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Biomedical subjects

F Muller

Publications and source records attributed to F Muller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Correlation of alkaline phosphatase (ALP) determination and analysis of the tissue non-specific ALP gene in prenatal diagnosis of severe hypophosphatasia.

Prenatal diagnosis of severe hypophosphatasia by mutation analysis of the tissue non-specific alkaline phosphatase (TNSALP) gene is reliable and mostly informative. However, alkaline phosphatase (ALP) assay of CVS may be a useful complementary and independent method, especially when a mutation is unidentified and DNA from the index case is unavailable, rendering impossible the use of DNA polymorphisms as genetic markers of the disease. We report here mutation analysis of the TNSALP gene and ALP assay in nine cases of prenatal diagnosis of severe hypophosphatasia. The results showed a good correlation between ALP assay and DNA analysis in all but one case, which suggested that in at least some cases low values of ALP may correspond to affected fetuses as well as to heterozygotes.

Alkaline Phosphatase↗
PubMed1999

Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).

Alkaline Phosphatase↗
PubMed1999

Early fetal megacystis between 11 and 15 weeks of gestation.

OBJECTIVE: The purpose of this study was to evaluate the prognostic criteria of early fetal megacystis. DESIGN: A prospective, transvaginal ultrasound, cross-sectional study at 11-15 weeks of gestation at a tertiary referral fetal medicine unit. SUBJECTS AND METHODS: Sixteen pregnancies out of a total of 5240 were identified with early fetal megacystis. Fetal biometry, morphology, amniotic fluid, bladder size and volume were also evaluated. The karyotype was available in 15 cases. Vesicocentesis was performed in six fetuses and three had concomitant cystoscopies. RESULTS: In six fetuses, the megacystis was isolated. In the remaining ten, we detected associated hygroma (n = 5), nuchal translucency (n = 3), omphalocele (n = 1), mild pyelectasis (n = 1) and bilateral talipes (n = 1). In three cases the fetuses demonstrated renal hyperechogenicity with cysts, and in two cases oligohydramnios was found; four cases (25%) had chromosomal abnormalities; 47, XY + 13 (two cases), 47, XY + 18 and 47, XY + 21. Only one fetus from this study survived. In the remaining 13 cases, termination was proposed after counselling of the patients on the poor prognosis. The mean gestational age at termination was 15.5 +/- 2.4 weeks (range 12-20). Three fetal transabdominal cystoscopies did not allow us to view the valves; one urethral atresia was suspected, and confirmed postnatally. CONCLUSIONS: We found a high rate of associated malformations, especially intestinal malformations. The systematic evaluation of the intestinal enzymes in the amniotic fluid and urine samples might be an important aid in the diagnosis of multiple malformations, such as cloacal dysgenesis.

Abnormalities, Multiple↗
PubMed1999

Correlations of genotype and phenotype in hypophosphatasia.

Hypophosphatasia, a rare inherited disorder characterized by defective bone mineralization, is highly variable in its clinical expression. The disease is due to various mutations in the tissue-non-specific alkaline phosphatase ( TNSALP ) gene. We report here the use of clinical data, site-directed mutagenesis and computer-assisted modelling to propose a classification of 32 TNSALP gene mutations found in 23 European patients, 17 affected with lethal hypophosphatasia and six with non-lethal hypophosphatasia. Transfection studies of the missense mutations found in non-lethal hypophosphatasia showed that six of them allowed significant residual in vitro enzymatic activity, suggesting that these mutations corresponded to moderate alleles. Each of the six patients with non-lethal hypophosphatasia carried at least one of these alleles. The three-dimensional model study showed that moderate mutations were not found in the active site, and that most of the severe missense mutations were localized in crucial domains such as the active site, the vicinity of the active site and homodimer interface. Some mutations appeared to be organized in clusters on the surface of the molecule that may represent possible candidates for regions interacting with the C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with other dimers to form tetramers. Finally, our results show a good correlation between clinical forms of the disease, mutagenesis experiments and the three-dimensional structure study, and allowed us to clearly distinguish moderate alleles from severe alleles. They also confirm that the extremely high phenotypic heterogeneity observed in patients with hypophosphatasia was due mainly to variable residual enzymatic activities allowed by missense mutations found in the human TNSALP gene.

Alkaline Phosphatase↗
PubMed1999

Outcome of posterior urethral valves: to what extent is it improved by prenatal diagnosis?

