Abstract
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%, p < 0.001). As compared to individuals with FXS without seizures, those with seizures were more likely to have autism spectrum disorder, current sleep apnea, later acquisition of expressive language, more severe intellectual disability, hyperactivity, irritability, and stereotyped movements. The mean age of seizure onset was 6.4 (SD 6.1) years of age with the great majority (>80%) having onset of seizures which was before 10. For those with epilepsy, about half (52%) had seizures for more than 3 years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for <3 years. Antiepileptic drugs were more often used in males (60.6%) than females (34.8%), and females more often required more than one medication. The most commonly used anticonvulsants were oxcarbazepine, valproic acid, lamotrigine, and levetiracetam. The current study is the largest and first longitudinal study ever conducted to describe seizures in FXS. Overall, this study confirms previous reports of seizures in FXS and extends previous findings by further defining the cognitive and behavioral phenotype of those with epilepsy in FXS. Future studies should further investigate the natural history of seizures in FXS and the characteristics of seizures in FXS in adulthood.
Highlights
Fragile X syndrome (FXS) is the most common known inherited cause of intellectual disability, learning disability, and autism spectrum disorder (ASD), with an estimated prevalence of about 1/4,000 [1]
The analyses for this report were performed using baseline and longitudinal data collected during follow-up visits from FORWARD Version 5, with data obtained from 1,607 individuals with FXS evaluated between 2012 and 2020, who had information available about seizures derived from the Clinician Report form
Subjects were divided into three groups based on seizure experience
Summary
Fragile X syndrome (FXS) is the most common known inherited cause of intellectual disability, learning disability, and autism spectrum disorder (ASD), with an estimated prevalence of about 1/4,000 [1]. FXS results from a trinucleotide repeat (CGG) expansion mutation of >200 repeats (full mutation) in the promoter of FMR1 (fragile X mental retardation 1) gene [3] which leads to transcriptional silencing of FMR1 and loss or significant reduction of expression of the gene product, FMRP (fragile X mental retardation protein) [4]. In the absence of FMRP in the Fmr knockout (k/o) mouse model of FXS, there is immature dendritic spine morphology and regionand cell-dependent deficits in synaptic plasticity [8]. These synaptic abnormalities result in abnormal epileptiform discharges [9] and a high frequency of audiogenic seizures in the Fmr k/o mouse [10], presumably modeling the increased risk of seizures in humans with FXS
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