Epilepsy in fragile X syndrome

doi:10.1016/S0387-7604(02)00102-X

Brain and Development

Volume 24, Issue 8, December 2002, Pages 766-769

https://doi.org/10.1016/S0387-7604(02)00102-X Get rights and content

Abstract

The occurrence of seizures in patients with fragile X syndrome (Fra-X) is reported. Among the 30 patients, six had epilepsy that was particularly severe and two also showed atypical facial dysmorphism that was different from that seen in classical Fra-X. From the study performed in this series of Fra-X patients the authors arrived at the following conclusions. (1) The occurrence of seizures in Fra-X population is around 20%, as reported in the literature. (2) The EEG pattern of benign childhood epilepsy with central-temporal spikes (BCECTS) was found in only three patients (10%). (3) According to the pattern of seizures and EEGs, four groups may be recognizable, the less frequent being the uncommon group characterized by severe epilepsy unresponsive to treatment. (4) In this group atypical facial dysmorphism (although not similar in the two patients and different from the classical facial pattern of Fra-X) was found. The authors maintain that additional genetic factors might influence the clinical course and neurological aspects of Fra-X syndrome.

Introduction

Fragile X syndrome (Fra-X) is the most frequent cause of familial mental retardation and it is also one of the more common genetic diseases as it constitutes about one third to a quarter of the patients with X-linked mental retardation [1]. It is also the second most common cause of mental disability after Down's syndrome.

The phenotype of this disorder includes moderate to severe mental retardation (MR), macroorchidism, large ears and protruding mandible. The incidence of Fra-X varies from 1/1200 in males to 1/2400 in females: no differences have been observed among ethnic groups and many different loci have been identified.

There are several sub-types of Fra-X. The most common is the Frax-A syndrome which is caused by a large expansion of a CGG trinucleotide repeat, usually more than 200 in the 5′ untranslated region of the FMR 1 gene, often associated with hypermethylation and downregulation of transcription [2]. Currently, three other Fra-X sites are known. Frax-D is localized near the Frax-A and does not express any clinical manifestation; Frax-E is localized in the region Xq 28 and is associated with moderate mental retardation, and Frax-F which shows a phenotype similar to FraX-E [3].

The present study was carried out to examine the occurrence of seizures in patients with Fra-X syndrome and to report on two patients who showed a particularly severe form of drug-resistant epilepsy.

Section snippets

Subjects and methods

Thirty Fra-X patients were observed between 1983 and 1998 at the Pediatric Clinic of the University of Catania, Italy and were enrolled in this study. The patients were all males; 29 had the classical mutation of Frax-A and one had Frax-E. The diagnoses were made between 2 and 18 years of age (median age 9±5.3 years). Mental retardation was the reason for referral to the hospital for all of the patients. Associated symptoms were language delay, hyperactivity and behavioral disturbances in all

Results

Among the patients with Fra-X syndrome, six out of 30 (20%) suffered from seizures and EEG anomalies. In these patients (see Table 1) the age at onset of seizures was between 6 months and 4 years (mean age 2 years). In patients 1 and 3 the seizures disappeared at 7 and 8 years, respectively. In patients 2 and 4 they were still present, though sporadic. In patients 5 and 6 they were frequent, severe and unresponsive to the treatment. In all cases, except case 4, the seizures were complex

Discussion

The association of Fra-X syndrome and seizures was first reported by Lubs in 1968 [5]and subsequently by Sutherland and Hecht [4]. Epilepsy is variably reported in patients with various types of mental retardation. In Fra-X syndrome the frequency of epilepsy is reported from 13–14% to 41–44% depending on the referral bias of different clinics [6], [7]. However, most of the reported data confirm that the prevalence of seizures in Fra-X syndrome is around 20% as was observed in the present study.

References (9)

M.J. Mattei
Le retard mental liè à la fragilité du chromosome X
Arch. Franc Pédiat
(1987)
J.M. Opitz et al.
Conference report: International workshop on the fragile X and X-linked mental retardation
Am J Med Genet
(1984)
B.B.A. de Vries et al.
The fragile X syndrome
J Med Genet
(1998)
G.R. Sutherland et al.
Fragile sites on human chromosomes
(1985)

There are more references available in the full text version of this article.

