Developmentally regulated expression of mtprd, the murine ortholog of tprd, a gene from the Down syndrome chromosomal region 1.
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The gene tprd, which contains three tetratricopeptide domains, has been recently localized in the Down syndrome (DS) chromosomal region 1. We have cloned a cDNA encoding part of the murine ortholog of tprd and used it to characterize the expression pattern of this gene during development and at the adult stage. At E8.5 the expression is uniform. In the later stages of embryogenesis, although expression remains ubiquitous, a pattern of tissues with particularly high expression develops: the strong expression is restricted to non proliferating zones of the nervous system such as the external layer of the cortex, the spinal cord, the cranial and root ganglia and the nerves. In the brain of adult mouse the strongest signals are observed in layers II-III and V-VI of the cortex, in the hippocampus and in the cerebellum, which correspond to the abnormal brain regions seen in DS patients. (+info)
Alu-splice cloning of human Intersectin (ITSN), a putative multivalent binding protein expressed in proliferating and differentiating neurons and overexpressed in Down syndrome.
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By Alu-splice PCR we have trapped two exons and subsequently identified the full length cDNA of a human gene, Intersectin (ITSN), which maps to chromosome 21q22.1 between markers D21S320 and D21S325. The gene has the potential to code for at least two different protein isoforms by alternative splicing (ITSN-L and ITSN-S). Intersectin exists with a high degree of similarity in flies, frogs and mammals, suggesting a conserved role in higher eukaryotes. Analysis of the expression pattern of human and mouse Intersectin detected mRNAs in all adult and foetal tissues tested, with the longer isoform present in brain. In situ hybridisation studies in the developing mouse brain showed ITSN expression in both proliferating and differentiating neurons. The genomic structure of ITSN was determined using the chromosome 21 sequences deposited in the public databases. The protein contains several known motifs which implicate ITSN in clathrin mediated endocytosis and synaptic vesicle recycling. The expression pattern of Intersectin in mouse brain, its presumed function and its overexpression in brains from Down syndrome patients, suggest that Intersectin may contribute in a gene dosage-dependent manner to some of the abnormalities of Down syndrome. (+info)
Chromosome abnormalities in a referred population for suspected chromosomal aberrations: a report of 4117 cases.
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A cytogenetic study was performed on 4,117 Korean patients referred for suspected chromosomal abnormalities. Chromosome aberrations were identified in 17.5% of the referred cases. The most common autosomal abnormality was Down syndrome and Turner syndrome in abnormalities of sex chromosome. The proportions of different karyotypes in Down syndrome (trisomy 21 92.5%, translocation 5.1%, mosaic 2.4%) were similar to those reported in other countries. However, it was different in Turner syndrome (45, X 28.1%, mosaic 50.8%, 46, X, del (Xq) 4.4%, 46, X, i (Xq) 16.7%), in which proportions of mosaics and isochromosome, 46, X, i(Xq), were higher than those reported in other countries. In structural chromosome aberrations of autosome, translocation was the most common (43.6%), and duplication (21.3%), deletion (14.4%), marker chromosome (7.9%) and ring chromosome (4.0%) followed in order of frequency. Rates of several normal variant karyotypes were also described. Inversion of chromosome 9 was observed in 1.7% of total referred cases. (+info)
Chromosomal abnormalities in child psychiatric patients.
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To determine the frequency of chromosomal abnormalities in a child psychiatric population, and to evaluate possible associations between types of abnormalities and patient's clinical characteristics, cytogenetic examination was performed on 604 patients. Demographic data, reasons for karyotyping, clinical signs, and other patient characteristics were assessed and correlated with the results from karyotyping. Chromosomal abnormalities were found in 69 patients (11.3%); these were structural in 49 cases and numerical in 20. Inversion of chromosome nine was found in 15 subjects, trisomy of chromosome 21 in 11, and fragile X in five patients. When karyotyping was performed because of intellectual impairment or multiple developmental delay, significantly more abnormalities were found than average; when performed because autistic disorder was suspected, the number of abnormalities was significantly fewer. There were no differences in clinical variables between structural and numerical abnormalities, nor among nine types of chromosomal abnormalities, except that numerical abnormalities and polymorphism were found at a later age, and that walking was more delayed and IQ was lower in patients with Down syndrome. Clinicians should be aware of the possible presence of chromosomal abnormalities in child psychiatric populations; the close collaboration with geneticists and the use of more defined guidelines for cytogenetic investigation are important. (+info)
Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome?
