35.: Case report: Concurrent occurrence of Fragile X syndrome and Fragile X associated tremor ataxia syndrome due to CGG repeat and methylation mosaicism

Abstract

Fragile X syndrome (FXS) is a genetic disorder resulting from CGG trinucleotide repeat lengths greater than 200 and subsequent methylation of the FMR1 gene on the X chromosome. Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently described syndrome of tremor and ataxia in a relative of a FXS patient with clinical signs not seen in typical FXS patients. This syndrome is typically seen in patients over the age of 50 and is thought to be a result of neuronal toxicity from excess mRNA production due to CGG repeat lengths of 55 to 200. We present a 34-year-old gentleman with a previous diagnosis of FXS presenting with phenotypic features of FXTAS including cerebellar ataxia. Genetic testing with methylation assay revealed that he is a FXS and FXTAS mosaic with methylated CGG repeat lengths of 110 and 540 contributing to FXS and unmethylated CGG repeat lengths of 90 and 600 contributing to cerebellar ataxia and diagnosis of FXTAS. Despite the close genotypic relationship between FXS an FXTAS there are distinct phenotypic differences attributable to different methylation state. To our knowledge this is the first case to be reported of FXS/FXTAS mosaicism and adds to the increasing understanding of the role played by methylation in determining phenotypic expression of genetic disorders, in particular the importance of methylation mosaicism. We suggest that in a FXS patient presenting with cerebellar ataxia or tremor without an apparent cause, further genetic testing with methylation analysis should be considered in the diagnostic process.