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Biomedical subjects

E Legius

Publications and source records attributed to E Legius.

At least 37 records · Page 2Linked to original sources
PubMed2002

Familial temporal lobe epilepsy with febrile seizures.

Described are the clinical, EEG, MR, and genetic characteristics of 106 members of a family with autosomal dominant temporal lobe epilepsy (TLE) and febrile seizures (FS), with 22 affected individuals. Eleven patients had a history of FS, and 10 patients had TLE. EEG showed epileptic activity in five. None had hippocampal sclerosis. There was no evidence for linkage to 13 candidate loci. This large family with autosomal dominant TLE has a distinct phenotype and shows no linkage to known candidate regions for familial partial epilepsy and FS.

Adolescent↗
PubMed2002

Rapid prenatal diagnosis of trisomy 21 in 5049 consecutive uncultured amniotic fluid samples by fluorescence in situ hybridisation (FISH).

OBJECTIVES: This was a retrospective study on the results of interphase fluorescence in situ hybridization (FISH), performed routinely for chromosome 21 and on ultrasonographic indications for chromosomes 13, 18, X and Y in a series of 5049 amniotic fluid samples. METHODS: Interphase FISH for chromosome 21 was performed in 5049 consecutive amniotic fluid samples for the rapid prenatal diagnosis of Down syndrome. Aneuploidy for four other chromosomes (13, 18, X and Y) was tested following ultrasonographic indications. Karyotypes from standard cytogenetic analysis were compared to the FISH results. RESULTS: Using conventional cytogenetics 3.6% (183/5049) chromosomal anomalies were detected. After exclusion of familial chromosome rearrangements, i.e. balanced autosomal reciprocal or Robertsonian translocations (30/5049) and inversions (19/5049), 2.65% chromosomal anomalies (134/5049) were diagnosed. Of this group 0.18% (9/5049) were chromosomal rearrangements not detectable by FISH and 2.47% (125/5049) were numerical chromosomal anomalies detectable by interphase FISH for chromosomes 13, 18, 21, X and Y. With routine interphase FISH for chromosome 21 and FISH on echographic indication for the other four chromosomes we detected 107/125 of these numerical chromosomal anomalies, i.e. 85.6%. All 70 cases of trisomy 21 were detected by FISH and confirmed with conventional cytogenetics (sensitivity=100%) and there were no false-positive results (specificity=100%). Maternal cell contamination of amniotic fluid samples occurred in 1.27% (64/5049) of samples; 0.26% (13/5049) of these samples were uninformative by FISH due to maternal cell contamination (12/5049) or absence of nuclei in one sample (1/5049). CONCLUSION: In this group of 5049 samples we found that FISH is a reliable technique for the rapid prenatal diagnosis of trisomy 21. The number of uninformative cases due to maternal cell contamination was low. The strategy to perform FISH for chromosome 21 in all samples and only on ultrasonographic indication for the four other chromosomes (13, 18, X and Y) followed by standard cytogenetics is effective.

Amniocentesis↗
PubMed2002

PTPN11 mutations in LEOPARD syndrome.

LEOPARD syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Deafness and genital abnormalities are less frequently found. We report a father and daughter and a third, unrelated patient with LEOPARD syndrome. Recently, missense mutations in the PTPN11 gene located in 12q24 were found to cause Noonan syndrome. All three cases of LEOPARD syndrome reported here have a Y279C mutation in the PTPN11 gene. We hypothesise that some PTPN11 mutations are associated with the typical Noonan syndrome phenotype and that other mutations, such as the Y279C mutation reported here, are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or café au lait spots.

Abnormalities, Multiple↗
PubMed2001

Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia.

We present a retrospective study of the frequency and type of associated malformations and chromosomal anomalies in 42 consecutive cases of congenital diaphragmatic hernia (CDH) diagnosed in utero during the period from 1985 to 1999. In 26% (11/42) of the cases, associated malformations were detected. Chromosomal anomalies were present in 9.5% (4/42). In this group of 15 cases (15/42 = 36%) with associated malformations or chromosomal anomalies, all cases, except one, had prenatal sonographic evidence of additional problems. The survival rate of fetuses with CDH and associated malformations or chromosomal anomalies was poor (1/15). Therefore, the overall survival rate of in utero-diagnosed CDH was only 31% (13/42), while isolated left CDH had a survival rate of 52% (12/23). The in utero diagnosis of CDH implies a detailed echographic examination to exclude additional anomalies. The risk for a syndromal or chromosomal malformation becomes small when no additional anomalies are seen on ultrasound.

Abnormalities, Multiple↗
PubMed2001

Recombination hotspot in NF1 microdeletion patients.