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AIMS: To examine the age of onset of insulin dependent diabetes mellitus (IDDM) in children with Down's syndrome compared with non-trisomic individuals, and to assess whether differences might be related to disomic homozygosity at the autoimmune polyglandular disease type 1 (APECED) gene locus. METHODS: Children with Down's syndrome and IDDM were identified through the Down's syndrome association newsletter and from paediatricians. DNA was extracted from mouthbrush preparations provided by the parents and patients using standard techniques. Mapping techniques were then used to identify areas of reduction to homozygosity, including a marker that overlaps the locus for APECED. The frequency of disomic homozygosity for all markers (n = 18) was compared with a control group of 99 patients with Down's syndrome and their parents. The families also answered a questionnaire concerning diabetes and related autoimmune conditions in the family. Details were compared with the British Paediatric Surveillance Group 1988 diabetes study. RESULTS: Children with Down's syndrome and IDDM were diagnosed significantly earlier than the general population (6.7 v 8.0 years) with a far higher proportion diagnosed in the first 2 years of life (22% v 7%). There was no evidence of increased disomic homozygosity in the region of the APECED locus in Down's syndrome patients with IDDM compared with simple Down's syndrome. CONCLUSIONS: The natural history of IDDM in Down's syndrome is different from that of the general population. Although children with Down's syndrome have features similar to cases of APECED, disomic homozygosity in this region does not explain the predilection for autoimmune disease. (+info)
The effect of changing attitudes to Down's syndrome in the management of complete atrioventricular septal defects.
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OBJECTIVES: To describe the evaluation, decision making, and care of children with a complete atrioventricular septal defect (CAVSD). STUDY DESIGN: Retrospective study of 136 consecutive cases from 1970 to 1996. RESULTS: A total of 115 (85%) children had Down's syndrome. Denial of surgery without obvious medical reasons was more common in the early years, as was parental refusal of offered surgery and institutional care of the children. Improved results in later years encouraged surgical treatment for all these patients, but more liberal attitudes towards patients with Down's syndrome preceded the improved results. The use of echocardiography as a screening method for all newborns with Down's syndrome made it possible to plan for correction within the 1st months of life. CONCLUSIONS: Changing attitudes in society and widespread use of echocardiography have significantly improved the management of children with a CAVSD and Down's syndrome. (+info)
Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.
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BACKGROUND: Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age. OBJECTIVE: On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers. DESIGN: The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status. RESULTS: A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03). CONCLUSION: The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene. (+info)
Amblyopia and visual acuity in children with Down's syndrome.
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BACKGROUND/AIMS: Amblyopia in people with Down's syndrome has not been well investigated. This study was designed to determine the prevalence and associated conditions of amblyopia in a group of home reared children with Down's syndrome. METHODS: All children in the study group underwent an evaluation of visual acuity. In addition, previous ophthalmological records were reviewed, and a subgroup of children was examined. For the purposes of this study, amblyopia was defined quantitatively as a difference of two Snellen acuity lines between eyes or if unilateral central steady maintained (CSM) vision and a clear fixation preference was observed. A high refractive error was defined as a spherical equivalent more than 3 dioptres and astigmatism more than 1.75 dioptres. Anisometropia was defined as a difference of at least 1.5 dioptres of sphere and/or 1.0 dioptre of cylinder between eyes. 68 children with Down's syndrome between the ages of 5 and 19 years were enrolled in the final study group. RESULTS: Amblyopia was observed in 15 (22%) of 68 patients. An additional 16 (24%) patients had bilateral vision less than 20/50. Strabismus, high refractive errors, and anisometropia were the conditions most commonly associated with decreased vision and amblyopia CONCLUSION: This study suggests that the prevalence of amblyopia is higher than previously reported. Fully 46% of these children with Down's syndrome had evidence of substantial visual deficits. These patients may be at higher risk for visual impairment and should be carefully examined for ophthalmological problems. (+info)