Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation

Background:Male carriers of the FMR1 premutation are at risk of developing the fragile X–associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling.Methods:The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score ⩽123 on the MDRS.Results:Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p