Immune mediated disorders in women with a fragile X expansion and FXTAS

Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late‐onset neurodegenerative disorder, fragile X‐associated tremor ataxia syndrome (FXTAS) and/or the fragile X‐associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms—often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre‐existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. © 2014 Wiley Periodicals, Inc.