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Spontaneous seizures in adult Fmr1 knockout mice: FVB.129P2-Pde6b+ Tyrc-ch Fmr1tm1Cgr/J
2022, Epilepsy Research
Citation Excerpt :
Therefore, no detectable AGS-eliciting stimulus was present. Seizures occur in ~25% of individuals with FXS, and epilepsy in FXS typically presents with similar clinical and electrographic features as childhood epilepsy with central-temporal spikes (Rolandic epilepsy), though several other seizures, including intractable generalized and tonic-clonic seizures that persist in adulthood, are also observed in individuals with FXS (Gauthey et al., 2010; Incorpora et al., 2002; Stone et al., 2021). To our knowledge, Fmr1 knockout mice have only been reported to display AGS (Curia et al., 2013; Ding et al., 2014; Goebel-Goody et al., 2012; Michalon et al., 2012; Osterweil et al., 2010; Qin et al., 2005; Yan et al., 2004, 2005; Yun et al., 2006).
The prevalence of seizures in individuals with fragile X syndrome (FXS) is ~25%; however, there are no reports of spontaneous seizures in the Fmr1 knockout mouse model of FXS. Herein, we report that 48% of adult (median age P96), Fmr1 knockout mice from our colony were found expired in their home cages. We observed and recorded adult Fmr1 knockout mice having spontaneous convulsions in their home cages. In addition, we captured by electroencephalography an adult Fmr1 knockout mouse having a spontaneous seizure—during preictal, ictal, and postictal phases—which confirmed the presence of a generalized seizure. We did not observe this phenotype in control conspecifics or in juvenile (age <P35) Fmr1 knockout mice. We hypothesized that chronic, random, noise perturbations during development caused the phenotype. We recorded decibels (dB) in our vivarium. The average was 61 dB, but operating the automatic door to the vivarium caused spikes to 95 dB. We modified the door to eliminate noise spikes, which reduced unexpected deaths to 33% in Fmr1 knockout mice raised from birth in this environment (P = 0.07). As the modifications did not eliminate unexpected deaths, we further hypothesized that building vibrations may also be a contributing factor. After installing anti-vibration pads underneath housing carts, unexpected deaths of Fmr1 knockout mice born and raised in this environment decreased to 29% (P < 0.01 compared to the original environment). We also observed significant sex effects, for example, after interventions to reduce sound and vibration, significantly fewer male, but not female, Fmr1 knockout mice died unexpectedly (P < 0.001). The spontaneous seizure phenotype in our Fmr1 knockout mice could serve as a model of seizures observed in individuals with FXS, potentially offering a new translationally-valid phenotype for FXS research. Finally, these observations, although anomalous, serve as a reminder to consider gene-environment interactions when interpreting data derived from Fmr1 knockout mice.
Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice
2021, Epilepsy Research
Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HT_2CR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HT_2ARs at therapeutic doses, we pretreated one group of mice with the selective 5-HT_2AR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HT_2ARs to AGSs. We also assessed lorcaserin’s in vitro pharmacology at human (h) and mouse (m) 5-HT_2CRs and 5-HT_2ARs and its in vivo interactions at m5-HT_2CRs and m5-HT_2ARs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HT_2CRs and m5-HT_2CRs, and near full efficacy agonist activity at h5-HT_2ARs and m5-HT_2ARs; selectivity for activation of 5-HT_2CRs over 5-HT_2ARs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HT_2CRs and 5-HT_2ARs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HT_2AR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HT_2CR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HT_2CRs as well as 5-HT_2ARs in mice at doses as low as 3 mg/kg. The similar activity at m5-HT_2CRs and m5-HT_2ARs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HT_2CRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.
PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice
2021, Biochimica et Biophysica Acta - Molecular Basis of Disease
Fragile X Syndrome (FXS) is an inherited developmental disorder caused by the non-expression of the Fmr1 gene. FXS is associated with abnormal social and anxiety behavior that is more prominent among males. Given that oxytocin (OXT) regulates both social and anxiety behavior, we studied the effect of FXS in the hypothalamic paraventricular nucleus (PVN), the major central source of OXT. We observed a significant suppression of protein kinase C epsilon (PKCε) (34%) in the ventral hippocampal CA1 region of postnatal day-18 (P18) male Fmr1 knockout (KO) mice, which displayed social behavior deficits and hyper-anxiety in adulthood. These mice also displayed a 39% increase in cell surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) at P18 (measured by the surface level of the AMPAR subunit GluR2), thereby indicating excitation of the CA1 neurons. It is known that neuronal activation at CA1 is linked to an inhibition of the PVN neurons. As expected, these mice also displayed a 25% suppression of oxytocin+ (OXT+) cells in the PVN at P20. Stimulating PKCε during postnatal days 6–,14 (P6–14) mice using a selective activator, dicyclopropyl-linoleic acid (DCP-LA), corrected AMPAR externalization in CA1 and suppression of OXT+ cell number in PVN in a PKCε dependent manner. Most notably, neonatal DCP-LA treatment rescued social behavior deficits and hyper-anxiety, displayed by adult (≥P60) male but not female KO mice. Thus, neonatal stimulation of PKCε could be a strategy to correct endophenotypic anomalies during brain development and aberrant adult behavior of the FXS males to the wild-type levels.
Seizures in Mouse Models of Rare Neurodevelopmental Disorders
2020, Neuroscience
Citation Excerpt :
