Developmental instability of the cerebellum and its relevance to Down syndrome

It has been recognized for many years that cerebellar abnormalities are fre quently observed in association with Down syndrome (DS). An important quest ion to be asked about these and other findings in DS is whether their occur rence (i) is attributable to specific loci on the triplicated chromosome or chromosomal segment or (ii) derives from exaggerated responses secondary t o the genetic imbalance resulting from trisomy (Ts). Recently, similar cere bellar alterations were observed in subjects with DS and in Ts65Dn mice (Ba xter et al., 2000), mice segmentally trisomic for a portion of chromosome 1 6, which is homologous for loci on the long arm of human chromosome 21. It was concluded by these authors that the occurrence of similar cerebellar ch anges in DS and in the DS mouse model resulted from triplication of these h omologous loci in the two trisomic organisms, i.e. cerebellar development i s affected similarly by homologous loci in each species. They wrote that th eir study of Ts65Dn mice "correctly predicts an analagous pathology in huma ns"... and that... "The candidate region of genes on chromosome 21 affectin g cerebellar development in DS is therefore delimited to the subset of gene s whose orthologs are at dosage imbalance in Ts65Dn mice, providing the fir st localization of genes affecting a neuroanatomical phenotype in DS." Find ings described in this review suggest otherwise - that cerebellar findings in DS and in the Ts65Dn mouse are a result of exaggerated vulnerability in general of the cerebellum to disturbing events and that liability to expres sion of response(s) is exacerbated by trisomy. This conclusion is based on the following: (i) the cerebellum has an extended postnatal development; (i i) numerous genetic, environmental, epigenetic and metabolic conditions exp ress cerebellar changes similar to those observed in Down syndrome; (iii) m ost if not all chromosomal imbalance syndromes express similar cerebellar a bnormalities; (iv) the cerebellum is particularly sensitive to diverse toxi c agents which may act prenatally, postnatally and/or in the mature organis m; and (v) cerebellar abnormalities similar to those found in Ts65Dn mice h ave been described in Ts19 mice which have no segments homologous to any se gment of human chromosome 21. An unavoidable conclusion from the review is that triplication of specific loci on 21q is an unlikely explanation for th e cerebellar findings in DS. A simple positive control, in which the effect of triplication of loci other than those in question on a specific phenoty pe, should be used in experiments comparing human and experimental trisomie s. As pointed out many years ago by Lorke and his coworkers (Lorke et al., 1989; Lorke, 1994; Lorke and Albrecht, 1994) similar phenotypic findings in the presence of different trisomies in the same species would suggest that the trisomic state itself rather than the gene content of a particular tri somy is responsible for the genesis of traits at issue.