PubMed Health⌕ Search

Biomedical subjects

D J Halley

Publications and source records attributed to D J Halley.

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

[Prader-Willi syndrome in a young infant].

Four children aged 2.5 years, 15.7 and 7 months, including a pair of twins, after birth displayed hypotonia which necessitated tube feeding. Other features were a narrow forehead and a thin triangular upper lip, but these abnormalities were not conspicuous. An extensive supplementary examination for cerebral and muscular disorders initially failed to produce a diagnosis. It was only when the Prader-Willi syndrome was suspected and a corresponding abnormality on chromosome 15 was looked for that this diagnosis could be made. Early diagnosis of this syndrome will avoid further invasive diagnostic procedures and make early treatment possible.

Child, Preschool↗
PubMed1997

Prenatal diagnosis of trisomy 9: cytogenetic, fish, and DNA studies.

A cytogenetic survey and follow-up studies were performed in eight cases of full, mosaic, and pseudomosaic trisomy 9 prenatally diagnosed among 36,213 prenatal samples in our department between August 1970 and July 1996. Besides conventional chromosome analysis, interphase fluorescent in situ hybridization (FISH) was employed. FISH turned out to be a rapid and accurate method for verification of trisomy cell lines and could provide additional information to the prenatal cytogenetic results. FISH also enables the study of uncultured specimens of amniotic fluid, not accessible for traditional cytogenetic analysis. In three cases, retrospective DNA analysis showed the supernumerary chromosome 9 to be of maternal origin. The disomic cell lines in both mosaic trisomy 9 cases showed maternal uniparental disomy.

Alleles↗
PubMed1997

Deletions spanning the neurofibromatosis type 1 gene: implications for genotype-phenotype correlations in neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by abnormalities of tissues predominantly derived from the neural crest. Symptoms are highly variable and severity cannot be predicted, even within families. DNA of 84 unrelated patients with NF1, unselected for clinical features or severity, were screened with intragenic polymorphic repeat markers and by Southern analysis with cDNA probes. Deletions of the entire gene were detected in five patients from four unrelated families. Their phenotype resembled that of five previously reported patients with deletions, including intellectual impairment and dysmorphic features, but without an excessive number of dermal neurofibromas. This report supports the hypothesis that large deletions spanning the entire NF1 gene may lead to a specific phenotype.

Adolescent↗
PubMed1997

Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin.

Sixty-four unrelated patients with infantile Krabbe disease (globoid cell leukodystrophy, GLD) of Dutch (n = 41) or other European origin (n = 23) were screened for the presence of a large 30 kb deletion starting in intron 10 (IVS10del30 kb), a base substitution 1538T(T513M) and a polymorphism, 502T. The deletion and the T513M mutation were present in 52% and 8.5%, respectively, of the 82 GALC alleles of the Dutch patients. The 502T polymorphism, which had an allele frequency of 5.3% in a Dutch control panel, occurred in 65% of the GLD alleles. Analysis of patients and both parents in 26 of the families showed that del30 kb was invariably associated with 502T. However, 502T was also present on 40% of the GLD alleles with an as yet unidentified mutation, which is 7.5 times higher than its frequency in controls. This suggests that besides del30 kb at least one other relatively frequent mutation has arisen on the 502T GALC allele. A relatively high incidence of del30 kb was also found in 23 other European (non-Dutch) patients (allele frequency 35%), but T513M did not occur in this group. Practical examples described in this report illustrate the potential usefulness of mutation analysis in many families with Krabbe disease for heterozygote detection and prenatal diagnosis.

Alleles↗
PubMed1997

Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group.

The fragile X syndrome is an X-linked mental retardation disorder caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene. Its frequency, X-linked inheritance, and consequences for relatives all prompt for diagnosis of this disorder on a large scale in all affected individuals. A screening for the fragile X syndrome has been conducted in a representative sample of 3,352 individuals in schools and institutes for the mentally retarded in the southwestern Netherlands, by use of a brief physical examination and the DNA test. The attitudes and reactions of (non)consenting parents/guardians were studied by (pre- and posttest) questionnaires. A total of 2,189 individuals (65%) were eligible for testing, since they had no valid diagnosis, cerebral palsy, or a previous test for the FMR1 gene mutation. Seventy percent (1,531/2,189) of the parents/guardians consented to testing. Besides 32 previously diagnosed fragile X patients, 11 new patients (9 males and 2 females) were diagnosed. Scoring of physical features was effective in preselection, especially for males (sensitivity .91 and specificity .92). Major motives to participate in the screening were the wish to obtain a diagnosis (82%), the hereditary implications (80%), and the support of research into mental retardation (81%). Thirty-four percent of the parents/guardians will seek additional diagnostic workup after exclusion of the fragile X syndrome. The prevalence of the fragile X syndrome was estimated at 1/ 6,045 for males (95% confidence interval 1/9,981-1/ 3,851). On the basis of the actual number of diagnosed cases in the Netherlands, it is estimated that >50% of the fragile X cases are undiagnosed at present.

