Reflections on the pathogenesis of Down syndrome

Abstract

Present efforts to identify, isolate, and characterize in molecular terms the "consensus" s e g ment of 21q sufficient to cause most of the major and some of the most characteristic minor manifestations of Down syndrome will soon provide answers to many questions. However, we think that a reductionist approach to explain the Down syndrome phenotype in a "linear" manner from the DNA sequence of the segment will be doomed to failure from the outset because of the open, complex, nonlinear, hierarchical nature of morphogenetic systems. Neo-Darwinism is under strong attack; most genetic changes accumulated over time may very well be of neutral effect, and detailed studies in several related groups of vertebrate species has shown that molecular and organismal evolution are largely independent of one another. It has been pointed out recently that biology lacks a theory of ontogenetic and phylogenetic development, and that a purely "genocentric" view of biology at the expense of the complexly hierarchical intrinsic epigenetic attributes of developmental systems is "out of focus with respect to.. . biological organization and morphogenesis," and may be "a residue of nineteenth century romantic idealism." Down syndrome impresses us as a paradigm of increased developmental variability due to a deceleration of the rate of development (neoteny) with many anomalies of incomplete morphogenesis (vestigial, atavisms, increased morphometric variability with many decreased means, increased variances, and increased fluctuating asymmetry. These abnormalities, together with highly increased risk of prenatal death and postnatal mor-

Unimanual and Bimanual Continuous Movements Benefit From Visual Instructions in Persons With Down Syndrome

“…Nine persons with DS were deemed left-handed and three persons with DS were deemed mixed-handed and were not included in the analyses. This representation of left-and mixed-handedness is consistent with literature that suggested that prevalence of non-right-handed persons with DS varies between 25% and 50% depending on criteria used for discrimination (GerardDesplanches et al, 2006;Opitz & Gilbert-Barness, 1990;Soper, Satz, Orsini, Van Gorp, & Green, 1987). MA and CA were asked prior to participation if they were right-handed and the handedness inventory confirmed that there were no left-handed individuals in our typical populations.…”

Correlation of Prenatal Sonographic Diagnosis and Morphologic Findings of Fetal Autopsy in Fetuses With Trisomy 21

“…Certain defects of closure of the embryo, often called "midline defects," have a very low incidence in Down syndrome. 24,26 These defects include the neural tube defects, cleft lip/palate, ectopia cordis, and exstrophy of the urinary bladder. Instead, some of these are characteristic symptoms of other trisomies.…”

Differences in purine metabolism in patients with Down's syndrome

“…Much progress has been made in understanding not only, the molecular basis of the pathophysiology and phenotype of Down's syndrome but also some of the biochemical modifications resulting from the chromosomal imbalance (Cooper & Hall 1988;Lejeune 1983Lejeune , 1990Lejeune et al 1992;Opitz & Gilbert-Bamess 1990;. Despite the clinical importance of trisomy 21, little is known about the mechanisms by which chromosomal imbalance results in specific and often highly deleterious phenotypic effects.…”