Modified cuspal relationships of mandibular molar teeth in children with Down's syndrome.
A total of 50 permanent mandibular 1st molars of 26 children with Down's syndrome (DS) were examined from dental casts and 59 permanent mandibular 1st molars of normal children were examined from 33 individuals. The following measurements were performed on both right and left molars (teeth 46 and 36 respectively): (a) the intercusp distances (mb-db, mb-d, mb-dl, db-ml, db-d, db-dl, db-ml, d-dl, d-ml, dl-ml); (b) the db-mb-ml, mb-db-ml, mb-ml-db, d-mb-dl, mb-d-dl, mb-dl-d angles; (c) the area of the pentagon formed by connecting the cusp tips. All intercusp distances were significantly smaller in the DS group. Stepwise logistic regression, applied to all the intercusp distances, was used to design a multivariate probability model for DS and normals. A model based on 2 distances only, mb-dl and mb-db, proved sufficient to discriminate between the teeth of DS and the normal population. The model for tooth 36 for example was as follows: p(DS) = (e(30.6-5.6(mb-dl)+25(mb-db)))/(1 + e(30.6 5.6(mb-dl)+25(mb db))). A similar model for tooth 46 was also created, as well as a model which incorporated both teeth. With respect to the angles, significant differences between DS and normals were found in 3 out of the 6 angles which were measured: the d-mb-dl angle was smaller than in normals, the mb-d-dl angle was higher, and the mb-dl-d angle was smaller. The dl cusp was located closer to the centre of the tooth. The change in size occurs at an early stage, while the change in shape occurs in a later stage of tooth formation in the DS population. (+info)
Increased phosphoglycerate kinase in the brains of patients with Down's syndrome but not with Alzheimer's disease.
Impaired glucose metabolism in Down's syndrome (DS) has been well-documented in vivo, although information on the underlying biochemical defect is limited and no biochemical studies on glucose handling enzymes have been carried out in the brain. Through gene hunting in fetal DS brain we found an overexpressed sequence homologous to the phosphoglycerate kinase (PGK) gene. This finding was studied further by investigating the activity levels of this key enzyme of carbohydrate metabolism in the brains of patients with DS. PGK activity was determined in five brain regions of nine patients with DS, nine patients with Alzheimer's disease and 14 controls. PGK activity was significantly elevated in the frontal, occipital and temporal lobe and in the cerebellum of patients with DS. PGK activity in corresponding brain regions of patients with Alzheimer's disease was comparable with controls. We conclude that our findings complement previously published data on impaired brain glucose metabolism in DS evaluated by positron emission tomography in clinical studies. Furthermore, we show that in DS, impaired glucose metabolism, represented by increased PGK activity, is a specific finding rather than a secondary phenomenon simply due to neurodegeneration or atrophy. These observations are also supported by data from subtractive hybridization, showing overexpressed PGK in DS brains at the transcriptional level early in life. (+info)
Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene.
Protein kinase C (PKC)-activated modulation of amyloid precursor protein (APP) metabolism has been investigated in natural models of altered APP expression due to the presence of one, two or three copies of the APP gene. We show that levels of APP present in human skin fibroblasts strongly influence the effect of PKC activation of soluble APP (sAPP) release. Thus fibroblasts derived from a patient with a deletion in chromosome 21 including the APP locus (Delta21) had lower levels of both APP mRNA and cell-associated APP, and showed an exaggerated phorbol-ester-induced sAPP release, when compared with fibroblasts from control individuals. In contrast, fibroblasts from chromosome 21 trisomic Down's syndrome patients failed to show a concentration-dependent response to phorbol ester treatment. These results suggest that the levels of APP expression can affect the degree of response to PKC-mediated modulation of the metabolism of this protein. (+info)
Maternal smoking and Down syndrome: the confounding effect of maternal age.
