This study examined the relationship between the Fragile X premutation and Restless Legs Syndrome (RLS). Demographic, medical history and survey responses related to sleep were collected from 213 participants (127 carriers and 86 age matched controls). Subjects were asked about the presence of the four formal diagnostic criteria for RLS. Individuals with the premutation were 1.9 times as likely to meet criteria for RLS (95% CI 1.1–3.2, p=0.025) as controls. Premutation carriers with RLS also experienced significantly worse symptoms than matched controls with adjusted mean scores of 15.1±8.8 vs. 7.9±4.4 respectively on the International Restless Legs Scale. As markers for domains of sleep disturbance, all subjects completed the Epworth Sleepiness Scale, the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. Premutation carriers demonstrated significantly more pathology on these tests except for the Epworth Sleepiness Scale where there was a trend towards increased daytime sleepiness in carriers. RLS joins a host of other conditions that should be carefully screened for in those carrying the Fragile X premutation and sleep should be a focus for clinicians providing care to them.

Background: Recent evidence has shown that mitochondrial dysfunction may be significant in carriers of the Fragile X premutation. Purpose: The present study examined fatigue severity and body mass index (BMI) (two possible outcomes related to mitochondrial dysfunction) in premutation carriers with and without the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) as compared to controls. Methods: Surveys to gather data on height and weight and fatigue impact (Fatigue Severity Scale) were sent out to previous research trial participants with Fragile X premutation-related disorders. Results: On the Fatigue Severity Scale, carriers with and without FXTAS had mean scores of 4.5 (SD 1.9) and 3.8 (SD 1.6), respectively, that differed significantly (p < 0.001) from the control mean score of 2.9 (SD 1.4). The mean BMI of carriers with FXTAS was 29.6 kg/m 2 (SD 5.3) which differed significantly (p = 0.003) from the mean BMI of carriers without FXTAS of 26.9 kg/m 2 (SD 5.1) and controls 26.7 kg/m 2 (SD 4.4). However, premutation carriers without FXTAS did not differ significantly in BMI from controls. Conclusions: The present study suggests potentially important clinical outcomes that may be related to the mitochondrial dysfunction seen in molecular studies previously done with premutation carriers.