The growth capacity of bone marrow CD34 positive cells in culture is drastically reduced in a murine model of Down syndrome

Human trisomy 21, Down syndrome (DS), is characterized by mental retardation. In addition, high risks of developing hematological and immune disorders, as well as cardiac, skeletal and other abnormalities are life-long concerns. Recent data suggested that bone marrow contains progenitors, hematopoietic or stromal cells, which may have the potential of generating non hematopoietic tissue such as neural cells, cardiac cells or osteoblasts. Therefore we have used a model of Down syndrome, Ts65Dn mice, to investigate their bone marrow. We have found that the vast majority of CD34(+) cells in the bone marrow of adult Ts65Dn mice, but not of the CD34(-) cells, exhibit a drastic reduction in their in vitro growth capacity. In addition to neural antigens, cultured CD34(+) cells from trisomic and diploid mice also expressed mast cell markers.     

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. The present study was undertaken with a larger sample size to determine whether the MTHFR 677C-->T polymorphism was associated with increased risk of having a child with Down syndrome. Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism. A common polymorphism in this gene was recently associated with increased risk of neural tube defects and might also contribute to increased risk for Down syndrome. The frequencies of the MTHFR 677C-->T and MTRR 66A-->G mutations were evaluated in DNA samples from 157 mothers of children with Down syndrome and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results are consistent with the preliminary observation that the MTHFR 677C-->T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91 (95% confidence interval [CI] 1.19-3.05). In addition, the homozygous MTRR 66A-->G polymorphism was independently associated with a 2. 57-fold increase in estimated risk (95% CI 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an odds ratio of 4.08 (95% CI 1.94-8.56). The two polymorphisms appear to act without a multiplicative interaction.     

Growth curves of children with Down syndrome.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight. These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.     

Social perceptions of the effects of Down syndrome facial surgery: a school-based study of ratings by normal adolescents

This study examines how 277 normal adolescents from five Israeli schools perceive the Down syndrome face before and after plastic surgery. A seven-point Likert scale was used to rate slides of normal and Down syndrome faces on four dimensions. Down syndrome patients were seen as less attractive, intelligent, good-hearted, and socially appealing than normal individuals. The slides were in nonapparent order and contained preoperative and 1-year postoperative views of eight plastic surgical patients. Paired t tests were used to examine operative changes, and all four dimensions showed overall postoperative improvement (p less than 0.001), but case-to-case variation was considerable. A linear relationship was found between change in appearance ratings and change in intelligence ratings. Findings suggest that when improvements in facial appearance are realized, peer normal social perceptions of the Down syndrome child may be enhanced. The relationship between school placement, intellectual level, and surgical decision making is discussed.     

The effect of a pattern in palmar interdigital II on a-b ridge count in black and white Down syndrome cases and controls

An unconfirmed study by Fang (Ph.D. thesis, Univ. of London, 1950) in Britain showed that individuals with Down syndrome had lower total a-b ridge counts in palmar Interdigital area II (ID II) than a group of controls. This study compares 603 white Down syndrome cases and 93 black Down syndrome cases with 668 white and 402 black controls. Our results confirm those of Fang in that the Down syndrome cases in both racial groups had lower total a-b ridge counts than their respective controls. In addition, the black controls and Down syndrome cases had lower a-b ridge counts than their white counterparts. The mean a-b ridge count was significantly lower in individuals with a pattern in ID II compared to individuals without a pattern in ID II in both the Down syndrome and control groups. Some of the lower a-b ridge counts in the Down syndrome samples can be accounted for by the fact that there is an increased frequency of a pattern in ID II in Down syndrome cases. Both Down syndrome and normal individuals who had a pattern unilaterally had a lower than expected a-b ridge count on the contralateral hand that did not have a pattern. There was a tendency also for increased asymmetry in Down syndrome cases with a pattern in ID II.     

Maternal fever and neural tube defects

It has been proposed that hyperthermia in the pregnant woman is associated with neural tube defects in her offspring. We analyzed retrospective interview data for a maternal history of probable febrile illness during the first trimester of pregnancy among mothers of infants with anencephaly or spina bifida. There were two control groups--mothers of infants with Down syndrome and mothers of infants with cleft lip or palate. With the Down syndrome group serving as controls, the incidence of febrile illness among mothers of all infants with neural tube defects was significantly elevated. With the cleft group as controls, the fever incidence was not significantly increased in the neural tube defect groups. When the combined cleft and Down syndrome controls were used, only mothers of the spina bifida group had an elevated fever incidence. Epidemiology data suggest an association of maternal fever during pregnancy with neural tube defects in the offspring.     

Germinal and Somatic Trisomy 21 Mosaicism: How Common is it,What are the Implications for Individual Carriers and How Does it Come About?

It is well known that varying degrees of mosaicism for Trisomy 21, primarily a combination of normal and Trisomy 21 cells within individual tissues, may exist in the human population. This involves both Trisomy 21 mosaicism occurring in the germ line and Trisomy 21 mosaicism documented in different somatic tissues, or indeed a combination of both in the same subjects. Information on the incidence of Trisomy 21 mosaicism in different tissue samples from people with clinical features of Down syndrome as well as in the general population is, however, still limited. One of the main reasons for this lack of detailed knowledge is the technological problem of its identification, where in particular low grade/cryptic Trisomy 21 mosaicism, i.e. occurring in less than 3-5% of the respective tissues, can only be ascertained by fluorescence in situ hybridization (FISH) methods on large cell populations from the different tissue samples.In this review we summarize current knowledge in this field with special reference to the question on the likely incidence of germinal and somatic Trisomy 21 mosaicism in the general population and its mechanisms of origin. We also highlight the reproductive and clinical implications of this type of aneuploidy mosaicism for individual carriers. We conclude that the risk of begetting a child with Trisomy 21 Down syndrome most likely is related to the incidence of Trisomy 21 cells in the germ line of any carrier parent. The clinical implications for individual carriers may likewise be dependent on the incidence of Trisomy 21 in the relevant somatic tissues. Remarkably, for example, there are indications that Trisomy 21 mosaicism will predispose carriers to conditions such as childhood leukemia and Alzheimer's Disease but there is on the other hand a possibility that the risk of solid cancers may be substantially reduced.     

