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Biomedical subjects

C Legum

Publications and source records attributed to C Legum.

At least 19 recordsLinked to original sources
PubMed2001

Phenotypic expression of tissue mosaicism in a 45,X/46,X,dicY(q11.2) female.

We describe a girl who presented at the age of 11 years with short stature. She had female external genitalia and some clinical features of Turner syndrome. At laparotomy a uterus and Fallopian tubes and small gonad-like tissue masses in the region of the Fallopian fimbria were found. The tissue masses were removed and histological examination revealed no organized testicular or ovarian morphology. Remnants of Fallopian tubes, epididymis, and clusters of Leydig cells were seen but no Sertoli cells were found. Endocrine studies showed levels of sex hormones consistent with primary gonadal failure. G-banding analysis of 16 blood lymphocytes revealed the karyotype 46,X,dicY(q11.2) in all cells. Varying proportions of X and Y centromeres in blood lymphocytes, skin fibroblasts, and in the incompletely formed Wolffian and Müllerian duct derivatives were demonstrated by FISH. Molecular studies confirmed the absence of most of the long arm of the Y chromosome and an intact short arm. The SRY gene was shown to be present, but we presume that due to the mosaicism the dose was insufficient to allow normal testicular development.

Child↗
PubMed2001

Novel mutations in the emerin gene in Israeli families.

Emery-Dreifuss Muscular Dystrophy (EMD or EDMD) is a rare X-linked recessive disorder, characterized by progressive muscle wasting and weakness, contractures, and cardiomyopathy, manifesting as heart block. Mutation analysis at the EMD gene locus was performed in 4 unrelated Israeli families with X-linked EMD and in one sporadic case. In the 4 families 4 different mutations were found, 3 of which were novel. These included two frame shift mutations in exon 2 (333delT and 412insA) and one base pair substitution at the consensus +1 donor splice in intron 5 (1429G-->A). The fourth mutation in exon 6 (1675-1678delTCCG) has been previously described. No mutations were identified in the one sporadic case. Two of the three novel mutations were found in exon 2. A summary of the previously published mutations described in the EMD Mutation Database (http://www.path.cam.ac.uk/emd/) as well as the mutations described in our study suggest that the distribution of mutations in EMD gene is not entirely random and that exon 2 is prone to mutations. Hum Mutat 17:522, 2001.

Base Sequence↗
PubMed1999

Fetal muscle biopsy as a diagnostic tool in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a relentless progressive disorder, leading to severe disability during childhood and death in adolescence or early adulthood. In most families, prenatal diagnosis is readily achieved by molecular detection of DNA deletions using chorionic villi or amniocytes, or by linkage analysis. In some cases, however, molecular methods fail to provide a definitive diagnosis and in such cases in utero fetal muscle biopsy may serve as a diagnostic option. We describe three families in whom fetal muscle biopsy was performed, focusing on the prenatal diagnostic dilemmas, the indications and timing for in utero fetal muscle biopsy, and the difficulties encountered.

Female↗
PubMed1999

Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer.

BACKGROUND & AIMS: Israeli Jews of European birth, i.e., Ashkenazim, have the highest colorectal cancer incidence of any Israeli ethnic group. The I1307K APC gene variant was found in 6.1% of American Jews, 28% of their familial colorectal cancer cases, but not in non-Jews. We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer. METHODS: DNA samples from 500 unrelated Jews of European or non-European origin, with or without a personal and/or family history of neoplasia, were examined for the I1307K variant by the allele-specific oligonucleotide (ASO) method. RESULTS: In persons at average risk for colorectal cancer, I1307K was found in 5.0% of 120 European and 1.6% of 188 non-European Jews (P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer (P = 0.02) and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia. CONCLUSIONS: The I1307K APC variant may represent a susceptibility gene for colorectal, or other, cancers in Ashkenazi Jews, and partially explains the higher incidence of colorectal cancer in European Israelis.

Adenomatous Polyposis Coli Protein↗
PubMed1999

A diagnostic fluorescent marker kit for six limb girdle muscular dystrophies.

The autosomal progressive muscular dystrophies which are grouped together under the term limb girdle muscular dystrophies (LGMD) are diseases characterized by a progressive impairment of the proximal limb muscles and myopathic changes on electromyogram and muscle biopsy. Eight independent purely recessive genetic entities have been recognized in this group of diseases by genetic localization or causative gene identification. We have developed fluorescent genetic markers bracketing six of these loci (LGMD2A-LGMD2F). The marker loci were genotyped in 96 LGMD2 families leading to genetic definition of 25 of them either with a high likelihood or with a suggested localization (7 LGMD2A, 5 LGMD2B, 4 LGMD2C, 4 LGMD2D, 2 LGMD2E and 3 LGMD2F). In addition, 18 families were excluded for all six tested loci; for 45 of the 53 remaining families at least one exclusion could be demonstrated. This kit, which makes the rapid genetic testing of LGMD2 families possible, may be useful in a diagnostic process.

Chromosome Mapping↗
PubMed1999

Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9.