Adolescent↗
PubMed1997

Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome.

PURPOSE: We studied a large Dutch-Canadian family, in which two very rare hereditary paroxysmal neurologic disorders, familial hemiplegic migraine (FHM) and a "benign familial infantile epileptic syndrome" concur and partially cosegregate. FHM is a dominantly inherited subtype of migraine with attacks of hemiparesis, linked to chromosome 19p13 in 50% of the families tested. Recently mutations in a brain-specific P/Q-type Ca2+ channel alpha1 subunit gene (CACNL1A4) were identified in families with chromosome 19-linked FHM. The infantile epileptic syndrome resembles to two other dominantly inherited benign epilepsies occurring in the first year of life, benign familial neonatal convulsions (BFNC), assigned to chromosomes 20q13.2 and 8q, and benign infantile familial convulsions (BIFC), as yet unlinked. METHODS: Linkage analysis was performed for the known locations of FHM and BFNC. The question whether the two conditions in this family can be caused by a single gene defect was addressed by additional linkage analysis. RESULTS: We excluded linkage of the infantile convulsions to markers on chromosome 20q13.2, 8q, or 19p13. This indicates the existence of a third locus for benign familial convulsions in the first year of life. Linkage of FHM to these markers was not formally excluded but seems very unlikely. Statistical analysis of whether, in this family, both conditions are caused by a single gene defect was inconclusive. CONCLUSIONS: We describe a "benign familial infantile epileptic syndrome" with attacks of FHM at a later age. Further genetic studies in this family may help to unravel the genetic basis of epilepsy or migraine or both.

Age of Onset↗
PubMed1997

DNA testing for fragile X syndrome: implications for parents and family.

The fragile X syndrome is an X linked, semidominant mental retardation disorder caused by the amplification of a CGG repeat in the 5' UTR of the FMR1 gene. Nineteen fragile X families in which the mutated FMR1 gene segregated were evaluated. The implications of the diagnosis for the parents and family were studied through pedigree information, interviews, and questionnaires. Information about the heredity of fragile X syndrome was only disseminated by family members to a third (124/366) of the relatives with an a priori risk of being a carrier of the fragile X syndrome. Twenty-six percent (94/366) of the relatives were tested. Transmission of information among first degree relatives seemed satisfactory but dropped off sharply with increasing distance of the genetic relationship, leaving 66% uninformed. This is particularly disadvantageous in an X linked disease. Of those subjects tested, 42% (39/94) had a premutation and 18% (17/94) had a full mutation. On average, in each family one new fragile X patient and two new carriers were found. When people have the task of transmitting genetic information to their relatives, they usually feel responsible and capable; however, reduced acquaintance and contact with more distant relative severely reduces the effectiveness of such transfer of information in fragile X families.

Adolescent↗
PubMed1997

Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus.

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical phenotype. Here we describe a prenatal diagnosis performed in a female from a fragile X family carrying a large premutation. In chorionic villus DNA of the male fetus the normal maternal CGG allele and a normal pattern on Southern blot analysis were found in combination with the FRAXAC2 and DXS297 allele of the maternal at risk haplotype. A second chorionic villus sampling was performed giving identical results on DNA analysis and, in addition, expression of FMRP was shown by immunohistochemistry. We concluded that the male fetus was not affected with the fragile X syndrome. Subsequent detailed haplotype analysis showed a complex recombination pattern resembling either gene conversion or a double crossover within a 20 kb genomic region.

Alleles↗
PubMed1997

Common C-to-T substitution at position -480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients.

We studied the molecular basis of low hepatic lipase (HL) activity in normolipidemic male patients with angiographically documented coronary artery disease (CAD). In 18 subjects with a lowered HL activity (< 225 mU/mL), all nine exons of the HL gene and part of the promoter region (nucleotides -524 to +7) were sequenced. No structural mutations in the coding part of the HL gene were found, but 50% of the subjects showed a C-to-T substitution at nucleotide -480. Screening for the base substitution in 782 patients yielded an allele frequency of 0.213 (297 heterozygotes, 18 homozygotes). In a group of 316 nonsymptomatic control subjects, the allele frequency was 0.189, which is significantly less than in the CAD patients (P = .035). In the CAD patients, the C-to-T substitution was associated with a lowered lipase activity (heterozygotes -15%, homozygotes -20%). The patients were divided into quartiles on the basis of HL activity. Sixty percent (allele frequency 0.32) of the patients in the lowest quartile (HL activity < 306 mU/mL) had the gene variant against 27% (allele frequency 0.14) in the highest quartile (HL activity > 466 mU/mL). In the noncarriers, but not in the carriers, HL activity was related with plasma insulin, being increased at higher insulin concentration. Homozygous carriers had a significantly higher HDL cholesterol level-than noncarriers (1.13 +/- 0.28 mmol/L versus 0.92 +/- 0.22 mmol/L, P < .02). Our results show that a C-to-T substitution at -480 of the HL promoter is associated with a lowered HL activity. The base substitution, or a closely linked gene variation, may contribute to the variation in HL activity and affect plasma lipoprotein metabolism.

