Developmental instability of the cerebellum and its relevance to Down syndrome

It has been recognized for many years that cerebellar abnormalities are frequently observed in association with Down syndrome (DS). An important question to be asked about these and other findings in DS is whether their occurrence (i) is attributable to specific loci on the triplicated chromosome or chromosomal segment or (ii) derives from exaggerated responses secondary to the genetic imbalance resulting from trisomy (Ts). Recently, similar cerebellar alterations were observed in subjects with DS and in Ts65Dn mice (Baxter et al., 2000), mice segmentally trisomic for a portion of chromosome 16, 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 changes in DS and in the DS mouse model resulted from triplication of these homologous loci in the two trisomic organisms, i.e. cerebellar development is affected similarly by homologous loci in each species. They wrote that their study of Ts65Dn mice "correctly predicts an analagous pathology in humans" ... and that... "The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS." Findings 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 expression of response(s) is exacerbated by trisomy. This conclusion is based on the following: (i) the cerebellum has an extended postnatal development; (ii) numerous genetic, environmental, epigenetic and metabolic conditions express cerebellar changes similar to those observed in Down syndrome; (iii) most if not all chromosomal imbalance syndromes express similar cerebellar abnormalities; (iv) the cerebellum is particularly sensitive to diverse toxic agents which may act prenatally, postnatally and/or in the mature organism; and (v) cerebellar abnormalities similar to those found in Ts65Dn mice have been described in Tsl9 mice which have no segments homologous to any segment of human chromosome 21. An unavoidable conclusion from the review is that triplication of specific loci on 21q is an unlikely explanation for the cerebellar findings in DS. A simple positive control, in which the effect of triplication of loci other than those in question on a specific phenotype, should be used in experiments comparing human and experimental trisomies. 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 trisomy is responsible for the genesis of traits at issue.