Mosaic autosomal trisomy in cultures from spontaneous abortions.

In a consecutive series of 592 karyotyped spontaneous abortions, ten of 103 autosomal trisomies were mosaic, with a normal cell line also present. The frequency of mosaicism (10%) is much higher than that reported in Down syndrome, but similar to that reported in amniotic fluid cultures and in induced abortions. The most likely explanations for this discrepancy are (1) previous underestimation of mosaicism in live births or (2) mosaicism which is often restricted to extraembryonic fetal tissue.     

Social smiling in normal and down syndrome infants: A comparative study

The aim of this work has been to compare social smiling in Down syndrome (mongolism) and normal infants, attending especially to the brow movements that appear before it. Facial responses of eight Down syndrome and eight normal infants from three to five months were analized by means of an anatomically based measurement technique during face-to-face interactions with their mothers. Despite their mental retardation, Down syndrome infants showed identical muscle movements as normal infants before and during smiling. However, some differences were found in smile frequency and leght, as well as in the brow movements frequency before smiling. Results are discussed in terms of the psychophisiological dysfunction of Down syndrome infants that are originated by a chromosome imbalance.     

The nucleotide sequence and the tissue-specific expression of Drosophila c-src

We have examined the coding capability and expression of the Drosophila homolog of the vertebrate proto-oncogene c-src. Sequence analysis of a cDNA clone representing the Drosophila c-src locus suggests that the gene encodes a 62 kd protein that is remarkably similar to the protein product of chicken c-src. The Drosophila c-src locus is transcribed into three mRNAs that are each regulated independently during development. Drosophila c-src RNA is abundant in embryos and pupae but rare in larvae and adults. In situ hybridization reveals that after the first 8 hr of development, c-src RNA accumulates almost exclusively in neural tissues such as the brain, ventral nerve chord, and eye-antennal discs, and in differentiating smooth muscle. We conclude that c-src may not be a mitotic signal but instead may play a role in the development of neural tissue and smooth muscle.     

Molecular changes in fetal Down syndrome brain

Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegeneration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of developmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of biochemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation.     

Fluctuating dental asymmetry: A measure of developmental instability in Down syndrome

Subjects with Down syndrome provide a useful model for investigating the effect of chromosomal aneuploidy on developmental pathways. Studies suggest that a major effect of trisomy is a decrease in developmental stability. The present study examines fluctuating dental asymmetry in Down syndrome. Mesiodistal crown diameters were measured from dental casts of 114 Down syndrome subjects. Correlation coefficients for antimeric permanent teeth served as an index of dental asymmetry. These values were compared with normal values obtained from the literature. Fluctuating dental asymmetry is thought to reflect the relative success of developmental homeostasis in countering developmental disturbances. Down syndrome subjects have significantly increased dental asymmetry. In addition, they show a disproportionate increase in dental asymmetry for those teeth reported to have the least developmental stability. These results support the contention that the chromosomal imbalance in Down syndrome results in amplified developmental instability.     

Auditory function in the Tc1 mouse model of down syndrome suggests a limited region of human chromosome 21 involved in otitis media

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.     

Communalities for rates of diaphyseal elongation of short bones of the hand of children with Down syndrome

Communality indices for rates of elongation of diaphyses of short bones of the hand were computed from serial data for children with Down syndrome, 7 to 14 years of age. Communalities were larger for adjacent than for nonadjacent bones and also larger for bones grouped in rows rather than rays of the hand. This pattern is similar to that reported for normal children. Communality indices for rates of diaphyseal elongation for girls with Down syndrome were lower than those of boys with Down syndrome and normal children.     

A systems biology approach to Down syndrome: Identification of Notch/Wnt dysregulation in a model of stem cells aging

Stem cells are central to the development and maintenance of many tissues. This is due to their capacity for extensive proliferation and differentiation into effector cells. More recently it has been shown that the proliferative and differentiative ability of stem cells decreases with age, suggesting that this may play a role in tissue aging. Down syndrome (DS), is associated with many of the signs of premature tissue aging including T-cell deficiency, increased incidence of early Alzheimer-type, Myelodysplastic-type disease and leukaemia. Previously we have shown that both hematopoietic (HSC) and neural stem cells (NSC) in patients affected by DS showed signs of accelerated aging. In this study we tested the hypothesis that changes in gene expression in HSC and NSC of patients affected by DS reflect changes occurring in stem cells with age. The profiles of genes expressed in HSC and NSC from DS patients highlight pathways associated with cellular aging including a downregulation of DNA repair genes and increases in proapoptotic genes, s-phase cell cycle genes, inflammation and angiogenesis genes. Interestingly, Notch signaling was identified as a potential hub, which when deregulated may drive stem cell aging. These data suggests that DS is a valuable model to study early events in stem cell aging.