Glutaric aciduria: Biochemical and morphologic considerations

Goodman, Stephen I.; Norenberg, Michael D.; Shikes, Robert H.; Breslich, Diana J.; Moe, Paul G.

doi:10.1016/s0022-3476(77)81240-7

Cited by 192 publications

(140 citation statements)

References 16 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Besides is seen in most cases. The present report, together with a recent report of Goodman et al (7), indicates that glutaryl-CoA dehydrogenase deficiency (glutaric aciduria) may present ketotic episodes, similar to those of the other organic acidurias.…”

Section: Speculationsupporting

confidence: 82%

Ketotic Episodes in Glutaryl-CoA Dehydrogenase Deficiency (Glutaric Aciduria)

Gregersen

Brandt

1979

Pediatr Res

View full text Add to dashboard Cite

Summawthe ketoacidosis, a pronounced lactic acidosis and lactic aciduria A 7-yr-old boy with glutaryl-CoA dehydrogenase deficiency (glutaric aciduria), presenting periodic episodes of lethargy and ketosis, was studied during two such episodes. The urinary excretions of glutaric and 3-OH-glutaric acids were 3100-7900 and 460-660 &mg creatinine, respectively, during these episodes. Urine samples collected before and after the attacks contained 100-5300 and 230-370 &mg creatinine of glutaric acid and 3-OH-glutaric acids, respectively. During the episodes, glutaconic acid excretion rose from 14-89 to 93-630 pg/mg creatinine. Adipic acid and suberic acid excretions were increased from 17-100 and 2-13 to 74-224 and 16-32 &mg creatinine, respectively. The excretions of conjugates of propionic, isobutyric, 2-Me-butyric, and isovaleric acids, outside and during the attacks, respectively, were: propionic acid, 7-13 and 5-19 &mg creatinine isobutyric acid, 1-7 and 3-15 pg/mg creatinine; 2-Me-butyric acid, 2-9 and 4-34 pg/mg creatinine; isovaleric acid, 0-6 and 3-11 pg/mg creatinine. The excretion of total 2-0x0-acids was increased from 0-12 to 29-75 pg/mg creatinine during the episodes. It is argued that one or more compounds, accumulated as a result of the primary glutarylCoA dehydrogenase deficiency, inhibit the oxidation of the branched-chain amino acids and the fatty acids. During excessive catabolism of amino acids and fatty acids this inhibition results in accumulation of metabolites that are excreted in the urine as conjugates and C6-Clodicarboxylic acids, respectively. Short-and medium-chain monocarboxylic acids are known to affect energy metabolism, and it is, therefore, argued that the short-chain monocarboxylic acids, shown to be accumulated in the patient during the ketotic episodes, may have some pathophysiologic significance. SpeculationKetotic episodes with lethargy and severe hypotonia are another feature of glutaric aciduria due to glutaryl-CoAdehydrogenase deficiency. During such episodes inhibition of the metabolism of branched-chain amino acids and fatty acids, secondary to the inability to metabolize glutaric acid, causes accumulation of branched short-chain monocarboxylic acids and of short-and medium-chain dicarboxylic acids.Straight short-and medium-chain fatty acids influence the mitochondria1 energy metabolism, and it is, therefore, speculated that the short-chain monocarboxylic acids, indicated in the present report to be accumulated in the mitochondria of the patient, contribute to the pathophysiology of the ketotic states.Severe ketoacidotic episodes are a well known feature in a number of the organic acidurias. Patients with propionic, isovaleric, and methylmalonic acidurias are often subject to recurrent crises induced by high protein intake or by infections (13,15,21). The clinical and biochemical presentations of these crises resemble one another closely: vomiting and lethargy followed by neurologic symptoms eventually leading to coma, and often to death. Besides is seen in most cases. The ...

show abstract

Section: Speculationsupporting

confidence: 82%

Ketotic Episodes in Glutaryl-CoA Dehydrogenase Deficiency (Glutaric Aciduria)

Gregersen

Brandt

1979

Pediatr Res

View full text Add to dashboard Cite

show abstract

“…The organic acids that accumulate are potential neuronal and mitochondrial toxins (29,30). Post mortem studies (11)(12)(13) and one brain biopsy (23) demonstrated that GA and 3-OH-GA concentrations are 10-to 1000-fold higher in brain tissue than in plasma and are found in a similar concentration range in high and low excretors. These results suggest there is de novo synthesis of GA and 3-OH-GA in the brain and because transport of dicarboxylic acids across the blood brain barrier is strongly limited these acids are trapped.…”

