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J C Deybach

Publications and source records attributed to J C Deybach.

At least 55 records · Page 3Linked to original sources
PubMed1997

Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase.

AIMS: Decreases in plasma alanine transaminase (ALA-T) activity of 20-100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti-epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000-fold difference between its activity against gamma-amino butyric acid aminotransaminase and ALA-T. However, some activity against other transaminases is not unexpected, and it, is important to determine the degree of vigabatrin's effect against ALA-T in man. METHODS: Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA-T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA-T activity was measured before and after a single dose of 1.5 g of vigabatrin. RESULTS: Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA-T, causing an inhibition of enzyme activity of 30-40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. CONCLUSIONS: The clinical significance of these findings is that the levels of ALA-T activity determined in patients receiving vigabatrin may be inaccurate. The "real' values must be assumed to be higher than those reported after routine testing. To obtain the most relistic measurement of ALA-T activity in patiets, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.

Adult↗
PubMed1997

Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France.

OBJECTIVES: Acute intermittent porphyria (AIP) is an autosomal dominant disorder resulting from a 50% deficiency in porphobilinogen deaminase (PBG deaminase). The true prevalence in the general population of mutations in the PBG deaminase gene capable of causing AIP is unknown. However, it is important to identify asymptomatic carriers of AIP mutations because all are at risk to have an acute attack. DESIGN: We measured erythrocyte PBG deaminase from 3350 healthy blood donors. When a clear cut deficiency (< mean minus 2.5 SD) was found, the PBG deaminase gene was analysed by molecular biology technics. SUBJECTS: Four subjects with PBG deaminase deficiency were identified. Two had mutations in the PBG deaminase gene which are known to cause AIP. CONCLUSION: We conclude that, in France, the mutations of the PBG deaminase gene show a high prevalence in the healthy population. If only these two confirmed latent cases are used for the calculation, in France the minimal prevalence of the AIP gene is 1:1675.

Blood Donors↗
PubMed1997

Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria.

Acute intermittent porphyria (AIP) is the major autosomal dominant form of acute hepatic porphyrias. The disease is due to mutations in the gene encoding for porphobilinogen (PBG) deaminase and is characterized by life-threatening neurovisceral attacks, often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases. This report describes a prospective study on the molecular epidemiology of PBG deaminase gene defects in AIP. It uses a sensitive, reliable, and easy-to-handle method for routine AIP molecular diagnosis and family study based on an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing. Fifteen genomic DNA fragments, including all the coding sequence and covering 3.35 kb of the PBG deaminase gene, were investigated in 405 subjects from 121 unrelated French Caucasian AIP families who had not been screened previously at the DNA level. PBG deaminase gene mutations were identified in 109 families, but only 78 were of different type, and each of them had a prevalence rate < 5%. Among these mutations, 33 had not been published previously. Sixty percent of these 78 mutations were located in only three exons (exons 10, 12, and 14), 44% were missense, 18% were splice defect, 19% were frameshift, and 16% were nonsense. In addition, two de novo mutational events were characterized. The evaluation of the efficiency of the standard PBG deaminase enzymatic screening method for gene-carrier detection indicated 95% of concordancy with the molecular-based diagnosis.

Base Sequence↗
PubMed1997

Molecular analysis of porphobilinogen (PBG) deaminase gene mutations in acute intermittent porphyria: first study in patients of Slavic origin.

Acute intermittent porphyria (AIP) is an autosomally dominant inherited metabolic disorders caused by decreased activity of porphobilinogen deaminase, the third enzyme in the human heme biosynthetic pathway. We report here the first mutations in the human porphobilinogen deaminase gene in seven unrelated patients from the Czech and Slovak Republics with acute intermittent porphyria. We used denaturing gradient gel electrophoresis to screen all 15 exons and exon/intron boundaries of the porphobilinogen deaminase gene. Polymerase chain reaction products of abnormal migration patterns were subjected to direct sequencing to identify the causative mutations. Thus we revealed four novel mutations and three which have been previously described. Of the four novel mutations, two were mis-sense (G24S, V267M), one was a single base insertion (158insA) that produced a stop codon 12 codons downstream, and one was a single base substitution in intron 12 (771 + 1) resulting in a splicing defect. The three previously detected mutations were mis-sense mutations (R26C, R26H, G111R). These results suggest a high allelic heterogeneity in Czech and Slovak patients.

Aminolevulinic Acid↗
PubMed1997

Acute intermittent porphyria: rapid molecular diagnosis.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial porphobilinogen (PBG) deaminase deficiency. An exon-by-exon denaturing gradient gel electrophoresis (DGGE) analysis followed by direct sequencing of the DNA fragments was performed to investigate molecular defect in 8 unrelated patients living in south of France: one Algerian, two Moroccan and five French patients. We have optimized the DGGE method in order to study at the same time the fifteen exons of the PBG deaminase gene in only one electrophoresis run. Six different mutations were detected by abnormal mobility patterns. After characterization, a C insertion (716 ins C), 2 deletions (589 del 17 bp; 730 del CT), a non-sense mutation (R149X) and 2 missense mutations (A270G; R173W) were found. The R173W missense mutation was found in 3 unrelated patients, and 716 ins C, 589 del 17 bp and A270G were newly described. According to this small AIP samples, sensitivity of the DGGE screening method was 100%.

DNA↗
PubMed1997

Occurrence of hepatocellular carcinoma in a case of hereditary coproporphyria.

An association between two types of acute hepatic porphyria (porphyria variegata and acute intermittent porphyria) and hepatocellular carcinoma has previously been reported. In these studies, etiological factors for hepatocellular carcinoma were not completely sought. We report here the first case of an association between hepatocellular carcinoma and hereditary coproporphyria, the third type of acute hepatic porphyria. A 58-yr-old woman with hereditary coproporphyria presented with a 3.5-cm-diameter hepatocellular carcinoma. Results of exhaustive investigation of etiological factors for hepatocellular carcinoma were negative. Results of microscopic histological analysis of the nontumorous liver were normal. Five years after surgical resection, the patient had no evidence of tumor recurrence.

Carcinoma, Hepatocellular↗
PubMed1996

Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene.

Variegate porphyria (VP) is an autosomal dominant disorder of heme synthesis caused by a partial deficiency of protoporphyrinogen oxidase (PPOX). Human cDNA encoding PPOX has been recently sequenced and the gene has been cloned, assigned to chromosome 1q23, and its exon/intron organization has been characterized. We report here the complete nucleotide sequence of the Human PPOX gene. Including 660 bp of its promotor region, the PPOX gene spans 5.5 kb. Introns vary in size from 84 bp to 507 bp. Two exonic and 3 intronic biallelic sequence variations have been characterized.

Amino Acid Sequence↗
PubMed1996

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.

Acetylserotonin O-Methyltransferase↗
PubMed1996

Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.

Variegate porphyria (VP) is an acute hepatic porphyria with autosomal dominant inheritance due to a partial deficiency of protoporphyrinogen oxidase (PPOX) activity. The molecular defect responsible for VP was investigated by sequencing PPOX gene coding sequence from four patients in three unrelated VP families of French Caucasian origin. In a first patient, a point insertion of a G at position 1022 of the cDNA, produced a frameshift resulting in a premature stop codon. In three other patients from two unrelated families we found a missense point mutation leading to glycine to arginine substitution (G232R) in exon 7. This Gly232 appears to be a strictly conserved residue through evolution. In one VP family, we observed the cosegregation of the G232R missense mutation and the deficient PPOX activity. The mutations reported here are the first to be described in patients with VP and support the conclusion that PPOX gene defects are disease causing mutations in human variegate porphyria.

Amino Acid Sequence↗
PubMed1996

Review: molecular pathogenesis of hepatic acute porphyrias.

The molecular cloning of cDNA and genes encoding enzymes of the haem biosynthetic pathway have permitted the genetic defects underlying acute intermittent porphyria (AIP) and hereditary coproporphyria to be unravelled. In AIP, many different gene abnormalities have been documented since 1989. The prevalence of specific defective alleles among AIP families depends on which human population is studied. Founder effects are likely to account for a high frequency of a single mutation in Finland and, to a lesser extent, in Holland, while many other mutations have only been found once, each of them in a single family. In hereditary coproporphyria several different mutations have already been identified since 1994, suggesting that a large allelic heterogeneity also exists. The search for mutations in variegate porphyria has just started since the recent publication of the human cDNA sequence. Direct detection of the mutations using DNA analysis brings a growing contribution to the detection of asymptomatic carriers among relatives of porphyric patients and will, therefore, improve the prevention of acute attacks.

Animals↗
PubMed1996

Detection by PCR of Toxoplasma gondii in blood in the diagnosis of cerebral toxoplasmosis in patients with AIDS.

