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Biomedical subjects

C R Roe

Publications and source records attributed to C R Roe.

At least 73 records · Page 4Linked to original sources
PubMed1990

2,4-Dienoyl-coenzyme A reductase deficiency: a possible new disorder of fatty acid oxidation.

Several inherited disorders of fatty acid beta-oxidation have been described that relate mainly to saturated precursors. This study is the first report of an enzyme defect related only to unsaturated fatty acid oxidation and provides the first in vivo evidence that fat oxidation in humans proceeds by the reductase-dependent pathway. The patient was a black female, presenting in the neonatal period with persistent hypotonia. Biochemical studies revealed hyperlysinemia, hypocarnitinemia, normal organic acid profile, and an unusual acylcarnitine species in both urine and blood. The new metabolite was positively identified by mass spectrometry as 2-trans,4-cis-decadienoylcarnitine, derived from incomplete oxidation of linoleic acid. In spite of dietary therapy, the patient died of respiratory acidosis at four months of age. Samples of liver and muscle from the autopsy were assayed for 2,4-dienoyl-coenzyme A reductase activity. Using the substrate 2-trans,4-cis-decadienoylcoenzyme A, the reductase activity was 40% of the control value in liver and only 17% of that found in normal muscle. It is suggested that unsaturated substrates should be used for in vitro testing to cover the full range of potential beta-oxidation defects and that acylcarnitine species identification be used for in vivo detection of this disorder.

Fatty Acid Desaturases↗
PubMed1990

Electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency in an adult.

A 19-year-old woman with mild myopathic symptoms from age 6 and fasting intolerance presented with a Reye-like syndrome and a myopathy. Investigations disclosed a lipid storage myopathy, type II glutaric acidemia, and carnitine deficiency in skeletal muscle. Riboflavin and carnitine treatment corrected the metabolic abnormalities and she improved clinically. She later died from pulmonary complications secondary to aspiration. Subsequent studies established electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency (fibroblast ETF:QO activity was 2.9 mU/mg, normal range is 14.1 +/- 3.8 mU/mg) as the cause of her illness. This is the first documented case of ETF:QO diagnosed in an adult.

Acidosis↗
PubMed1990

Carnitine homeostasis in the organic acidurias.

The detection of acylcarnitines by FAB-MS in human physiological fluids has added another valuable diagnostic tool for the recognition of specific metabolic diseases. The newly developed technique of FAB-MS/MS, which embodies the principles of tandem mass spectrometry, affords a quantum leap in specificity, enabling the detection and quantification of acylcarnitines in concentrations well within the physiological ranges in urine, blood and tissue. The therapeutic use of L-carnitine appears to offer protection against the harmful consequences of catabolism. A reduction in the number of clinical episodes requiring hospitalization has been observed in most cases. When such occurrences have necessitated intravenous fluids, the addition of L-carnitine to the IV infusate has led to dramatic reduction in recovery times. It has also been shown that there is no discernable toxicity associated with carnitine therapy, even under high-dose IV conditions.

Carnitine↗
PubMed1989

Application of fast atom bombardment with tandem mass spectrometry and liquid chromatography/mass spectrometry to the analysis of acylcarnitines in human urine, blood, and tissue.

Using a precursor-ion scan function on a triple quadrupole mass spectrometer, acylcarnitines were detected in the target matrices at or below concentrations of 1 nmol per gram by fast atom bombardment mass spectrometry. Acylcarnitine profiles from patients with known metabolic disorders were consistent with previously acquired data. Putative acylcarnitine signals were confirmed in one case by administration of stable isotope-labeled carnitine, which equilibrated rapidly with the endogenous pool. The addition of a continuous flow system enabled rapid sequential analysis without operator intervention, indicating the potential for automation of the analytical procedure. Incorporation of a micro-LC column enabled on-line liquid chromatographic/mass spectrometric analysis of selected patient samples. Large-scale screening and quantitative analysis of urine or blood for diagnostic acylcarnitines are now practicable.

Acylation↗
PubMed1989

Parenteral nutrition in propionic and methylmalonic acidemia.

Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino acid metabolism often complicated by chronic anorexia and vomiting, are not usually treated with parenteral nutrition for fear of amino acid overload and exacerbation of biochemical derangements, we gave long-term parenteral nutrition to two critically ill patients with these disorders. Health and growth were restored, and there was minimal production of abnormal metabolites. The dramatic clinical and biochemical improvement of these patients bolsters the concept that most of the toxic metabolites produced in these diseases are not related to the administered load of nutrient precursors, but rather to endogenous turnover of amino acids, particularly during a chronic catabolic state. Suppression of catabolism can produce striking biochemical and clinical improvement. With appropriate monitoring, parenteral nutrition can be used safely in the management of patients with these disorders.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

Acute profound dystonia in infants with glutaric acidemia.