Inconsistent results have been reported from studies evaluating the association of maternal smoking with birth of a Down syndrome child. Control of known risk factors, particularly maternal age, has also varied across studies. By using a population-based case-control design (775 Down syndrome cases and 7,750 normal controls) and Washington State birth record data for 1984-1994, the authors examined this hypothesized association and found a crude odds ratio of 0.80 (95% confidence interval 0.65-0.98). Controlling for broad categories of maternal age (<35 years, > or =35 years), as described in prior studies, resulted in a negative association (odds ratio = 0.87, 95% confidence interval 0.71-1.07). However, controlling for exact year of maternal age in conjunction with race and parity resulted in no association (odds ratio = 1.00, 95% confidence interval 0.82-1.24). In this study, the prevalence of Down syndrome births increased with increasing maternal age, whereas among controls the reported prevalence of smoking during pregnancy decreased with increasing maternal age. There is a substantial potential for residual confounding by maternal age in studies of maternal smoking and Down syndrome. After adequately controlling for maternal age in this study, the authors found no clear relation between maternal smoking and the risk of Down syndrome. (+info)
Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development.
BACKGROUND: Learning disability and short stature are cardinal signs of Down's syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development. AIMS: To study long term effects of GH on linear growth and psychomotor development in young children with Down's syndrome. Study design-Fifteen children with Down's syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied. RESULTS: The mean height of the study group increased from -1.8 to -0.8 SDS (Swedish standard) during treatment, whereas that of a Down's syndrome control group fell from -1.7 to -2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment. CONCLUSIONS: GH treatment results in normal growth velocity in Down's syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops. (+info)
Trisomy 21 associated transient neonatal myeloproliferation in the absence of Down's syndrome.
Although usually associated with Down's syndrome, transient neonatal myeloproliferation (TMD) can occur in the absence of a constitutional trisomy 21. This report describes two such cases, both of whom had a trisomy 21 restricted to clonal cells. Unlike in previous such reported cases, spontaneous morphological, cytogenetic, and molecular remission in both cases was followed by re-emergence, in one case, of an evolved clone with a more malignant phenotype which required pharmacological intervention. Awareness that trisomy 21 bearing leukaemia in the neonatal period can be transient even in the absence of Down's syndrome is important to prevent unnecessary treatment. Equally, such cases require indefinite follow up as a proportion may have a recurrence which may require treatment. (+info)
Asynchronous replication of alleles in genomes carrying an extra autosome.
Transcriptional activity of genes appears to be highly related to their replication timing; alleles showing the common biallelic mode of expression replicate highly synchronously, whereas those with a monoallelic mode of expression replicate asynchronously. Here we used FISH to determine the level of synchronisation in replication timing of alleles in amniotic fluid cells derived from normal foetuses and from those with either of the trisomies for autosomes 21, 18 or 13, or for sex chromosomes (47,XXX and 47,XXY). Two pairs of alleles, not associated with the extra chromosome, were studied in subjects with each trisomy and three in normal subjects. In cells derived from normal foetuses and from foetuses with sex chromosome trisomies, each pair of alleles replicated synchronously; yet these very same alleles replicated asynchronously in cells derived from foetuses with trisomy for any of the three autosomes studied. The results suggest that the gross phenotypic abnormalities associated with an extra autosome are brought about not only by over-expression of genes present in three doses, but also by modifications in the expression of genes present in the normal two doses. (+info)
Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells.
A PCR strategy is described for global amplification of DNA from a single eukaryotic cell that enables the comprehensive analysis of the whole genome. By comparative genomic hybridization, not only gross DNA copy number variations, such as monosomic X and trisomic 21 in single male cells and cells from Down's syndrome patients, respectively, but multiple deletions and amplifications characteristic for human tumor cells are reliably retrieved. As a model of heterogeneous cell populations exposed to selective pressure, we have studied single micrometastatic cells isolated from bone marrow of cancer patients. The observed congruent pattern of comparative genomic hybridization data, loss of heterozygosity, and mutations as detected by sequencing attests to the technique's fidelity and demonstrates its usefulness for assessing clonal evolution of genetic variants in complex populations. (+info)