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Biomedical subjects

M Duran

Publications and source records attributed to M Duran.

At least 163 records · Page 9Linked to original sources
PubMed1993

[Type D Sanfilippo disease in an 8-year-old boy; a rare cause of mental retardation].

This case report describes the history of an 8-year-old boy of full Dutch extraction with mucopolysaccharidosis type III D (Sanfilippo's syndrome type D). Learning problems started at age 5 years; deterioration is only slow at present, and consistent with most of the cases described in literature. Eight of the nine cases described in the literature so far are known to be of Italian origin. Eye investigations showed bilateral peripheral cataract and a fine diffuse white corneal opacity. Ocular abnormalities of this kind have not been reported before in this type of Sanfilippo's syndrome.

Cataract↗
PubMed1993

L-2-hydroxyglutaric acidaemia: clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase.

L-2-Hydroxyglutaric acidaemia represents a newly defined inborn error of metabolism, with increased levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. The concentration in cerebrospinal fluid is higher than in plasma. The other consistent biochemical finding is an increase of lysine in blood and cerebrospinal fluid, but lysine loading does not increase L-2-hydroxyglutaric acid concentration in plasma. This autosomal recessively inherited disease is expressed as progressive ataxia, mental deficiency with subcortical leukoencephalopathy and cerebellar atrophy on magnetic resonance imaging. Since these features were described in 8 patients by Barth and co-workers in 1992, 4 more patients with similar findings have been diagnosed and added to the present series. L-2-Hydroxyglutaric acid is found in only trace amounts on routine gas chromatographic screening in normal persons, and its origin, its fate and even its relevance to normal metabolism are unknown. Therefore its catabolism was studied in normal liver. Incubation of rat liver with L-2-hydroxyglutaric acid did not produce H2O2, which excluded (peroxisomal) L-2-hydroxyacid oxidase as the main route of catabolism. However, L-2-hydroxyglutaric acid is rapidly dehydrogenated if NAD+ is added as a co-factor to the standard reaction medium. This could also be demonstrated in human liver. The preliminary evidence for this enzyme activity in rats and humans, L-2-hydroxyglutaric acid dehydrogenase, is given. Further investigations are required to clarify the possible relevance to the metabolic defect in L-2-hydroxyglutaric acidaemia.

Adolescent↗
PubMed1993

Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria.

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.

Acidosis, Lactic↗
PubMed1993

Holocarboxylase synthetase deficiency: early diagnosis and management of a new case.

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the "early-onset" form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxpropionic acid and methylcitric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10(-8) mol/l) but normal in a high biotin medium (10(-5) mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%-29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patient's physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.

Biotin↗
PubMed1993

Detection of inborn errors of fatty acid oxidation from acylcarnitine analysis of plasma and blood spots with the radioisotopic exchange-high-performance liquid chromatographic method.

Sixty-one plasma samples from patients with inborn errors of fatty acid oxidation and from control subjects were analyzed in a blinded fashion for acylcarnitines by the radioisotopic exchange-high-performance liquid chromatographic method. All samples from patients with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency (n = 30), some of which had been stored in a frozen state for several years, showed a prominent octanoylcarnitine peak. In all blood spots from 11 patients with MCAD deficiency, octanoylcarnitine was also detected. Control plasma specimens and blood spots contained small amounts of octanoylcarnitine; however, the octanoylcarnitine/acetylcarnitine ratio differentiated patients with MCAD deficiency. Longer-chain acylcarnitines were found in plasma of all three patients with defects in long-chain fatty acid oxidation. Plasma and blood spots from a patient with multiple acyl-coenzyme A dehydrogenase deficiency contained C4-acylcarnitine, hexanoylcarnitine, octanoylcarnitine, and decanoylcarnitine. The results suggest that the method may be highly sensitive in detecting MCAD deficiency and other defects in fatty acid oxidation from plasma or blood spots.

Acyl-CoA Dehydrogenase↗
PubMed1993

A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD).

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are compound heterozygous with G985 in one allele. By sequencing of cloned PCR-amplified MCAD cDNA from a G985 compound heterozygous patient, we identified a C-to-T transition at position 157 as the only change in the entire coding sequence of the non-G985 allele. The presence of the T157 mutation was verified in genomic DNA from the patient and her mother by a PCR-based assay. The mutation changes conserved arginine at position 28 (R28C) of the mature MCAD protein. The effect of the T157 mutation on MCAD protein was investigated by expression of mutant MCAD cDNA in COS-7 cells. On the basis of knowledge about the three-dimensional structure of the MCAD protein, we suggest that the mutation destroys a salt bridge between arginine28 and glutamate86, thereby affecting the formation of enzymatically active protein. Twenty-two additional families with compound heterozygous patients were tested in the PCR-based assay. The T157 mutation was identified in one of these families, which had an MCAD-deficient child who died unexpectedly in infancy. Our results indicate that the mutation is rare. It is, however, noteworthy that a homologous mutation has previously been identified in the short-chain acyl-CoA dehydrogenase (SCAD) gene of a patient with SCAD deficiency, suggesting that the conserved arginine is crucial for formation of active enzyme in the straight-chain acyl-CoA dehydrogenases.

Acyl-CoA Dehydrogenase↗
PubMed1993

Diagnosis of mitochondrial fatty acid oxidation defects.

