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Biomedical subjects

D Rabier

Publications and source records attributed to D Rabier.

At least 19 recordsLinked to original sources
PubMed1992

Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation.

In this paper we report the identification of a new disorder of mitochondrial fatty acid beta-oxidation in a patient which presented with clear manifestations of a mitochondrial beta-oxidation disorder. Subsequent studies in fibroblasts revealed an impairment in palmitate beta-oxidation and in addition, a combined deficiency of long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA-dehydrogenase and long-chain 3-oxoacyl-CoA thiolase. The recent identification of a multifunctional, membrane-bound beta-oxidation enzyme protein catalyzing all these three enzyme activities (Carpenter et al. (1992) Biochem. Biophys. Res. Commun. 183, 443-448; Uchida et al. (1992) J. Biol. Chem. 267, 1034-1041) suggested an underlying basis for this peculiar combination of three enzyme deficiencies. We show by means of size-exclusion chromatography that there is, indeed, a deficiency of the multifunctional beta-oxidation enzyme protein in this patient.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1992

Alpha-ketoglutarate dehydrogenase deficiency presenting as congenital lactic acidosis.

We report an inborn error of the tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase deficiency, in three siblings with hypotonia, metabolic acidosis, and hyperlactatemia immediately after birth. Neurologic deterioration resulted in death at about 30 months of age. We propose low molar ratios of ketone bodies in plasma of neonates with congenital lactic acidosis as an indication of dysfunction of the tricarboxylic acid cycle.

Acidosis, Lactic↗
PubMed1992

Site specific screening for point mutations in ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is a frequent X linked disorder of the urea cycle which is responsible for lethal neonatal hyperammonaemia in males and for various clinical symptoms in heterozygous females. In order to improve the efficiency of our screening for mutant genotypes, we focused on molecular domains of functional or structural importance in the OTC gene, namely the carbamyl phosphate binding domain (encoded by the third exon) and the MspI restriction sites (CCGG) of the coding sequence (located in exons 2 and 7 respectively), as they contain mutation hot spots (CpG doublets). Using this procedure, we were able to identify three new mutant genotypes in OTC deficient children including one nonsense mutation (E 87 K, G 50 ter, G 162 R). Since genetic counselling for OTC deficiency is frequently difficult, molecular screening directed towards specific sites of the coding sequence could allow rapid detection of mutant genotypes and help solve diagnostic problems, especially when carrier status cannot be clarified easily.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

[Amino acids and trisomy 21].

The relative concentrations of plasmatic and urinary amino acids were analysed in 79 trisomic-21 patients, 322 mentally retarded non-trisomic patients, and 206 controls. No true amino acidopathy was found in 21-trisomy, but in plasma a deficit of serine and an excess of cysteine and lysine are highly significant. Excesses of cysteine, methionine, tyrosine, and methyl-histidine are also typical in urine. The increased activity of superoxide-dismutase, cystathionine-beta-synthase, and purine synthesis enzymes, together with the sensitivity to methotrexate, atropine, and dysthyroidism, are in accordance with this shift of equilibrium. A nutritional compensation seems worth investigating.

Amino Acids↗
PubMed1991

Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene.

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of the urea cycle in humans and is responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes. The cosegregation of the trait with a 5.8-kb abnormal MspI fragment in an affected family led us to hypothesize that this unexpected migration pattern was related to the mutation event in this particular family. Using polymerase chain reaction amplification of the specific mRNA derived from a post-mortem biopsy of the liver, we found that the MspI site located in the seventh exon of the gene was abolished and we finally identified a C-to-T transition at codon 225 of the cDNA, changing a proline to a leucine in the protein. Subsequent digestion of amplified exon 7 using the restriction enzyme MspI allowed direct screening for the mutant genotype during the next pregnancy. The present study supports the view that direct detection of the mutant genotype using either Southern blotting or digestion of amplified exons of the gene can contribute to genetic counselling in noninformative families. Finally, since MspI digestions are routinely performed for restriction fragment length polymorphism-based family studies in OTC deficiency, we suggest that the possible presence of the 5.8-kb abnormal fragment should be investigated on Southern blots of affected individuals.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

[Hyperlysinemia and hyperammonemia].

A quite important increase of plasma lysine was often reported in different cases of hyperammonemia. This retrospective study of patients with different types of hyperammonemia shows that hyperlysinemia is not automatically associated to hyperammonemia (lysinemia is expressed as the percent of total aminoacidemia). Hyperlysinemia was observed with neonatal propionic and methylmalonic acidurias. Reye's syndrome and to a less extent with ornithine transcarbamylase deficiency.

Ammonia↗
PubMed1991

[Methodological errors in amino acid assay in biological fluids].

Numerous methodological errors have been observed in the measurement of free-amino acids in the biological fluids. Some of them are related to the presence or the formation of amino acids or ninhydrin-positive compounds in tubes or anticoagulants used for the blood sampling. Hemolysis or blood clotting modify the concentration of some amino acids in plasma. A special error observed with the capillary blood is related to the amino acids present on area of the skin. Bacterial contamination of urines or buffers used for the analysis can also modify the results of the amino acids assays.

Amino Acids↗
PubMed1990

Glycine/serine ratio and the prenatal diagnosis of non-ketotic hyperglycinaemia.

We describe our experience of prenatal diagnosis of non-ketotic hyperglycinaemia in four at-risk pregnancies using the glycine/serine ratio in amniotic fluid obtained between 18 and 20 weeks of gestation. All glycine levels were in the normal range. Serine levels were normal in two patients and borderline in the others. Glycine/serine ratios were normal in two patients, moderately increased in one patient (+3 SD), and highly increased in one patient (+8 SD). All the children were perfectly normal at birth. Because of this false-positive prediction and the false-negative prediction recently reported, we suggest that this unreliable method should not be used.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.

Bayes Theorem↗