Atypical neurological symptoms associated with CGG expansions of the FMR1 gene

Abstract

More than 40 CGG expansions in the 5’ noncoding region of the fragile X mental retardation 1 (FMR1) gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion. First, more than 200 CGG expansions (full mutation) cause an inherited mental retardation called fragile X syndrome. Second, CGG expansions between 55 and 199 (premutation) cause a disorder called fragile X-associated tremor/ataxia syndrome (FXTAS) which typically includes intention tremor, ataxia and specific magnetic resonance imaging (MRI) findings. Indeed, it could develop parkinsonism although it usually shows features of postsynaptic parkinsonism. Finally, CGG expansions between 41 and 54 CGG (gray zone) are not consider normal but rarely develops abnormal neurological conditions. In this sense, the aim of this study is to report two atypical cases associated with CGG expansions of the FMR1 gene. First, a FMR1 premutation alleles carrier with an unusual phenotype, such as a presynaptic parkinsonism indistinguishable from Parkinson disease (PD) and a FMR1 gray zone alleles carrier presented with neurological features, namely hand tremor, parkinsonism and ataxia, usually described in FXTAS, as well as orthostatic tremor. We conclude that, on the one hand, FMR1 premutation alleles might cause two phenotypes of parkinsonism, such as a presynaptic phenotype, indistinguishable from PD, and a postsynaptic phenotype, associated with clinical features of FXTAS. On the other hand, although FMR1 gray zone alleles carriers were believed to have no abnormal neurological conditions, our study supports that they could develop FXTAS and other neurological disorders such as orthostatic tremor which has not been reported before associated with the FMR1 gene.

Keywords: Fragile X-associated tremor/ataxia syndrome, Fragile X mental retardation, Gray zone, Parkinsonism, Orthostatic tremor

Core tip: In this study we report two atypical cases associated with CGG expansions of the fragile X mental retardation 1 (FMR1) gene. First, a FMR1 premutation alleles carrier presented with a parkinsonism indistinguishable from Parkinson disease. Second, a FMR1 gray zone alleles carrier presented with orthostatic tremor and neurological features associated with the fragile X-associated tremor/ataxia syndrome, such as hand tremor, parkinsonism and ataxia.