Alleles↗
PubMed1997

The Han:SPRD rat is not a genetic model of human autosomal dominant polycystic kidney disease type 1.

Human autosomal dominant polycystic kidney disease (ADPKD) is a high incidence disorder leading to renal failure in many patients. The majority of cases results from a mutation in the PKD1 gene. The only well documented animal model of ADPKD is the Han:SPRD-Pkd strain. Its genetic basis is unknown as yet. In the current study we determined whether the disease in these rats is genetically linked to the rat homologue of the PKD1 gene. We used the protamine gene as a polymorphic marker (Prm1) of the PKD1 region. Matings of Han:SPRD-Pkd with BB rats and backcross of the offspring with BB yielded animals informative for linkage analysis. This analysis revealed random segregation of the defect and the Prm1 marker, indicating that the model is not caused by a mutation in the PKD1 gene. We conclude that the Han:SPRD-Pkd rat strain is not a genetic model of PKD1.

Animals↗
PubMed1997

Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1.

OBJECTIVE: To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. DESIGN: A prospective follow-up study. Setting. A multidisciplinary neurofibromatosis clinic. PATIENTS: A total of 122 children diagnosed with NF1 according to diagnostic criteria set by the National Institutes of Health. RESULTS: Central precocious puberty (CPP) was diagnosed in 3 children and growth hormone deficiency (GHD) in 3 children. Optic pathway gliomas were observed in 15 children; in 9 of the 15 cases, the optic chiasm was involved. Of the 3 children with CPP, only 1 showed a chiasma glioma on magnetic resonance imaging. In 1 case with GHD, an optic chiasm glioma was detected on neuroimaging. Two of the 9 children with an optic chiasm glioma presented with CPP or GHD. CONCLUSIONS: It has been suggested that CPP in children with NF1 is found exclusively in the presence of a chiasma glioma. We conclude that chiasma glioma may not be obligatory in children with NF1 and CPP or GHD. Moreover, we report a prevalence of GHD in children with NF1 of 2.5%, which has not been established earlier.

Brain↗
PubMed1996

Angelman syndrome in an inbred family.

Angelman syndrome (AS) is characterized by severe mental retardation, absent speech, puppet-like movements, inappropriate laughter, epilepsy, and abnormal electroencephalogram. The majority of AS patients (approximately 65%) have a maternal deficiency within chromosomal region 15q11-q13, caused by maternal deletion or paternal uniparental disomy (UPD). Approximately 35% of AS patients exhibit neither detectable deletion nor UPD, but a subset of these patients have abnormal methylation at several loci in the 15q11-q13 region. We describe here three patients with Angelman syndrome belonging to an extended inbred family. High resolution chromosome analysis combined with DNA analysis using 14 marker loci from the 15ql1-q13 region failed to detect a deletion in any of the three patients. Paternal UPD of chromosome 15 was detected in one case, while the other two patients have abnormal methylation at D15S9, D15S63, and SNRPN. Although the three patients are distantly related, the chromosome 15q11-q13 haplotypes are different, suggesting that independent mutations gave rise to AS in this family.

Alleles↗
PubMed1996

Haplotype identity between individuals who share a CFTR mutation allele "identical by descent": demonstration of the usefulness of the haplotype-sharing concept for gene mapping in real populations.

Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G-->T mutation share a common haplotype of more than 14 cM. In contrast, haplotypes containing the delta F508 mutation show haplotype identity over a much shorter genomic distance within and between populations, probably because of the multiple introduction of this most common mutation. Haplotype analysis for specific mutations in CF or in other recessive diseases can be used as a model for studying the occurrence of genetic drift conditional on gene frequencies. Moreover, from our results, it can be inferred that analysis of shared haplotypes is a suitable method for genetic mapping in general.

Base Sequence↗
PubMed1996

Tuberous sclerosis: between genetic and physical analysis.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder with extensive clinical variability. Present estimates of the prevalence of TSC suggest that it may exceed 1:6,000. New mutations are frequent, as about 2/3 of all cases are apparently sporadic. Locus heterogeneity has been established, with one gene on chromosome 9q34 (TSC1) and the other on chromosome 16p13.3 (TSC2). The majority of TSC2 mutations are probably subtle alterations. In some cases, somatic and germline mosaicism might be explanations for intrafamilial phenotype variation and apparent non penetrance. A role of the predicted protein product tuberin in growth suppression would be in agreement with allelic losses observed in tumors of TSC patients. Studies on tuberin using antibodies raised against various parts of the protein can be expected to provide insight into its normal and impaired function.

Genetic Linkage↗
PubMed1996

Positional cloning of a gene involved in hereditary multiple exostoses.

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.

Amino Acid Sequence↗