aphidicolin and Tourette-Syndrome

An analysis of all aphidicolin-inducible breakpoints has been carried out in PHA stimulated T-lymphocytes of five patients with classical Rett syndrome, their mothers and a group of age matched controls. Observed breakpoints were divided into two groups: common, rare, and those recorded by others but not assigned as fragile sites by CCM92 and a group of non-specified breakpoints recurrently found in our ongoing study of fragile sites. In addition cooccurrence of trisomy X in one patient and de novo pericentromeric inversion on chromosome 2 in another Rett syndrome patient are reported. The co-occurrence with the Tourette syndrome in two of our families, and the fact that both Rett and Tourette syndrome are associated with movement disorders, possible dopaminergic hypersensitivity and increased chromosomal fragility in subsets of fragile sites, may suggest a possible avenue for further research. The cytogenetic findings indicate that both X-linked and autosomal regulatory region(s) may be part of a complex genetic alteration in association with Rett syndrome.

Topics: Aphidicolin; Chromosome Aberrations; Chromosome Fragile Sites; Chromosome Fragility; Chromosomes, Human, Pair 2; Female; Humans; Karyotyping; Matched-Pair Analysis; Rett Syndrome; T-Lymphocytes; Tourette Syndrome; Trisomy; X Chromosome

In a comparison of 80 common aphidicolin-induced fragile sites (FS) between 26 DSM-IV Tourette syndrome (TS) and 24 control individuals, the mean of the summed break frequencies following mild aphidicolin pretreatment was significantly higher in TS individuals than in controls (P < 0.001). Other breakpoints encountered during this study, i.e., random breaks, breaks corresponding to rare FS, and breakpoints recorded by others but not listed as common FS according to the Chromosome Coordinating Meeting [1992] were listed as category II breakpoints. By using the most significantly different mean FS breakage figures between TS and control individuals, further stepwise discriminant analysis allowed identification of TS individuals from only a few sites in both the common FS and category II breakpoint groups. Future research needs to focus on confirmation of altered common fragile site expression in association with behavioral variation, whether expression of certain discriminatory sites concurs with specific comorbid disorder expression; the nature of the molecular alterations at these FS and the implications of a genomic instability phenotype for the mapping of a primary TS gene or genes.

Topics: Adult; Aphidicolin; Case-Control Studies; Cells, Cultured; Chromosome Fragile Sites; Chromosome Fragility; Comorbidity; Female; Humans; Lymphocytes; Male; Phenotype; Tourette Syndrome