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. 2021 Dec 30:9:736255.
doi: 10.3389/fped.2021.736255. eCollection 2021.

Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort

Elizabeth Berry-Kravis  1   2 , Robyn A Filipink  3 , Richard E Frye  4   5 , Sailaja Golla  6 , Stephanie M Morris  7 , Howard Andrews  8 , Tse-Hwei Choo  9 , Walter E Kaufmann  10 ; FORWARD Consortium
Collaborators, Affiliations

Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort

Elizabeth Berry-Kravis et al. Front Pediatr. .

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.

Keywords: Fragile X syndrome; autism spectrum disorder; epilepsy; longitudinal; seizures.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Association between intellectual disability (ID), autism spectrum disorder (ASD), and seizures in FXS. (A) The bar graph depicts the proportion (in percentages) of individuals with and without seizures at each level of ID. Note the higher proportion of patients with seizures at the higher levels of ID severity. DD corresponds to developmental delay in younger individuals. (B) The graph shows the proportion (in percentages) of individuals with and without seizures diagnosed (or not) with ASD. Note in the group with ASD, a higher proportion of patients with seizures.
Figure 2
Figure 2
Age of onset and resolution of seizures. (A) Bar graph showing the proportion (in percentages) of individuals, divided by sex, with onset of seizures at different 5 year bins. Note that, with exception of a subset of females with onset after age 15, most patients with FXS displayed an onset before age 10. (B) Bar graph showing the proportion (in percentages) of individuals, divided by sex, experiencing last seizures at different 5 year bins. As for seizure onset, most patients had their last seizure before age 15, with exception of a subset of females who has seizure resolution after this age.
Figure 3
Figure 3
Seizure types and anticonvulsant use in FXS. (A) Pie graph depicting the proportion of each seizure type in the entire FXS cohort. (B) Graphs showing the number of anticonvulsants per patient in males and females, respectively. Note the higher proportion of males on anticonvulsants. (C) Number of patients with FXS using the most common anticonvulsants. Oxcarbazepine, valproic acid, and lamotrigine were the three most commonly prescribed anticonvulsants.
Figure 4
Figure 4
Plot of time to first seizure. (A) Reverse Kaplan–Meier estimates show the estimated proportion of subjects who had their first seizure onset reported, over ages 0 to 30. Band shows 95% confidence intervals for estimates. For example, approximately 7% of subjects had first seizure onset by age 5, approximately 12% of subjects had first seizure onset by age 10, and approximately 14% of subjects had first seizure onset by age 15. Bar chart of the model-estimated proportion of having any seizures during selected age periods (B). Proportion estimates are derived from mixed-effect logistic regression models fit for the odds of having experienced a seizure, with categorized age as the predictor, and random intercepts for subject.
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References

    1. Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, et al. . Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. (2009) 85:503–14. 10.1016/j.ajhg.2009.09.007 - DOI - PMC - PubMed
    1. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, et al. . Fragile X syndrome: a review of associated medical problems. Pediatrics. (2014) 134:995–1005. 10.1542/peds.2013-4301 - DOI - PubMed
    1. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, et al. . Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. (1991) 65:905–14. 10.1016/0092-8674(91)90397-H - DOI - PubMed
    1. Devys D, Lutz Y, Rouyer N, Bellocq JP, Mandel JL. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet. (1993) 4:335–40. 10.1038/ng0893-335 - DOI - PubMed
    1. Volk LJ, Pfeiffer BE, Gibson JR, Huber KM. Mutiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation. J Neurosci. (2007) 43:11624–34. 10.1523/JNEUROSCI.2266-07.2007 - DOI - PMC - PubMed