EEG abnormalities in pediatric patients are largely consistent with childhood epilepsy with centrotemporal spikes (CECTS, previously known as Rolandic epilepsy) (Fig. 3) (Berry-Kravis, 2002; Incorpora et al., 2002; O’Leary and Benke, 2017). Although interictal EEG background activity can appear relatively normal, particularly during wakeful periods (Fig. 3), background slowing or slowing of the posterior dominant rhythm, increased generalized rhythmic theta activity, focal spikes, and multi-focal or diffuse spike waves have also been reported on EEG, particularly during periods of sleep (Musumeci et al., 1999; Heard et al., 2014; Incorpora et al., 2002; Sabaratnam et al., 2001) (Fig. 3). Several models of FXS have been generated, which include classic knockout (KO), conditional knockout (CKO), and knock-in (KI) mice.
Genetic neurodevelopmental disorders - that often include epilepsy as part of their phenotype - are a heterogeneous and clinically challenging spectrum of disorders in children. Although seizures often contribute significantly to morbidity in these affected populations, the mechanisms of epileptogenesis in these conditions remain poorly understood. Different model systems have been developed to aid in unraveling these mechanisms, which include a number of specific mutant mouse lines which genocopy specific general types of mutations present in patients. These mouse models have not only allowed for assessments of behavioral and electrographic seizure phenotypes to be ascertained, but also have allowed effects on the neurodevelopmental alterations and cognitive impairments associated with these disorders to be examined. In addition, these models play a role in advancing our understanding of these epileptic processes and developing preclinical therapeutics. The concordance of seizure phenotypes – in a select group of rare, genetic, neurodevelopmental disorders and epileptic encephalopathies – found between human patients and their model counterparts will be summarized. This review aims to assess whether models of Rett syndrome, CDKL5 deficiency disorder, Fragile-X syndrome, Dravet syndrome, and Ohtahara syndrome phenocopy the seizures seen in human patients.
GABAergic abnormalities in the fragile X syndrome
2020, European Journal of Paediatric Neurology
Citation Excerpt :
Most commonly used are valproic acid, lamotrigine, levetiracetam and oxcarbazepine. However, severe epilepsy resistant to anticonvulsant therapy has also been described [29,32]. To what extend seizures in early live affect developmental outcome is not known, but in fragile X knockout mice it has been reported that a single seizure in early life can negatively influence the outcome of behavioural and cognitive testing in adulthood [33].
Many pathways have been involved in pathophysiology of the fragile X syndrome, one of the more frequent genetic causes of intellectual disability and autism. This review highlights the recent insights in the role the abnormalities in the GABAergic system play in the disorder. Since the initial observations showed that the expression of specific subunits of the GABA(A) receptor were underexpressed in the fragile X knockout mouse model more than a decade ago, evidence has accumulated that the expression of approximately half of the GABAergic system is compromised in multiple species, including in fragile X patients. Functional consequences of the GABAergic deficiencies could be measured using whole-cell voltage clamp recordings. Pharmalogical treatment with agonist of the receptor was been able to restore several behavioral deficits in the fragile X mouse model, including seizures, marble burying and, in part, prepulse inhibition. Trials in patients with the same agonist have demonstrated encouraging post-hoc results in the most severely affected patients, although no effect could be demonstrated in the patient group as a whole. In conclusion, there can be little doubt that the GABAergic system is compromised in the fragile X syndrome and that these abnormalities contribute to the clinical abnormalities observed. However, at the moment the difference in treatment effectiveness of agonist of the receptor in animal models as opposed to in patients remains unexplained.
Autism and Fragile X Syndrome
2017, Models of Seizures and Epilepsy: Second Edition
Autism spectrum disorder (ASD) is diagnosed as a developmental disorder characterized by persistent deficits in social communication and social interaction, and restricted, repetitive patterns of behavior, interests, or activities. ASD is not caused by one genetic defect, rather it is estimated that hundreds of genes could be involved. Genes identified are frequently associated with epilepsy. The estimates of prevalence of epilepsy in ASD ranges from 8% to 34%, with higher rates associated with the additional presence of intellectual disability (ID), overlap with the rate of ASD in epilepsy. The wealth of patient genetic information has led to the generation of several mouse models with modification of individual genes to parse out the role of each gene in ASD, and potential relationships to epilepsy. This chapter focuses on FMRP, CDKL5, Ube3A, PTEN, Shank3, Cntnap2, Neuroligin-3, and SynGAP1, due to the presence of comorbid epilepsy, and/or abnormal electroencephalography (EEG) found in ASD patients with genetic changes in these proteins.

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Brain and Development

Abstract

Introduction

Section snippets

Subjects and methods

Results

Discussion

References (9)

Le retard mental liè à la fragilité du chromosome X

Arch. Franc Pédiat

Conference report: International workshop on the fragile X and X-linked mental retardation

Am J Med Genet

The fragile X syndrome

J Med Genet

Fragile sites on human chromosomes

Cited by (50)

Spontaneous seizures in adult Fmr1 knockout mice: FVB.129P2-Pde6b<sup>+</sup> Tyr<sup>c-ch</sup> Fmr1<sup>tm1Cgr</sup>/J

Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice

PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice

Seizures in Mouse Models of Rare Neurodevelopmental Disorders

GABAergic abnormalities in the fragile X syndrome

Autism and Fragile X Syndrome

Original articleEpilepsy in fragile X syndrome

Abstract

Introduction

Section snippets

Subjects and methods

Results

Discussion

Le retard mental liè à la fragilité du chromosome X

Arch. Franc Pédiat

Conference report: International workshop on the fragile X and X-linked mental retardation

Am J Med Genet

The fragile X syndrome

J Med Genet

Fragile sites on human chromosomes

Original article
Epilepsy in fragile X syndrome