Acute profound dystonia developed in three previously well infants who were found to have glutaryl-CoA dehydrogenase deficiency in cultured skin fibroblasts. Two patients had excessive urinary excretion of glutaric acid, but one did not. Neuroradiologic studies performed in all three patients at the onset of their illnesses revealed large CSF-containing spaces both within the sylvian fissures and anterior to the temporal lobes. Pathologic examination of the brain of one patient demonstrated cerebral and cerebellar atrophy, shrinkage of the putamen, and white matter vacuolation. Glutaric acidemia may be a common cause of acquired persistent dystonia or choreoathetosis in infancy.

Atrophy↗
PubMed1988

Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria.

The use of hydroxocobalamin (OH-B12), betaine, carnitine, and folinic acid were studied in two children with the cobalamin C form of methylmalonic acidemia and homocystinuria. When daily injections of 1 mg OH-B12 were discontinued for 3 weeks, there was no significant change in total plasma homocysteine or methionine levels and only a modest increase in methylmalonate. Orally administered OH-B12 1 mg/d in one patient was associated with an increase in plasma homocystine and a decrease in methionine within 1 month. Withdrawal of betaine 250 mg/kg/d was also associated with a rise in plasma homocystine and a fall in methionine levels. Carnitine 100 mg/kg/d lead to an increase in urinary excretion of propionylcarnitine, but did not affect plasma methylmalonate levels. No beneficial biochemical effect of folinic acid could be documented at a dose of 25 mg/d. Our results suggest that daily injections of OH-B12 are not necessary to maintain metabolic control and that orally administered OH-B12 is unlikely to be effective. Betaine appears to act synergistically with OH-B12 and should be part of the treatment regimen. Although there are theoretical reasons for using L-carnitine and folinic acid, we could not document their effectiveness in these two patients.

Administration, Oral↗
PubMed1987

Characterization of new diagnostic acylcarnitines in patients with beta-ketothiolase deficiency and glutaric aciduria type I using mass spectrometry.

Direct analysis of unpurified urine from patients with beta-ketothiolase deficiency and glutaryl-coenzyme A dehydrogenase deficiency was carried out by methylation and fast atom bombardment mass spectrometry. Previously unidentified signals consistent with unusual acylcarnitines were detected. In the former disease, thermospray liquid chromatography/mass spectrometry analysis confirmed the identification of tiglylcarnitine and differentiated it from a biological isomer, 3-methylcrotonylcarnitine. In glutaric aciduria, glutarylcarnitine was confirmed by detection of glutaric acid liberated upon base hydrolysis of a purified acylcarnitine fraction. The discovery of these metabolites suggests that L-carnitine therapy might be beneficial for the enhanced excretion of toxic metabolites that accumulate in patients with these disorders.

Acetyl-CoA C-Acyltransferase↗
PubMed1987

Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia.

A patient with isovaleryl-coenzyme A dehydrogenase deficiency was given a synthetic oral feed containing L-(2H3-methyl)-leucine of high isotopic purity as the only dietary precursor to the defective enzyme. Metabolites derived from this source were readily distinguished from their unlabeled endogenous counterparts by mass spectrometry. During 6 consecutive days of labeled leucine ingestion, the average daily excretion of labeled metabolites was only about 10% of the total derived from leucine. It is suggested that therapy should be directed toward the control of endogenous protein turnover rather than the restriction of dietary protein intake.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reye-like syndromes.

The medium-chain acyl-CoA dehydrogenase (MCAD) deficiency of mitochondrial beta oxidation has been identified in two asymptomatic siblings in a family in which two previous deaths had been recorded, one attributed to sudden infant death syndrome and the other to Reye syndrome. Recognition of this disorder in one of the deceased and in the surviving siblings was accomplished by detection of a diagnostic metabolite, octanoylcarnitine, using a new mass spectrometric technique. This resulted in early treatment with L-carnitine supplement in the survivors, which should prevent metabolic deterioration. Further studies suggest that breast-feeding may be protective for infants with MCAD deficiency. Families with children who have had Reye syndrome or in which sudden infant death has occurred are at risk for MCAD deficiency. We suggest that survivors and asymptomatic siblings should be tested for this treatable disorder.

Acyl-CoA Dehydrogenase↗
PubMed1986

Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

Deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) lyase affects the metabolism of leucine as well as ketogenesis. This disorder is one of an increasing list of inborn errors of metabolism that presents clinically like Reye's Syndrome or nonketotic hypoglycemia. Four patients with proven 3-hydroxy-3-methylglutaryl-CoA lyase deficiency were shown to excrete a new diagnostically specific metabolite. The technique of fast atom bombardment and tandem mass spectrometry revealed that only 3-methylglutaryl-CoA is a substrate for acylcarnitine formation. Neither 3-methylglutaconyl-CoA nor 3-hydroxy-3-methylglutaryl-CoA are excreted as acylcarnitines. The excretion of 3-methylglutarylcarnitine may explain, in part, the apparent secondary carnitine deficiency in this disorder. Carnitine supplementation with moderate dietary restrictions may be a useful treatment strategy for this disorder.

Amino Acid Metabolism, Inborn Errors↗