Expanded clinical phenotype of women with the FMR1 premutation

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Abstract
Fragile X‐associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20–75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age‐matched controls (mean, 45.8 years; range, 21–78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co‐morbidity, with increased prevalence of thyroid disease (P = 0.0096), hypertension (P = 0.0020), seizures (P = 0.0077), peripheral neuropathy (P = 0.0040), and fibromyalgia (P = 0.0097), in addition to the typical symptoms of FXTAS–tremor (P < 0.0001) and ataxia (P < 0.0001). The non‐FXTAS premutation group had more complaints of chronic muscle pain (P = 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co‐morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non‐FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS.