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Biomedical subjects

Y Nordmann

Publications and source records attributed to Y Nordmann.

At least 19 recordsLinked to original sources
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

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

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↗
PubMed1994

Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms.

Coproporphyrinogen oxidase is a mitochondrial heme-biosynthetic enzyme that converts coproporphyrinogen to protoporphyrinogen. Inherited deficiency of this enzyme causes the human genetic disease hereditary coproporphyria. Recently, we isolated, sequenced and expressed the cDNA encoding human coproporphyrinogen oxidase. This allowed us to investigate the nature of the defect leading to a profound deficiency of coproporphyrinogen oxidase in a patient with homozygous hereditary coproporphyria. Using reverse-transcription, amplification of the cDNA and direct sequencing of the amplified products, we found a point mutation resulted in an arginine to tryptophane substitution (R231W). Expression studies of normal and mutated cDNAs in a bacterial system demonstrated that this substitution resulted in the synthesis of an unstable protein with a residual catalytic activity. This is the first mutation to be found at the coproporphyrinogen oxidase locus. Furthermore, three common polymorphisms within the coproporphyrinogen oxidase gene were detected. Two DNA polymorphisms resulted in amino acids changes (H172N and V194I) and the third one was silent (E230E).

Amino Acid Sequence↗
PubMed1994

A case of association between hepatocellular carcinoma and porphyria variegata.

BACKGROUND: A correlation between acute intermittent porphyria or porphyria cutanea tarda and hepatocellular carcinoma (HCC) has been noted in several studies, but only one case of association between HCC and porphyria variegata has been reported. We therefore report another case of association between HCC and porphyria variegata. METHODS: A 54-year-old nurse with familial porphyria variegata who developed an HCC was studied. The diagnosis of porphyria variegata was made in the course of a familial survey by means of measuring lymphocyte protoporphyrinogen oxidase activity, at a time when the patient had no symptoms. Eighteen years later the patient presented with a firm enlargement of the liver. RESULTS: Histologic examination showed a well-differentiated HCC. The diagnosis was confirmed by positive immunostaining for alpha-foetoprotein antibodies. DISCUSSION: Sixteen months after surgical resection of the HCC the patient was still alive.

Carcinoma, Hepatocellular↗
PubMed1993

Early administration of heme arginate for acute porphyric attacks.

BACKGROUND: We investigated the efficacy of early administration of heme arginate in acute porphyric attacks. METHODS: The series consisted of 51 consecutive acute attacks in 22 patients with acute intermittent porphyria and in two patients with variegate porphyria referred to a hospital in France or in Finland. Four attacks were associated with pareses, and 47 attacks were not. Heme in a dose of 250 mg or 3 mg/kg was started within 24 hours after admission in 37 (72.5%) of the attacks and within 4 days in 49 (96%) of the attacks. During all except five attacks, four daily infusions were given. RESULTS: The mean (+/- SD) duration of abdominal or nonabdominal pain was 2.5 +/- 0.97 days, and opiates were stopped an average of 2.8 +/- 0.72 days after the first heme infusion was started. All patients responded. In 46 (90%) of the attacks, the total hospitalization time was 7 days or less. The mean urinary excretion of porphobilinogen decreased to 16.2% +/- 7.7% and that of 5-aminolevulinic acid to 11.6% +/- 5.6% of pretreatment values. The only side effect was moderate thrombophlebitis in one patient. CONCLUSION: Favorable responses in every attack suggest specific effects of heme. In patients with acute attacks, heme therapy should be started immediately on admission.

Adult↗
PubMed1993

Ferrochelatase structural mutant (Fechm1Pas) in the house mouse.

The molecular basis of an inherited defect of ferrochelatase in mouse (Fechm1Pas/Fechm1Pas, described by Tutois et al., 1991, J. Clin. Invest. 88:1730-1736) was investigated. cDNA clones encoding ferrochelatase, isolated by amplification of the mRNA from the liver of a mutant mouse using the polymerase chain reaction, were sequenced by the dideoxynucleotide chain-termination method. All the clones carried a T to A transversion at nucleotide 293, leading to a methionine to lysine substitution at position 98 in the protein (mutation M98K). Hybridization with allele-specific oligonucleotides (ASOs) confirmed the mutation at the cDNA and genomic levels. Finally, expression of the mutant ferrochelatase protein in E. coli demonstrated a marked deficiency in activity in agreement with the activity of the deficient enzyme in vivo. This Fechm1Pas/Fechm1Pas mutant mouse represents a useful model for studying the pathophysiological feature of the human disease and the first accessible model for gene therapy in the field of porphyrias.

Animals↗
PubMed1993

High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a deficiency of porphobilinogen deaminase (PBGD). Up to now 14 different mutations have been described. In an effort to investigate 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, exon 8 from 82 unrelated Dutch and French AIP patients was examined using single strand confirmation polymorphism analysis (SSCP) after polymerase chain reaction (PCR) amplification. A single base mutation, C to T, at position 346 of the sequence coding for PBGD was observed in 15 Dutch families but in only 1 French family. A simple PCR assay is described to facilitate the diagnosis of this common mutation at the DNA level.

Base Sequence↗
PubMed1993

Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks.

Acute intermittent porphyria (AIP) is a hereditary disease characterized biochemically by a defect in the heme pathway enzyme porphobilinogen deaminase. There is wide variability in the neurologic clinical expression of AIP, and the disorder remains latent in most gene carriers. The natural history of the disease and results in a porphyric rat model suggest a significant relationship between tryptophan metabolites and clinical expression of the disease. In the present study, we examined urine and blood tryptophan metabolite levels in AIP women before, during and after acute attacks and treatment by heme arginate. Heme arginate treatment promptly decreased total tryptophan levels (from 69 +/- 9, to 44 +/- 5, mean +/- SEM, mumole/l, p < 0.001), serotonin blood levels (from 629 +/- 103, to 356 +/- 80, nmole/l, p < 0.01) and the urinary excretion of 5-HIAA (from 3.9 +/- 0.6, to 2.2 +/- 0.4, mumole/mmole creatinine, p < 0.01). The plasma level of melatonin was found much lower than the normal control level at night (86.2 +/- 70.3, vs the normal range, 409 +/- 78.9, pmole/l +/- SEM) and day time (38.8 +/- 22.0, vs 75 +/- 13.7). Heme arginate treatment did not influence melatonin levels. Our results support the involvement of abnormal tryptophan metabolism in the pathophysiology of AIP acute attacks. Low melatonin plasma levels in porphyric women suggest that the defect of the pineal hormone may be responsible for the recurrent aspect of porphyric attacks. A desynchronization of biological rhythms in AIP patients may increase the inducibility of hepatic ALA synthase to environmental risk factors and, specially, to sex steroid hormones.

Adult↗
PubMed1993

Biochemical diagnosis of a fatal case of Günther's disease in a newborn with hydrops foetalis.

The birth of a male baby was induced at 32 weeks. In utero, the child presented, inter alia, signs of hydrops, hepatosplenomegaly and anaemia. Two in utero transfusions for correction of the anaemia were performed at 28 and 29 weeks, respectively. The baby rapidly presented respiratory distress with mixed acidosis. Three hours after birth, pink urine was excreted. Signs of icterus necessitated phototherapy, after which photosensitivity occurred. Erythrocytes were fluorescent under long-wavelength UV light. The baby died 24 hours after birth, displaying severe acidosis, a diffuse haemorrhagic syndrome, and repeated brady-cardia which did not respond to isoprenaline. The analysis of porphyrins in urine, blood and faeces of the baby gave the following results: 1) uroporphyrin (I and III isomeric series) was increased in urine and faeces, with traces in erythrocytes and plasma; 2) heptacarboxyporphyrin I was found mainly in urine and much less in erythrocytes, plasma and faeces; 3) coproporphyrin I was increased in urine, erythrocytes, plasma and faeces, and 4) 5-aminolaevulinic acid and porphobilinogen in urine and plasma were within the reference ranges. Determination of the enzymes of haem biosynthesis in erythrocytes and lymphocytes showed that both parents possessed only 50% of the normal activity of cosynthase. A previously described point mutation in codon 73 was observed in one parent. Fatal cases of neonatal Günther's disease are extremely rare and such an observation, according to our knowledge, is probably one of the first described.

Aminolevulinic Acid↗
PubMed1993

[Acute attacks of hepatic porphyria: specific treatment with heme arginate].

Severe hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are hereditary diseases. Each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of heme biosynthesis. Acute attacks are very serious: the abdominal pains are severe and the neurological manifestations can lead to death or incomplete recovery with irreversible sequelae (usually paralysis). Since 1985, the prognosis of acute attacks has been greatly improved by the introduction of heme-arginate. The 69 acute attacks (30 patients, 4 men and 26 women) that we treated with heme-arginate between 1988 and 1991 are described in this report. All patients were infused with 250 mg/d of heme-arginate for 4 days: the mean duration of abdominal pain was 2.5 days (SD 0.72). For 95 p. 100 of the attacks, the total hospitalization time was 5 days or less; side effects were very minor. In every case, a favorable response was dependent upon the early initiation of heme therapy.

Acute Disease↗
PubMed1992

Heterogeneity of mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) or Günther's disease is an inborn error of heme biosynthesis transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase (UROIIIS) activity. We have previously described two missense mutations in the UROIIIS gene, confirming that the primary defect responsible for CEP is a structural alteration of this gene. We have extended our work to 5 additional unrelated families. Two new point mutations, a deletion and an insertion have been found in the messenger RNA. Our study shows that a molecular heterogeneity of the mutations exists in Günther's disease. One mutation (C73R), however, appears to be more frequent than the others. Finally, the different normal and mutated proteins have been expressed in Escherichia coli to determine the consequence of the mutations on the enzyme activity.

Amino Acid Sequence↗
PubMed1992

Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria.

A deficiency in the activity of uroporphyrinogen decarboxylase (UROD), the fifth enzyme of the haem biosynthetic pathway, is found in familial porphyria cutanea tarda (F-PCT) and hepatoerythropoietic porphyria (HEP). A new mutation (R292G) and a deletion have been found in a pedigree with two HEP patients (two sisters). The R292G mutation was not detected in 13 unrelated affected patients with F-PCT, so it appears to be uncommon. The possibility that the arginine 292 may participate at the active site of the enzyme is discussed. A summary of the 7 mutations/deletions found in the UROD gene with their frequency is presented.

Amino Acid Sequence↗