Clinical Heterogeneity in a Scandinavian FMR1 Premutation Carrier Cohort and Basal Ganglia Atrophy in FXTAS

Pathological CGG expansions in the FMR1 gene, encompassing premutations (55–200 repeats) and full range mutations (> 200 repeats), cause a spectrum of complex and incurable disorders. Premutation carriers (PMC), particularly men, face the risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS). Other conditions associated with premutations in FMR1 include both Fragile X-associated primary ovarian insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). Hyperintensities in the middle cerebellar peduncle (MCP), known as the MCP sign, have been considered a radiological hallmark for FXTAS. FMR1-related disorders have not been characterized in Scandinavia. Here, we delineate the clinical spectrum of FMR1 related disorders among PMC emphasizing neuroimaging abnormalities and assess the correlation between CGG repeat size and clinical parameters as well as neuroimaging abnormalities at a tertiary center in Sweden. In total 33 PMC were evaluated (19 women and 14 men) of which 21 received a FMR1 related disorder (64%). As expected, penetrance for a FMR1 related disorder was higher among men (11/14 [79%]) than in women (12/19, [63%]). We also found that hyperintensities in the splenium of corpus callosum (CCS sign) were more prevalent than the MCP sign, and volumetric analyses revealed atrophy in the basal ganglia, cerebellar grey and white matter among FXTAS patients. CGG expansion size correlated with motor scores but not with age of onset. Our findings indicate a high prevalence of FMR1-related disorders in this PMC cohort in which the CCS sign is more common than the MCP sign. Larger cohort studies are necessary to assess atrophy of the basal ganglia and its clinical correlations among FMR1 PMC.