Inherited defects of mitochondrial beta-oxidation of fatty acids lead to hypoketotic hypoglycemia during prolonged fasting. Affected patients may present with episodes of a Reye-like illness or even sudden child death. The number of currently detected patients with medium-chain acyl-CoA dehydrogenase deficiency--the most common disease in this area--is indicative of a high frequency, possibly comparable to that of phenylketonuria. A comprehensive system of biochemical analyses is described, which enables the differential diagnosis of the various defects. An indispensable part of the diagnostic system is the gas chromatographic/mass spectrometric analysis of plasma and urinary organic acids. A correct diagnosis is a prerequisite for the installment of specific treatment.

Acyl-CoA Dehydrogenase↗
PubMed1992

L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease.

Routine screening for organic acids revealed increased and isolated urinary excretion of L-2-hydroxyglutaric acid in 8 mentally retarded patients from five unrelated families, including three pairs of siblings. L-2-Hydroxyglutaric acid concentration was also found to be increased in the cerebrospinal fluid (CSF) and to a lesser extent in plasma. The only other biochemical abnormality was an increased concentration of lysine, both in plasma and in CSF. No organic acid abnormality was found on screening of asymptomatic family members. Patients were of either sex, and became symptomatic during childhood, with moderate to severe mental deficiency in all and definite cerebellar dysfunction in 7. Magnetic resonance imaging revealed an identical abnormal pattern with subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamina and dentate nuclei, in all patients. No specific biochemical function or catabolic pathway involving L-2-hydroxyglutaric acid is known in mammals, including humans. Preliminary loading and dietary studies failed to reveal the origin of the compound. The elevated CSF/plasma ratio suggests that it is in part generated within the central nervous system. This report describes a novel inherited neurometabolic disease, probably autosomal recessive, with distinct clinical, biochemical, and neuroimaging features.

Adolescent↗
PubMed1992

Enzyme studies on human and snail beta-mannosidase using a fluorescence assay and an HPLC/diode array method with Man beta (1-4)GlcNAc as substrate.

1. Snail beta-mannosidase showed a Km value of 0.05 mM toward MU-beta-Man and could not be inhibited by Man, GlcNAc, Man beta(1-4)GlcNAc, Man beta(1-4)GlcNAc beta(1-N)urea or Man beta(1-4) GlcNAc beta(1-4)GlcNAc. 2. The Km value of the snail enzyme towards Man beta(1-4)GlcNAc, as measured by HPLC, was 10 mM, explaining the lack of inhibition. 3. The Km value of the human serum beta-mannosidase towards MU-beta-Man was 0.3 mM, but the human enzyme was not capable of degrading Man beta(1-4)GlcNAc in detectable amounts.

Animals↗
PubMed1992

Skin collagen changes related to age and hormone replacement therapy.

A total of 76 nulliparous women who had been hospitalized for minor operations, classified according to age group (by decade from 20s to 60s) and 118 postmenopausal women randomly allocated to one of four groups were studied. In all, 312 skin biopsies were taken from the lower abdomen at 0 and 12 months and the skin collagen changes noted. Collagen content decreased significantly with age beyond the 40s (P < 0.001) and after the menopause (P < 0.01). The decrease was preventable by the use of hormone replacement therapy. All the therapeutic regimens induced increases in skin collagen content, whereas in the control group a significant decrease was observed (P < 0.05).

Adult↗
PubMed1992

Diagnosis of medium-chain acyl-CoA dehydrogenase deficiency in lymphocytes and liver by a gas chromatographic method: the effect of oral riboflavin supplementation.

The activity of medium-chain acyl-CoA dehydrogenase (MCAD) with octanoyl-CoA as a substrate was measured in human lymphocytes by a gas chromatographic technique. Phenazine methosulfate was used as the primary electron acceptor. After the addition of crotonase and subsequent hydrolysis, the reaction product 3-hydroxyoctanoic acid was quantitated by capillary gas-liquid chromatography of the trimethylsilyl derivatives. Control subjects had MCAD activities of 3.46 +/- 0.18 nmol/mg protein/min (n = 15). Five patients were investigated while receiving no therapy at all; MCAD activity ranged from 0.08 to 0.23 in four of them and was 0.65 in the fifth one. Subsequent to the long-term administration of 50-150 mg/d of riboflavin to MCAD-deficient patients (n = 11), these activities increased to an average of 0.41 in 10 patients and 2.22 in one. The activities in 15 obligate heterozygotes were 1.91 +/- 0.41 nmol/mg protein/min, thus enabling a clear distinction from controls. Neither heterozygotes nor a control responded to riboflavin. The method was also applicable to postmortem liver tissue. One patient, who had died suddenly and unexpectedly at the age of 19 mo, was correctly diagnosed as MCAD-deficient, whereas five additional children who died of the sudden infant death syndrome showed normal activities.

Acyl-CoA Dehydrogenase↗
PubMed1992

Detection and quantitation of acylcarnitines in plasma and blood spots from patients with inborn errors of fatty acid oxidation.

Acylcarnitine profiling in plasma and dried blood spots by radioisotopic exchange/HPLC demonstrates that MCAD deficiency can be reliably detected in the asymptomatic state without L-carnitine therapy. The OC/AcC ratio differentiates MCAD deficiency from normal controls. A longer chain acylcarnitine (r.t. 43 min.) was detected in all 3 patients with a defect in long chain fatty acid oxidation. Detection of C4- and C5-acylcarnitine isomers in plasma helped characterize a metabolic defect affecting branched chain acyl-CoA oxidation in 3 patients. Quantitative data in 2 patients with MCAD deficiency showed that plasma concentrations of OC and AcC are dependent on both the availability of free carnitine and the severity of metabolic decompensation.

Acyl-CoA Dehydrogenase↗