Prenatally Diagnosed Uncommon Mosaic Autosomal Trisomy

Prenatal diagnosis of rare autosome mosaicism involvingchromosomes other than chromosome 13, 18, 21 or the sex chromosome is encountered prognostic dilemma during genetic counseling. We report four cases of level III uncommon mosaicism of trisomy 5, 16 and 20,diagnosed prenatally. In case 1 with mosaic trisomy 20, there was a higher mosaic ratio of trisomy 20 in the repeat amniocentesis (62.1%) than in the first (36.6%) with normal fetal ultrasound finding except for a relatively small aorta on a 3-vessel view of the fetal heart. Case 2 showed a low rate of mosaic trisomy 20 (5.25%) in cultured amniocytes but normal karyotype in the repeat amniocentesis, who delivered a normal healthy baby. Case 3 showed a 13.6% of trisomy 16 mosaicism in the 30 cells of cultured amniocytes. Sixty cells from a fetal blood sample at termination showed non-mosaic 46,XX normal karyotype, while skin fibroblasts had 22.5% trisomy 16 in 40 metaphases. The autopsy showed ventricular septal defect (VSD). Case 4 with low grade mosaicism (10.5%) of trisomy 5 resulted in elective termination, though the ultrasoumd showed growsly normal fetus. Although level III mosaicism is regarded as true mosaicism, it is difficult to predict the outcome of the fetus with rare mosaic autosome trisomy. Therefore mosaic autosome trisomy of fetus should be carefully interpreted with more various approaches including repeat sampling and targeted fetal ultrasound.

Small-molecule aggregation inhibitors reduce excess amyloid in a trisomy 16 mouse cortical cell line

We have previously characterized a number of small molecule organic compounds that prevent the aggregation of the β-amyloid peptide and its neurotoxicity in hippocampal neuronal cultures. We have now evaluated the effects of such compounds on amyloid precursor protein (APP) accumulation in the CTb immortalized cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down's syndrome. Compared to a non-trisomic cortical cell line (CNh), CTb cells overexpress APP and exhibit slightly elevated resting intracellular Ca2+ levéis ([Ca2+]¡). Here, we show that the compounds 2,4-dinitrophenol, 3-nitrophenol and 4-anisidine decreased intracellular accumulation of APP in CTb cells. Those compounds were non-toxic to the cells, and slightly increased the basal [Ca2+]¡. Results indícate that the compounds tested can be leads for the development of drugs to decrease intracellular vesicular accumulation of APP in trisomic cells.

Cell Proliferation and Apoptosis in Heart of Trisomy 16 in Mice

PURPOSE: Although abnormal developments of cushion and atrioventricular septum have been suggested, the exact mechanism for the development of atrioventricular septal defect is not well known. We aimed to identify the role of cell proliferation and apoptosis on cardiac morphogenesis in trisomy 16 mice(an animal model for Down's syndrome in human). METHODS: We examined the difference in cardiac masses and structures of trisomy 16 mice and normal control mice at stages of embryonal day 11, day 14 and day 16, when the endocardial cushion grows rapidly. We prepared cardiac section slides with PCNA and TUNEL staining and measured the amount, location of cell proliferation and apoptosis with computerized image analysis system. RESULTS: Atrioventricular septal defects were evident at day 14 and day 16 trisomy embryos. The ventricle areas were smaller in trisomy mice especially at day 14 embryos(P=0.04). And the cell proliferation rates were lower in trisomy mice along these periods. The rate of apoptosis was lower in trisomy embryo than control at both ventricular myocytes and interventricular septum, but characteristically apoptotic bodies were condensed at endocardial cushion area in trisomy 16 embryo. CONCLUSION: The developmental problems of atrioventricular septal defect of trisomy 16 mice resulted from myocardial hypoplasia and late localized apoptosis at cushion area, and these changes may play an important role in ventricular remodelling of atrioventricular septal defect.

Abnormal Development and Apoptosis Observed in Brains of the Trisomy 16 Mouse

We have studied morphologic characteristics and apoptosis on the fetal brain of the trisomy 16 mouse, a model for human trisomy 21 syndrome. This study was based on serial sections of the whole brain from a sample of sixteen trisomy 16 mice and forty-six age-matched control littermates from embryonic day (ED) 12 to ED 18. Trisomy 16 brains showed a reduction of telencephalic size and abnormal cortical development. At ED 13 trisomy 16 and control brains appeared similar. By ED 14 difference in the cortical thickness and telencephalic growth became evident, and by ED 16 a marked size difference had developed between the trisomy 16 and control brains. By ED 18, however, the thickness of the trisomy 16 cortex had increased considerably and was not significantly different with respect to the thickness and cross-sectional areas of the pallium and its constituent cortical layers. The cell density of the trisomy 16 cortex had persistently decreased before ED 17, when the cell density of control and trisomy 16 corteces was similar within each layer. At ED 18 cell density of trisomy 16 cortex in each layer increased. There was inverse relationship between a number of TUNEL positive apoptotic cells and cell density in the trisomy 16 brains. Our results suggest that developmental abnormalities of the trisomy 16 brain indicated developmental delay of the telencephalon growth, which may be caused by apoptosis rather than by a proliferation defect.

Craniofacial Morphogenesis of Mouse with Trisomy 16

Based on the genetic homology between mouse chromosome 16 and human chromosome 21, experimentally induced trisomy 16 mouse has been considered to serve as a suitable model for human Down syndrome. Mice with trisomy 16 express several phenotypic characteristics of human trisomy 21 syndrome; i.e., intrauterine growth retardation, anarsarca, congenital heart disease, brain abnormality, etc. To elucidate morphogenesis of characteristic craniofacial malformation in human Down syndrome, we studied trisomy 16 mouse fetuses that were produced by crossing karyotypically normal C57BL/6 female ice with males carrying the two Robertsonian translocation chromosome Rb(16.17)/Rb(11.16). We examined a series of trisomy 16 conecptuses and their normal littermate controls from day 14 to day 18 of gestation by gross observation and serial microscopic sections. In addition to smaller size and generalized edema, we observed variable, but definite delay in brain and craniofacial development in trisomy 16 mice. The brain revealed less stratified telencephalon, underdeveloped thalamus and hypothalmus with relatively wide third ventricle, and small rhombencephalon. Craniofacial underdevelopment was characterized by persistent open eye, cochlea with fewer turns, delayed closure of the palate, more simple nasal cavity, etc. The tongue was shorter and convex upward, that were especially prominent at 14 days of gestation. The convex tongue and underdeveloped brain made the cranial base convex upward, and the angle between the cranial base an vertebral axis more obtuse. Small head with increase cephalic index and midfacial hypoplasia appeared to account for brain underdevelopment.