Neurofibromatosis type 1 (NF1) patients that are heterozygous for an NF1 microdeletion are remarkable for an early age at onset and an excessive burden of dermal neurofibromas. Microdeletions are predominantly maternal in origin and arise by unequal crossover between misaligned NF1REP paralogous sequence blocks which flank the NF1 gene. We mapped and sequenced the breakpoints in several patients and designed primers within each paralog to specifically amplify a 3.4 kb deletion junction fragment. This assay amplified a deletion junction fragment from 25 of the 54 unrelated NF1 microdeletion patients screened. Sequence analysis demonstrated that each of the 25 recombination events occurred in a discrete 2 kb recombination hotspot within each of the flanking NF1REPs. Two recombination events were accompanied by apparent gene conversion. A search for recombination-prone motifs revealed a chi-like sequence; however, it is unknown whether this element stimulates recombination to occur at the hotspot. The deletion-junction assay will facilitate the prospective identification of patients with NF1 microdeletion at this hotspot for genotype-phenotype correlation studies and diagnostic evaluation.

Alleles↗
PubMed2001

Semilobar holoprosencephaly in a 46,XY female fetus.

We report the prenatal echographic diagnosis of holoprosencephaly (HPE) at 11 weeks' gestation. Fetopathological examination revealed an unusual variant of semilobar HPE with middle interhemispheric fusion associated with sex-reversal: 46,XY normal male karyotype, normal external and internal female genitalia and streak gonads.

Adult↗
PubMed2000

Characterization of the Fugu rubripes NLK and FN5 genes flanking the NF1 (Neurofibromatosis type 1) gene in the 5' direction and mapping of the human counterparts.

To complete the analysis of the Neurofibromatosis type 1 (NF1) gene region in Fugu rubripes, we characterized the upstream flanking region of the NF1 gene and identified the FN5 (flanking the Fugu NF1 gene in 5' direction) gene and the NLK (Nemo-like kinase) gene as its flanking genes. The FN5 gene spans 3807bp and encompasses four exons, three of which belong to the expanded 5' UTR. Only 11% of the FN5 transcript is protein-coding. The function of the FN5 protein spanning 59 amino acids is unknown. We also characterized the human and the mouse FN5 transcripts and found 85% and 83% similarity of deduced amino acid sequences compared with Fugu. Two copies of the human FN5 gene were identified, one on chromosome 17q21.3-q22 several megabases distal to the NF1 gene at 17q11.2. The second copy of the FN5 gene was mapped to 11q13.3-q23.3. In Fugu, the FN5 gene is flanked by the NLK gene, which spans 4513bp from the translation start to the stop codon and encompasses 11 exons. Comparing the deduced amino acid sequences, 82% overall similarity was observed between Fugu and mouse or human NLK and 67% similarity between the Fugu NLK and the highly related LIT-1 kinase of Caenorhabditis elegans, which has been shown, like the vertebrate counterpart, to be involved in the Wnt signalling pathway. We mapped the human NLK gene to 17q11.2 between markers D17S935 and D17S120, more than 1Mb proximal to the NF1 gene. The characterization of the 5' flanking region presented here, together with that of the 3' region, demonstrates the profound differences between Fugu and human considering the gene content within the region flanking the NF1 gene.

Amino Acid Sequence↗
PubMed2000

Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked syndrome characterized by pre- and postnatal overgrowth (gigantism), which clinically resembles the autosomal Beckwith-Wiedemann syndrome (BWS). Deletions and translocations involving the glypican-3 gene ( GPC3 ) have been shown to be associated with SGBS. Occasionally, these deletions also include the glypican-4 gene ( GPC4 ). Glypicans are heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. We have examined the mutational status of the GPC3 and GPC4 genes in one patient with Perlman syndrome, three patients with overgrowth without syndrome diagnosis, ten unrelated SGBS-patients and 11 BWS patients. We identified one SGBS patient with a deletion of a GPC3 exon. Six SGBS patients showed point mutations in GPC3. One frameshift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein. One missense mutation, W296R, changes an amino acid that is conserved in all glypicans identified so far. A GPC3 protein that reproduces this mutation is poorly processed and fails to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation. In three SGBS patients and in all non-SGBS patients, no mutations could be identified. We found three single nucleotide polymorphisms in the GPC4 gene but no evidence for loss-of-function mutations in GPC4 associated with SGBS.

Amino Acid Sequence↗
PubMed2000

Unequal meiotic crossover: a frequent cause of NF1 microdeletions.

Neurofibromatosis type 1 is a common autosomal dominant disorder caused by mutations of the NF1 gene on chromosome 17. In only 5%-10% of cases, a microdeletion including the NF1 gene is found. We analyzed a set of polymorphic dinucleotide-repeat markers flanking the microdeletion on chromosome 17 in a group of seven unrelated families with a de novo NF1 microdeletion. Six of seven microdeletions were of maternal origin. The breakpoints of the microdeletions of maternal origin were localized in flanking paralogous sequences, called "NF1-REPs." The single deletion of paternal origin was shorter, and no crossover occurred on the paternal chromosome 17 during transmission. Five of the six cases of maternal origin were informative, and all five showed a crossover, between the flanking markers, after maternal transmission. The observed crossovers flanking the NF1 region suggest that these NF1 microdeletions result from an unequal crossover in maternal meiosis I, mediated by a misalignment of the flanking NF1-REPs.