BACKGROUND: The phenotypic spectrum of familial adenomatous polyposis (FAP) varies from the classic appearance of hundreds of adenomatous colonic polyps in the young adult and early onset colorectal cancer, to the occurrence of sparse adenomas in the older adult, "attenuated" FAP, due to mutations at the 5' or 3' ends of the APC gene. AIMS: To investigate marked intrafamilial phenotypic variation occurring in a family with an APC gene mutation in exon 9. PATIENTS: An extended kindred of 22 people of whom 16 had colorectal neoplasia and/or were APC mutation carriers. RESULTS: Phenotypic manifestation varied from classic FAP to a complete lack of clinical or endoscopic, or bioptic disease in five people in three different generations. This occurred in four of them over two generations, in spite of having a confirmed 11 bp insertion causing a frame shift and stop codon (363) in exon 9 of the APC gene. CONCLUSIONS: At present, it is assumed that in this family there is alternative splicing of the APC gene, and/or unidentified modifying genetic factors. The family illustrates the importance of genetic testing in evaluating carrier status and not just clinical examination. This clinical observation also high- lights the dilemma in recognising the possible contribution of low penetrance germline APC mutations to what has been considered "sporadic" colorectal neoplasia.

Adenomatous Polyposis Coli↗
PubMed1999

Subclinical audiological findings in carriers of recessive genes for deafness.

The existence of subclinical signs in the hearing of carriers of recessive mutations for deafness has aroused much controversy in the literature. The present study comprised 30 carriers of recessive mutations for deafness, and a control group of 30 healthy volunteers, matched for gender and age. All participants underwent a series of hearing tests, including pure-tone audiometry, speech tests, Bekesy audiometry and notch noise tests. The main results were: hearing loss in high frequencies (3000 and 4000 Hz), an elevation of the acoustic reflex threshold, as well as an elevation of the identification of 2000 Hz pure tone in the presence of white noise and notch noise. A notch in the Bekesy audiogram was also identified in several carriers. An interaction was found between gender and the carrier trait in the hearing threshold at 4000 Hz, and in the ipsi- and contralateral acoustic reflex at 500 Hz and 1000 Hz. These subclinical signs may be complementary to DNA research in the investigation of genetic deafness of unknown origin.

Adult↗
PubMed1998

Mutations of the adenomatous polyposis coli and p53 genes in a child with Turcot's syndrome.

Turcot's syndrome is a rare heritable complex that is characterized by an association between a primary neuroepithelial tumor of the central nervous system and multiple colonic polyps. The aim of this study was to analyze genetic alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a colorectal tumor developed 3.5 years following astrocytoma. An APC germline non-sense mutation at codon 1284 leading to a truncated protein was identified, as was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The latter was not identified in the primary astrocytoma. However, immunohistochemistry revealed high p53 protein expression in both tumors, suggesting an additional p53 mutation in the primary astrocytic tumor. The diverse p53 mutations observed in this unique syndrome in two different sites and stages of the disease may shed light on the multistep progression of the malignant events.

Adenomatous Polyposis Coli↗
PubMed1998

SMA type 2 unrelated to chromosome 5q13.

We describe two brothers with clinical and histological findings of type 2 spinal muscular atrophy (SMA) associated with small head circumference (<2%) and normal cognitive development. No survival motor neuron (SMN) or neuronal apoptosis-inhibitory protein (NAIP) deletions were detected in these sibs, and they were discordant for the haplotypes determined by DNA markers flanking the 5q13 SMA locus. These findings support the presence of a distinct anterior horn disease unrelated to 5q13. This entity may have either autosomal recessive or X-linked inheritance.

Child, Preschool↗
PubMed1998

High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi individuals. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.

Adenosine Triphosphatases↗
PubMed1997

Heterogeneity in adducted thumbs sequence.

We report on a boy with adducted thumbs, microcephaly, swallowing difficulties, hypotonia, and severe mental retardation, but without craniostenosis or arthrogryposis. An MRI scan showed myelinization according to age and mild ventricular enlargement. A muscle biopsy documented irregular-shaped and swollen mitochondriae, but results of mitochondrial function tests were normal. The clinical findings were consistent with a developmental defect of the central nervous system. We include a brief review of the 9 reported cases with adducted thumbs sequence.

Abnormalities, Multiple↗
PubMed1997

[Familial adenomatous polyposis: establishing a registry and genetic and molecular analysis].