The polymerase chain reaction (PCR) for amplification of Toxoplasma gondii DNA was performed prospectively in the blood of 19 patients with AIDS and cerebral toxoplasmosis. The B1 gene and TGR1E sequence were used as targets and results were confirmed by hybridisation. Controls consisted of 24 HIV infected patients with tissue culture proven T gondii parasitaemia and 57 HIV infected patients without toxoplasmosis. PCR was positive with both targets in 20 of 24 samples (84%) from patients with parasitaemia. Three of 57 samples (5%) from patients without toxoplasmosis were PCR positive with either target, but none was positive with both targets. Only three of the 19 patients (16%) with cerebral toxoplasmosis had a positive PCR with both targets before the start of specific treatment. PCR performed in blood is of little diagnostic value in cases of cerebral toxoplasmosis but could be useful in patients with disseminated infection.

AIDS-Related Opportunistic Infections↗
PubMed1996

Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.

Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency. EPP is generally considered to be transmitted as an autosomal dominant disease with incomplete penetrance, although autosomal recessive inheritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients than in asymptomatic carriers, suggesting a more complex mode of inheritance. To account for these findings, we tested a multiallelic inheritance model in one EPP family in which the enzymatic data were compatible with this hypothesis. In this EPP family, the specific FC gene mutation was an exon 10 skipping (delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of all FC alleles within the family was followed using the delta Ex10 mutation and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from each FC allele were then subjected to relative quantification by a primer extension assay and to absolute quantification by a ribonuclease protection assay. The data support the hypothesis that in this family the EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele.

Base Sequence↗
PubMed1995

Variegate porphyria: diagnostic value of fluorometric scanning of plasma porphyrins.

Variegate porphyria (VP) is a dominantly inherited acute hepatic porphyria characterized by a 50% decrease in activity of protoporphyrinogen oxidase (PO) which catalyses the last step of heme biosynthesis. In VP families, most of the gene carriers are asymptomatic but at risk of developing acute attacks if subjected to precipitating factors. Recognition of the carrier status is the first step of an efficient preventive care. This could be achieved by measurement of PO activity which is a sensitive and specific but tedious method. A specific plasma fluorometric emission at 626 nm has been shown in VP patients. Here we show that this simple and inexpensive method is specific but poorly sensitive, especially in detection of asymptomatic carriers. We conclude that this procedure should not replace PO activity measurement in VP family studies.

Adolescent↗
PubMed1995

Porphobilinogen deaminase gene structure and molecular defects.

Porphobilinogen deaminase (PBGD) is the third enzyme of the heme biosynthetic pathway. The half-normal activity of human PBGD causes acute intermittent porphyria (AIP), an autosomal dominant inherited disease. Two PBGD isoforms, one ubiquitous and one erythroid specific, are encoded by a single gene localized to chromosomal region 11q24.1-11q24.2. The 10-kb PBGD gene comprises 15 exons and two distinct promoters initiate the ubiquitous and the erythroid transcripts by alternative splicing. In AIP, diagnosis of asymptomatic heterozygotes is crucial to prevent occurrence of life-threatening acute attacks by avoiding known precipitating factors. Difficulties with the biochemical diagnosis could be overcome by the ability to identify the PBGD gene defects in AIP patients. Mutational analysis of the PBGD gene or the use of intragenic polymorphisms offer accurate identification of the gene carriers. To date, 58 mutations and 10 polymorphisms have been reported at the PBGD locus. The great heterogeneity of the mutations in AIP patients requires appropriate screening and diagnostic strategies to identify gene defects in AIP families.

Animals↗
PubMed1995

A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria.

Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E. coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed.

Amino Acid Sequence↗
PubMed1994

Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.

Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by mutations of the gene coding for porphobilinogen deaminase (PBGD). Until now, sixteen different mutations have been described. In an effort to investigate further the molecular epidemiology of AIP, we have undertaken a systematic study of different exons of the PBGD gene from a large number of unrelated patients. Here, we have examined seven of the fifteen exons of the gene from 43 unrelated Dutch and French AIP patients using denaturing gradient gel electrophoresis after polymerase chain reaction amplification. Eleven new mutations were found, accounting for the enzymatic defect in about half of the patients. This study further documents the molecular heterogeneity of the mutations responsible for AIP and describes an efficient strategy to detect the mutations in patients with previously unknown abnormalities.

Base Sequence↗
PubMed1994

[Hepatic porphyria: diagnostic and therapeutic strategies].

Acute hepatic porphyrias are genetic diseases of heme synthesis with severe prognosis due to strong or acute abdominal pain and neurological complications. Clinical evolution is characterized by acute attacks frequently induced by either forbidden drugs, or infections, alcohol intake or often unknown factors. Modern treatment is perfusion of hematin, which is a stable form of heme. Hematin will induce again delta-aminolévulinic (ALA)-synthase synthesis repression. Its tolerance is perfect whereas clinical and biochemical efficiency is absolute in our experience, if initiated very early. This drug is now considered as the treatment of acute intermittent porphyria crises.

Acute Disease↗