Adolescent↗
PubMed2000

Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common inherited cancer predisposition syndrome. The NF1 gene product, neurofibromin, is hypothesized to function as a tumor suppressor and nearly all NF1 patients develop benign peripheral nerve tumors. These neurofibromas presumably arise from NF1 inactivation in S100(+)Schwann cells, but there is no formal proof for this mechanism. We demonstrate that fibro-blasts isolated from neurofibromas carried at least one normal NF1 allele and expressed both NF1 mRNA and protein, whereas the S100(+)cells typically lacked the NF1 transcript. Our findings further indicate that additional molecular events aside from NF1 inactivation in Schwann cells and/or other neural crest derivatives contribute to neurofibroma formation.

Adult↗
PubMed2000

Increased frequency of chromosomal abnormalities in female partners of couples undergoing in vitro fertilization or intracytoplasmic sperm injection.

OBJECTIVE: To determine the prevalence of chromosomal abnormalities in female partners of couples undergoing IVF or intracytoplasmic sperm injection (ICSI). DESIGN: Prospective study. SETTING: Leuven University Fertility Center. PATIENT(S): Female candidates for IVF or ICSI. INTERVENTION(S): An initial cytogenetic study was performed on peripheral blood lymphocyte cultures using G- and R-banding. In all patients, > or =25 metaphases were examined. If a chromosomal aberration was detected, additional cytogenetic studies were performed for precise identification. MAIN OUTCOME MEASURE(S): Abnormal female karyotypes in comparison with the general female population. RESULT(S): Cytogenetic analysis was performed in 263 female partners of couples before entering an IVF or ICSI program. The prevalence of autosomal reciprocal balanced translocations was seven times higher in the study group (1.14%) than in the general population (0.16%). All abnormal karyotypes were found in the IVF group with male factor infertility. CONCLUSION(S): Chromosomal abnormalities are more frequent in the female partners of couples seeking fertility treatment. We recommend chromosomal analysis in women before starting IVF or ICSI treatment, even in the presence of male factor infertility.

Adult↗
PubMed2000

Predictive testing for hereditary breast and ovarian cancer: a psychological framework for pre-test counselling.

Since the identification of two breast-ovarian cancer susceptibility genes (BRCA1/2), predictive testing for hereditary breast/ovarian cancer (HBOC) has been available. Given the complexity and uncertainties of HBOC and the potential impact of predictive testing on psychological well-being, we offer the test applicants a combination of information-oriented and psychological counselling. In this paper, we describe the multidisciplinary approach for predictive testing for HBOC as a clinical service in Leuven, hereby focusing on psychological and decision counselling practice. Attention is paid to the theoretical framework used for pre-test psychological counselling in Leuven. We discuss three important interacting dimensions of psychological counselling: individual emotional support, decision counselling and support of the family communication process. Decision counselling consists of an evaluation of the cognitive and the emotional processing of the information given and strategies and resources for coping. This serves as a starting point to facilitate free informed decision making. Scenario development is used as a decision aid.

Belgium↗
PubMed2000

Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia).

The R141H mutation in the PMM2 gene is the most frequent mutation in type Ia of the congenital disorders of glycosylation (formerly carbohydrate-deficient glycoprotein syndromes)(CDG-Ia). However, it has never been observed in the homozygous state. Homozygosity for this mutation is probably incompatible with life. In this study, we determined the frequency of R141H in two normal populations: in neonates of Dutch origin 1/79 were carriers, whilst in the Danish population, a carrier frequency of 1/60 was found. These figures are clearly in disequilibrium with the frequency of CDG-Ia that has been estimated at 1/80,000 to 1/40,000 in these populations. Haplotype analysis of 43 patients with the R141H mutation of different geographic origins indicated that the R141H is an old mutation in the Caucasian population. Based on the new data, the disease frequency has been calculated at 1/20,000 in these populations. It is concluded that the disease is probably underdiagnosed.

Abortion, Spontaneous↗
PubMed2000

Visual loss as the presenting sign of Jeune syndrome.

We describe a 5-year-old girl with Jeune syndrome. The presenting symptoms included visual loss and night blindness only. In the neonatal period she had surgery on both hands for bilateral polydactyly. Following clinical and radiological examination a diagnosis of Jeune syndrome was proposed. Although Jeune syndrome is often characterized by multiple organ abnormalities, our patient presented with ocular symptoms at the age of 5 years.

Abnormalities, Multiple↗