitive inhibitor, which implies that the compounds share a common organic acid carrier.

3-Hydroxybutyric Acid↗
PubMed1991

Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II.

Newly identified forms of electron transfer flavoprotein (ETF) deficiency in two patients with glutaric aciduria type II (GA II) were described. GA II has been attributed to a defect of either ETF or ETF dehydrogenase, resulting in multiple acyl-CoA dehydrogenation deficiency. ETF is a mitochondrial flavoprotein consisting of an alpha-subunit, alpha-ETF, and a beta-subunit, beta-ETF. We used pulse-chase experiments to examine the biosynthesis of ETF in fibroblasts from two patients with GA II. Patient 1 was a boy with the neonatal onset form, but without congenital anomalies, who is living at age 2 y. A defect of beta-ETF biosynthesis was noted in this patient. Patient 2 was a boy with the neonatal onset form with congenital anomalies who died on the 3rd postnatal day. He presented with a peculiar face and polycystic kidneys. In patient 2, both alpha- and beta-ETF were synthesized, but both the subunits were rapidly degraded. The lability of ETF was considered to be the cause of GA II in this patient. These two cases appear to be new forms of ETF deficiency in GA II.

Child, Preschool↗
PubMed2006

Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I.

Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. 3-OH-GA affects the morphology of VEGF-induced endothelial tubes in vitro because of partial disintegration of endothelial cells. These effects correlate with Ve-cadherin loss. Remarkably, 3-OH-GA treatment of human dermal microvascular endothelial cells leads to disruption of actin cytoskeleton. Local application of 3-OH-GA alone or in combination with VEGF in chick chorioallantoic membrane induces abnormal vascular dilatation and hemorrhage in vivo. The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-D-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1.

Actins↗
PubMed2002

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.

Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.

Adult↗
PubMed1980

Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis.

A boy with glutaric acidemia had psychomotor retardation first noted at age 6 months, recurrent metabolic acidosis, and a progressive quadriparesis with choreoathetosis. He died at age 3 1/2 years. Cultured skin fibroblasts lacked glutaryl-CoA dehydrogenase activity. There was a biochemical, but not a clinical, response to dietary restriction of lysine and tryptophan. The caudate and putamen of the brain showed severe loss of nerve cells and fibers with proliferation of astrocytes, as well as markedly reduced gamma-aminobutyric acid and glutamate decarboxylase activity.

Acidosis↗
PubMed1986

L-carnitine treatment in glutaric aciduria type I.

Patients with organic aciduria may have a higher than normal requirement for L-carnitine. In a patient with type I glutaric aciduria, serum total L-carnitine levels were 8.5 microM (normal, 54.4 +/- 14.2 [2 SD] microM). After treatment with L-carnitine for 1 month, serum levels of both free and total L-carnitine were normal with an acyl-to-total ratio of 0.18. The fractional clearance rates of free and acylcarnitine were increased fourfold by treatment. Acetylcarnitine accounted for a lower than normal percentage of acylcarnitine recovered in serum and urine. Data suggest that this patient may have been carnitine-deficient.

Carnitine↗
PubMed1986

Riboflavin-responsive lipid-storage myopathy and glutaric aciduria type II of early adult onset.

A 17-year-old girl with progressive lipid-storage myopathy for 2 years had low muscle carnitine levels. There was no therapeutic response to prednisone and DL-carnitine-HCl. Chemical findings indicated glutaric aciduria type II. Riboflavin therapy and a fat-restricted, carbohydrate-enriched diet resulted in dramatic improvement. Low carnitine concentrations in plasma and muscle were observed in three asymptomatic sisters who had normal urinary excretion patterns. There was impaired mitochondrial beta-oxidation in cultured skin fibroblasts from the index patient and all three siblings.

Adolescent↗
PubMed2002

Antitumor activities of conjugates of mitomycin C with estradiol benzoate and estradiol via glutaric acid in suspension dosage form.

Conjugates of mitomycin C (MMC) with estradiol bezoate and estradiol via glutaric acid (EB-glu-MMC and E-glu-MMC, respectively) were examined for their antitumor activities against P388 leukemia and sarcoma 180. EB-glu-MMC and E-glu-MMC were suspended in 10% (v/v) propylene glycol in saline and administered intraperitoneally to mice bearing P388 leukemia intraperitoneally or to mice bearing sarcoma 180 subcutaneously. The antitumor effect against P388 leukemia was greater in the order MMC>E-glu-MMC>EB-glu-MMC, and only the former two compounds significantly increased life span. On the other hand, EB-glu-MMC and E-glu-MMC showed suppression of sarcoma 180 growth at higher doses close to or better than MMC. In the mixture of 1/15 M phosphate buffer (pH 7.4, ionic strength (mu) adjusted to 0.3 with NaCl)-propylene glycol (9:1, v/v) at 37 degrees C, MMC was released much more slowly from EB-glu-MMC suspension than from E-glu-MMC suspension. With regard to chemotherapy against sarcoma 180, both conjugates were considered to supply MMC slowly but effectively at higher doses.

Animals↗