Familial adenomatous polyposis (FAP), a dominantly inherited disease, is caused by a mutation in the adenomatous polyposis coli gene in chromosome 5q21. The gene has 15 exons, a physical length of 10 Kb and an open reading frame of 8.5 Kb. Exon 15 codes 66% of the mRNA and has a mutation cluster region which accounts for over 50% of mutations. The disease usually leads to the appearance of hundreds of adenomatous polyps in the transverse and descending colon between puberty and age 20 years and to colon cancer before the age of 40. Early detection is essential to prevent the development of metastasizing cancer. Since 1994 we have recruited 23 families for genetic counseling. DNA was obtained from 19 unrelated FAP patients and 219 high risk relatives in 19 unrelated families following confirmation of the diagnosis. In addition to linkage studies, direct mutational analysis was performed using the protein truncation test for most of exon 15 and single strand conformation polymorphism analysis for the other exons. These exons account for most of the mutations identified to date. Of 19 unrelated probands, 14 had detectable mutations. Exon 15 accounted for 6 families, exons 5, 7 and 14 for 1 each, exon 9 for 3, and exon 8 for 2. Combined mutational and linkage analysis identified 18 presymptomatic carriers who received genetic and clinical counseling. Our FAP patients did not differ significantly from those of larger studies in other countries with regard to the distribution of the mutations, gender and genotype-phenotype correlation, or ethnic distribution.

Adenomatous Polyposis Coli↗
PubMed1997

Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins.

Limb-girdle muscular dystrophies (LGMDs) are a group of neuromuscular diseases presenting great clinical heterogeneity. Mutations in CANP3, the gene encoding muscle-specific calpain, were used to identify this gene as the genetic site responsible for autosomal recessive LGMD type 2A (LGMD2A; MIM 253600). Analyses of the segregation of markers flanking the LGMD2A locus and a search for CANP3 mutations were performed for 21 LGMD2 pedigrees from various origins. In addition to the 16 mutations described previously, we report 19 novel mutations. These data indicate that muscular dystrophy caused by mutations in CANP3 are found in patients from all countries examined so far and further support the wide heterogeneity of molecular defects in this rare disease.

Adolescent↗
PubMed1996

Second-trimester maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated oestriol after early transvaginal multifetal pregnancy reduction.

Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and unconjugated oestriol (UE3) are used as second-trimester screening markers for the detection of various fetal abnormalities. Previous studies have suggested that second-trimester MSAFP is consistently elevated after late first-trimester transabdominal multifetal pregnancy reduction (MFPR). The present study was undertaken to evaluate the levels of all three markers after early transvaginal MFPR. Maternal serum was examined for MSAFP, hCG, and UE3 at 16-18 weeks' gestation in 28 patients who underwent transvaginal MFPR at approximately 10 weeks' gestation. The mean interval between the reduction procedure and the screening test was 7.2 +/- 0.9 weeks. The mean MSAFP value in 24 patients carrying viable twins was 2.49 +/- 0.99 multiples of the median (MOM). Two patients had elevated MSAFP values: one in association with omphalocoele and the other in relation to an adverse pregnancy outcome. All but two patients had normal hCG values (mean 1.98 +/- 1.26 MOM). Two cases with elevated hCG were associated with an adverse pregnancy outcome. Unconjugated oestriol values were within the normal range in all patients (mean 1.69 +/- 0.61 MOM). These results suggest that early transvaginal MFPR, at approximately 10 weeks' gestation, does not appear to influence second-trimester MSAFP, hCG, and UE3 levels. The values of these markers may therefore be interpreted by using the same criteria as those for the general obstetric population.

Adult↗
PubMed1995

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family.

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. "Idiopathic" hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia.

Base Sequence↗
PubMed1995

Amniocentesis rate and the detection of Down syndrome and other chromosomal anomalies in Israel.

We investigated the contribution of different screening criteria to the prenatal detection of Down syndrome (DS) as well as other chromosomal anomalies in the Jewish population in Israel during 1990 and 1992. There was a significant decrease (P < 0.03) in the incidence of DS live-births during 1992 (40:78 442) compared with 1990 (69:73 751) which paralleled a marked increase in total prenatal testing and in DS cases detected prenatally. Private laboratories, which perform amniocenteses mostly for women with a low risk of DS and without genetic counselling, had a significantly lower detection rate (1:917) compared with that of the genetic institutes, which following genetic counselling test both women > or = 37 years of age (1:91) and women younger than 37 years (1:113). The detection of chromosomal anomalies other than DS was less affected by the reason for amniocentesis. Amniocentesis indicated by maternal serum marker screening of women younger than 37 years identified a greater number of chromosomal anomalies other than DS than amniocentesis based on age (> or = 37 years) alone (111:9604 versus 94:9810; P < 0.06). Prenatal detection of DS is most effective when the indication for amniocentesis follows genetic counselling. The increasing use of maternal serum marker screening leads to a significant improvement in the positive detection rate of chromosomal anomalies other than DS in young women.

Adult↗
PubMed1995

Solar activity cycle and the incidence of foetal chromosome abnormalities detected at prenatal diagnosis.

We studied 2001 foetuses during the period of minimal solar activity of solar cycle 21 and 2265 foetuses during the period of maximal solar activity of solar cycle 22, in all women aged 37 years and over who underwent free prenatal diagnosis in four hospitals in the greater Tel Aviv area. There were no significant differences in the total incidence of chromosomal abnormalities or of trisomy between the two periods (2.15% and 1.8% versus 2.34% and 2.12%, respectively). However, the trend of excessive incidence of chromosomal abnormalities in the period of maximal solar activity suggests that a prospective study in a large population would be required to rule out any possible effect of extreme solar activity.

Adult↗