Origins of Epilepsy in Fragile X Syndrome

Abstract

Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of information regarding the synaptic dysfunction that underlies the hyperexcitability and epileptiform features associated with this disorder.Fragile X syndrome is the most common heritable form of cognitive impairment and the principal single-gene disorder associated with autism currently known (1,2). The disorder arises when a CGG-repeat tract in the 5 noncoding region of the fragile X mental retardation 1 (FMR1) gene exceeds approximately 200 repeats (i.e., the full mutation range), at which point the gene becomes hypermethylated and transcriptionally silent (3). The absence of the FMR1 protein, FMRP, is responsible for the syndrome's clinical phenotype (4-7). The frequency of full mutation alleles in the general population is approximately 1 in 2,500 (8,9). Physical features of fragile X syndrome typically include prominent ears, long face, higharched palate, macroorchidism, and hyperextensibility of finger joints. Approximately 85% of males and 25% of females experience cognitive impairment (IQ < 70); however, nearly all patients present with behavioral dysregulation, with males tending to present with attention deficit hyperactivity disorder and FMRP is an RNA-binding protein that is believed to have multiple functions, including involvement in the dendritic transport of various mRNA species (11) and the translational regulation of mRNAs whose protein products are involved in synaptic development, function, and plasticity (12). Among known targets of FMRP-coupled translational downregulation are: 1) the microtubule-associated protein 1B (MAP1B), which is important for modulating microtubule-coupled growth of dendritic spines and for dendritic arborization (13,14), and 2) Arc, which plays a role in the internalization of subunits of AMPA (15,16) and GABA A (17) receptors.One important characteristic of fragile X syndrome is the cooccurrence of seizures in 10 to 20 percent of individuals with full mutations (18,19). Seizure patterns on EEG typically reflect features of benign focal epilepsy of childhood (especially benign childhood epilepsy with centrotemporal spikes, also known as benign Rolandic epilepsy). In the study by Berry-Kravis involving 16 children with fragile X syndrome and epilepsy, 12 children exhibited partial seizures, with 10 of the 12 having an EEG with centrotemporal spikes (19). In addition, 23% of the children who did not have seizures displayed abnormal patterns on EEG, typically centrotemporal spikes. For most individuals, seizures are readily controlled and tend to disappear in adolescence. Therefore, ...

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…Increased body weight [111,117] Obesity in a subgroup of patients [174] Neuronal hyperactivity Audiogenic seizures~40-80 % seizure susceptibility (many studies; see Table 4) Increased susceptibility to epilepsy [175] PPI Increased PPI (most studies, some show decreased PPI; see Shown in bold are phenotypes that have been used frequently (≥4 times) and showed consistent results. Phenotypes in regular font have been used less frequently but showed consistent defects.…”

Astrocytes and disease: a neurodevelopmental perspective

“…It is notable that of those that do, including Rett syndrome, fragile X mental retardation, and tuberous sclerosis, two have been recently shown to have developmental defects in postnatal astrocyte function (Prince and Ring 2011). For example, 10%-20% of children with fragile X syndrome also have epilepsy (Hagerman and Stafstrom 2009), and up to 80% of cases of Rett syndrome have seizures (Jian et al 2006).…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…Seizures associated with FXS are infrequent, are often partial, and are typically controlled with medications (82,83). Fmr1 KO mice have not been reported to display spontaneous seizures, but are more susceptible to audiogenic seizures, induced by exposure to a 125 decibel, high-intensity siren (48,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93).…”