PURPOSE: To assess the impact of prenatal diagnosis and evaluation on the outcome of posterior urethral valves we studied all cases of valves detected prenatally, including cases of pregnancy termination due to posterior urethral valves. MATERIALS AND METHODS: Between 1989 and 1996, 30 neonates with prenatally detected posterior urethral valves were treated at our hospital. The prenatal parameters analyzed were age of gestation at diagnosis, ultrasonographic appearance of renal parenchyma and amniotic fluid volume. Fetal urine was analyzed in 9 cases. We reviewed the outcome of 10 neonates treated for posterior urethral valves which were not diagnosed prenatally during the same period. RESULTS: Of the 30 neonatal survivors 6 (20%) had renal failure, including end stage renal disease in 2, after a mean followup of 4 years. Renal failure developed in 2 of 5 cases detected before 24 weeks of gestation, in 1 of 6 with oligohydramnios and in 2 of 5 with abnormal parenchymal renal ultrasound. Normal parenchymal ultrasound and amniotic volume could not predict for good outcome. Renal failure developed in 2 of 7 cases predicted by fetal urinalysis as good prognosis and in 1 of 2 cases predicted as poor prognosis. Pregnancy was terminated for posterior urethral valves in 5 cases based on prenatal criteria of severe renal impairment. Considering these cases as poor outcome, the rate of poor prognosis increased from 20 to 31%. Among the 10 neonates without a prenatal diagnosis of posterior urethral valves renal failure developed in 2 (20%), including end stage renal disease in 1. CONCLUSIONS: When negative parameters were absent and/or fetal urine predicted good outcome there were no cases of end stage renal disease in early infancy, which was a significant help in parent counseling. The predictive value of the currently available prenatal parameters needs to be updated with larger series specifically dealing with posterior urethral valves. According to the current data, the outcome of posterior urethral valves is not yet significantly improved by prenatal diagnosis.

Female↗
PubMed1998

Evaluation of the Abbott system in maternal serum screening for Down syndrome: the AxSym analyzer, AFP and hCG reagents and Maciel Prenatal Interpretive Software.

Multi-marker maternal serum screening for Down syndrome in the second trimester is now part of routine care in many centers. Most protocols use a combination of hCG (or its free beta-subunit) and alpha-fetoprotein (AFP) or unconjugated estriol (UE3), or both. Risk calculation is based on these maternal serum marker values combined with maternal age and trisomy 21 maternal age-related risk. Computer programs are therefore necessary. Both technical and statistical efficiency are included in the final risk evaluation. We studied the Abbott system, comprising AxSym analyzer, AFP and hCG kits and Prenatal Interpretive Software (Maciel). Median values were established between 14 and 18 weeks of amenorrhea in a population of 1822 patients and in twin pregnancies in 157 cases. Forty maternal sera from trisomy 21 affected pregnancies were analyzed. Software was evaluated in a population of 429 patients and in 124 cases of trisomy 21. We conclude that this system constitutes an accurate and efficient method of maternal serum screening for Down syndrome.

Adult↗
PubMed1998

Age-specific variation in aneuploidy incidence among biochemical screening programs.

OBJECTIVE: Our purpose was to compare the observed age-related incidence of Down syndrome in two large screening programs with the commonly quoted incidences used in biochemical screening programs. STUDY DESIGN: Data from two large prenatal screening programs were stratified in 5-year age groups. The age-related incidence of Down syndrome was compared with the commonly used incidence as reported by Cuckle. RESULTS: No significant differences were found in age-related incidences of Down syndrome in any age group between the screening groups or among women ages 15 through 29 in any of the three groups. However, for women 30 to 34 and > or = 40 years old, a trend was noted toward a higher incidence in the screening groups. For women ages 35 to 39, the observed incidence was significantly greater in the screening groups compared with the data of Cuckle. CONCLUSION: Our data suggest an underascertainment in Down syndrome risk built into the Cuckle model, particularly in high-risk patients.

Adolescent↗
PubMed1998

Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case.

BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the incidence of cystic fibrosis in 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. The diagnosis of cystic fibrosis was based on prenatal screening for the eight mutations most frequently observed in France (deltaF508, deltaI507, 1717-1G-->A, G542X, G551D, R553X, W1282X, N1303K) and at postnatal follow up. RESULTS: The overall incidence of cystic fibrosis was 7/209 (3.3%) which is 84 times the estimated risk of CF in the general population (112500). Of these seven cases, six were diagnosed prenatally based on DNA analysis (deltaF508/deltaF508, n=5; deltaF508/G542X, n=1). One case in which only one mutation had been recognised was diagnosed clinically after birth (deltaF508/unidentified mutation). Of the seven cases, none was diagnosed at 16-19 weeks, four at 16-24 weeks, and three after this. The incidence of heterozygous fetuses (15/209, 7%) was not significantly higher than the 5% expected in the general population. The mutations involved in these heterozygous cases were deltaF508 (n=13), G542X (n=1), and G551D (n=1). CONCLUSIONS: Screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. This underlines the need to review genetic counselling in this situation where the fetus is the index case for a genetic disease.

Cystic Fibrosis↗
PubMed1998

Isolation and functional analysis of the histone H3 promoter from atlantic salmon (Salmo salar L.).

The histone H3 (sH3) promoter of Atlantic salmon (Salmo salar) was cloned via polymerase chain reaction using primers designed from the rainbow trout (Oncorhynchus mykiss) promoter sequence. A comparison of the nucleotide sequence with the equivalent sequences from rainbow trout and sockeye salmon (Oncorhynchus nerka) revealed a high degree of conservation. In vivo expression analysis of the sH3 promoter was carried out in both rainbow trout and zebrafish (Danio rerio) embryos. A direct comparison of the sH3 promoter with the viral RSV promoter in rainbow trout resulted in stronger expression of the sH3 promoter. Furthermore, lacZ expression directed by the sH3 promoter was ubiquitous in several different cell types in developing zebrafish embryos. These results suggest that the sH3 promoter will be useful in transgenic studies in Atlantic salmon.

Animals↗
PubMed1997

Amniotic fluid and maternal serum levels of CA125 in pregnancies affected by Down syndrome: a re-evaluation of the role of CA125 in Down syndrome screening.

In a study of amniotic fluid from 91 Down syndrome cases and 240 controls, we have shown that the median value of CA125 in pregnancies affected by Down syndrome on the whole reflects those observed in the maternal serum from 106 affected cases and 238 controls. The median MOM for CA125 in amniotic fluid from Down syndrome pregnancies was 1.04 and in maternal serum 1.06, neither value being significantly different from that for the control population. We confirm our previous observation that CA125 is not a marker of Down syndrome and conclude that CA125 has no role to play in Down syndrome screening.

Amniotic Fluid↗
PubMed1997

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD.

Anencephaly↗
PubMed1997

Development of human fetal kidney in obstructive uropathy: correlations with ultrasonography and urine biochemistry.

In utero urethral obstruction results in bilateral hydronephrosis and severe fetal and post-natal morbidity and mortality. Obstetrical management depends on the indirect evaluation of fetal renal function by ultrasonography and biochemical analysis. No direct evaluation of the severity and possible reversibility of renal lesions is available. In this paper we analyzed kidneys from 34 fetuses (14 to 37 gestational weeks) in which (1) isolated bilateral urinary tract obstruction had been detected in utero by sonography, and (2) the severity of sonographic and biochemical prognostic indicators led to the indication of termination of pregnancy or to perinatal death. Pure hydronephrosis was observed in two young fetuses [14 and 20 gestational weeks (GW)] and was associated with regressive changes in two others. In contrast, a wide spectrum of dysplastic renal lesions was present in 30 fetuses and was classified into four subgroups according to the association of dysplasia, hypoplasia and cysts. They had the following characteristics in common: (1) premature cessation of nephrogenesis assessed by the medullary ray counting method; (2) early disappearance or myofibroblastic differentiation of metanephric blastema; (3) early increase in interstitial mesenchyme with widespread expression of alpha-smooth muscle actin by mesenchymal cells; (4) frequent absence of classical criteria of dysplasia (nests of cartilage were observed in only 5 fetuses); (5) an identification, based upon the detection of alpha-smooth muscle actin expression, of the muscular phenotype of mesenchymal cells encircling primitive ducts. In conclusion, (1) the value of prognostic markers in fetuses less than 20 GW should be reconsidered; (2) after 20 GW there is a good correlation between markers predicting poor prognosis and the severity of renal lesions; (3) hypoplasia with disappearance of blastema cells, dysplasia and early interstitial fibrosis are evidence of the irreversibility of renal lesions and preclude any possibility of new nephron formation; (4) these findings suggest that most surgical in utero procedures are performed when irreversible renal lesions have developed.

Actins↗