Section: Discussionmentioning

confidence: 99%

“…GCDH is a key enzyme in the degradative pathways of L-lysine, L-hydroxylysine, and L-tryptophan (8 -10). The biochemical hallmark is an accumulation of GA and 3-OH-GA, in particular in the CNS (11)(12)(13). These pathologic dicarboxylic acids and their corresponding carnitine (glutaryl carnitine) and glycine ester (glutaryl glycine) can be detected Abbreviations: GA, glutaric acid; GCDH, glutaryl-CoA dehydrogenase (EC 1.3.99.7); MS/MS, tandem mass spectrometry; 3-OH-GA, 3-hydroxyglutaric acid by gas chromatography/mass spectrometry in body fluids (14), or MS/MS in dried blood spots (15,16).…”

mentioning

confidence: 99%

Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

et al. 2006

View full text Add to dashboard Cite

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n ϭ 218) or presymptomatically by neonatal screening (n ϭ 23), high-risk screening (n ϭ 24), or macrocephaly (n ϭ 14). Most symptomatic patients (n ϭ 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

show abstract

“…Poor weight gain and chronic regurgitation persisted and he died at the age of 5 months, with autopsy showing severe fatty changes in the liver, kidneys, and skeletal and cardiac muscle. No changes were noted in the basal ganglia (13). (The amount of protein given the child after diagnosis is in question; the diet prescribed contained 1.2-1.4 g/kg/day but the amount given may have been half that.…”

mentioning

confidence: 99%

“…While activity of glutaryl-movement disorder (dystonia, athetosis, etc. ), increased excretion CoA dehydrogenase was completely deficient in liver and almost of glutaric, glutaconic, and P-hydroxyglutaric acids, and chronic completely so in kidney, it was normal in cultured fibroblasts in degeneration of the caudate and putamen (13,15,20), and which the presence of flavin adenine dinucleotide (FAD) and only mar-is due to recessively inherited deficiency of glutaryl-CoA dehyginally low in its absence. Incorporation of D-(~-'~C) riboflavin drogenase into flavin mononucleotides (FMN) and FAD by kidney tissue was The purpose of this paper is to report biochemical studies in a normal.…”

mentioning

confidence: 99%

Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria Type II) with Transient Hypersarcosinemia and Sarcosinuria; Possible Inherited Deficiency of an Electron Transfer Flavoprotein

et al. 1980

Self Cite

View full text Add to dashboard Cite

Summarywith the urinary excretion of large amounts of glutaric acid and smaller, albeit also abnormal, quantities of a-hydroxyglutaric, When acids were infused at a rate d k d d a y , an ethylmalonic, lactic, isobutyric, isovaleric, and a-methylbutyric infant with hypoglycemia, metabolic acidemia and chronic regur-acids. older male sibling had died of a clinically similar gitation hypersarcOsinemia and excreted disorder. Intact fibroblasts from the patient metabolized valine, ~~o u n t s of sarcosine, isovalerylgl~cine, isobut~r~lgl~cine, a-meth-isoleucine, leucine, and glutaric acid at reduced rates, while oxiylbutyrylglycine, and fl-hydroxyis0valeric, glutaric, a-h~drox~glu-dation of pyruvic acid was normal. As these findings were contaric, methylsuccinic, and a-hydroxyisobutyric acids in urine. On sistent with simultaneous deficiency of several ~~~-all other occasions, when protein intake was lower and lipid intake enzymes, an of either FAD synthesis or the electron higher, urine organic acids were dominated by methylsuccinic, transport chain was suggested as the possible site of a primary ethylmalonic, and a-hydroxyglutaric acids, and hypersarcosinemia gene defect (24). was absent. Autopsy showed severe fatty changes in liver, kidneys, The type II designation was meant to distinguish this condition and skeletal muscle. A previous female sibling had died with from glutaric aciduria, a condition is associated with a similar autopsy findings at 4 days of age. While activity of glutaryl-movement disorder (dystonia, athetosis, etc.), increased excretion CoA dehydrogenase was completely deficient in liver and almost of glutaric, glutaconic, and P-hydroxyglutaric acids, and chronic completely so in kidney, it was normal in cultured fibroblasts in degeneration of the caudate and putamen (13,15,20), and which the presence of flavin adenine dinucleotide (FAD) and only mar-is due to recessively inherited deficiency of glutaryl-CoA dehyginally low in its absence. Incorporation of D-(~-'~C) riboflavin drogenase into flavin mononucleotides (FMN) and FAD by kidney tissue was The purpose of this paper is to report biochemical studies in a normal.child with the organic aciduria of glutaric aciduria type I1 inThe authors conclude that this disorder is not due to generalized whom transient hypersarcosinemia and sarcos,nu,.ia were also deficiency glutaryl-COA dehydrOgenase Or a defect in FAD detected. The results presented indicate that the disorder is not synthesis. The amino and organic acid abnormalities noted are due to generalized deficiency o f g l u t a r y l -~o~ dehydrogenase and most consistent with a defect in the flavoprotein which transfers not to a block in FAD synthesis. *lthough the specific the FAD sarcOsine and acy'-COA dehydrOgenases cause of the disease remains obscure, the results are most consistent into the respiratory chain, although a defect in intercompartmental with a defect of the electron transfer flavoprotein which transfers transfer of C4-5 acyl CoA esters across cell membranes is not electrons fr...

show abstract

Glutaric aciduria: Biochemical and morphologic considerations

Cited by 192 publications

References 16 publications

Ketotic Episodes in Glutaryl-CoA Dehydrogenase Deficiency (Glutaric Aciduria)

Ketotic Episodes in Glutaryl-CoA Dehydrogenase Deficiency (Glutaric Aciduria)

Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria Type II) with Transient Hypersarcosinemia and Sarcosinuria; Possible Inherited Deficiency of an Electron Transfer Flavoprotein

Contact Info

Product

Resources

About