Epilepsy and fragile X gene mutations

doi:10.1016/S0887-8994(96)00251-2

Pediatric Neurology

Volume 15, Issue 4, November 1996, Pages 358-360

https://doi.org/10.1016/S0887-8994(96)00251-2 Get rights and content

Abstract

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood epilepsy with centrotemporal spikes (BECT, Rolandic epilepsy). Fourteen young male patients with fragile X syndrome, verified by a full mutation in exon 1 of the fragile X mental retardation-1 gene, were studied by electroencephalography. In eight boys aged between 4–8 years we observed focal sharp waves, activated by sleep. In six of these patients, partial seizures occurred during sleep. We detected no epileptiform electroencephalographic abnormalities under the age of 4 and over the age of 8. In 16 children with Rolandic epilepsy who were studied for fragile X gene mutations, one boy proved to carry a fragile X premutation. In the waking state electroencephalography of a 5-year-old girl with a premutation in one of her fragile X mental retardation-1 genes, we found groups of generalized spike wave complexes. Our observations suggest a possible impact of the fragile X mental retardation-1 gene mutations on brain maturation and epileptogenesis.

References (14)

R.G. Pergolizzi et al.
Detection of full fragile X mutation
The Lancet
(1992)
H. Siomi et al.
Essential role for KH domains in RNA binding: Impaired RNA binding by a mutation in the KH domain of FMR-1 that causes fragile X syndrome
Cell
(1994)
F. Rousseau et al.
A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases
Am J Hum Genet
(1994)
C. Hull et al.
A study of the physical, behavioral, and medical phenotype, including anthropometric measures, of females with fragile X syndrome
Am J Develop Child Dis
(1993)
D.Z. Loesch et al.
Transmitting males and carrier females in fragile X-revisited
Am J Med Genet
(1994)
A.L. Reiss et al.
Neurobehavioural effects of the fragile X premutation in adult women: A controlled study
Am J Hum Genet
(1993)
S.A. Musumeci et al.
Epilepsy and fragile X syndrome: A follow-up study
Am J Med Genet
(1991)

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

Cited by (33)

Fragile X Syndrome
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability
Fragile X syndrome (FXS) is recognized as the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASDs), with many overlapping phenotypic features. Fragile X syndrome is caused by absence or reduction of expression of the fragile X mental retardation protein and is associated with a variety of behavioral, physical, and medical problems, which are managed through supportive treatment, often incorporating psychopharmacology to ameliorate limiting behaviors. Specific patterns of cognitive, language, and adaptive strengths and weaknesses are typically present and can be used to tailor educational and therapeutic programming to the needs of the individual with FXS. Recent major advances in the understanding of the underlying neurobiology in FXS have led to the discovery of agents that rescue phenotypes in the FXS mouse model and to early clinical trials of targeted treatments in humans with FXS. Thus, translational strategies in FXS may serve as models for ASD and other cognitive disorders.
Mechanism-based approaches to treating fragile X
2010, Pharmacology and Therapeutics
Fragile X is the leading inherited cause of mental retardation and autism. Recent advances in our mechanistic understanding of the disease have led to the identification of the metabotropic glutamate receptor (mGluR) as a therapeutic target for the disease. These studies have revealed that core defects in multiple animal models can be corrected by down regulation of mGluR5 signaling. Although it remains to be seen if mGluR5 antagonists or related approaches will succeed in humans with fragile X, the progress in fragile X stands as a strong testament to the power of applying knowledge of basic neurobiology to understand pathophysiology in a genetically validated model of human psychiatric disease. These breakthroughs and several of the resulting drug development efforts are reviewed.
The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome
2009, Epilepsy Research
Citation Excerpt :
The FXS man with multiple AEDs had unilateral centrotemporal epileptiform changes in sleep EEG recording. In the present population based study, epilepsy was found in 15% of FXS individuals in accordance with the previous estimations for the prevalence of epilepsy and seizures in FXS at 13–44% (Kluger et al., 1996; Musumeci et al., 1999; Sabaratnam et al., 2001; Berry-Kravis, 2002). As seen in the present study, epileptic seizures in FXS show an age-related appearance in the childhood or young adulthood.
The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS males to epilepsy.
Fragile X mice develop sensory hyperreactivity to auditory stimuli
2001, Neuroscience
Fragile X syndrome is the most prevalent cause of mental retardation. It is usually caused by the transcriptional inactivation of the FMR-1 gene. Although the cognitive defect is the most recognized symptom of fragile X syndrome, patients also show behavioral problems such as hyperarousal, hyperactivity, autism, aggression, anxiety and increased sensitivity to sensory stimuli. Here we investigated whether fragile X mice (fmr-1 gene knockout mice) exhibit abnormal sensitivity to sensory stimuli. First, hyperreactivity of fragile X mice to auditory stimulus was indicated in the prepulse inhibition paradigm. A moderately intense prepulse tone, that suppresses startle response to a strong auditory stimulus, elicited a significantly stronger effect in fragile X than in control mice. Second, sensory hyperreactivity of fragile X mice was demonstrated by a high seizure susceptibility to auditory stimulation. Selective induction of c-Fos, an early-immediate gene product, indicated that seizures involve auditory brainstem and thalamic nuclei. Audiogenic seizures were not due to a general increase in brain excitability because three different chemical convulsants (kainic acid, bicuculline and pentylenetetrazole) elicited similar effects in fragile X and wild-type mice.
These data are consistent with the increased responsiveness of fragile X patients to auditory stimuli. The auditory hypersensitivity suggests an abnormal processing in the auditory system of fragile X mice, which could provide a useful model to study the molecular and cellular changes underlying fragile X syndrome.
Epilepsy and EEG findings in 18 males with fragile X syndrome
2001, Seizure
Of the 24 males identified as having fragile X syndrome in the Northeast Essex screening programme, 25% had epilepsy. Epilepsy in individuals with fragile X syndrome is known to follow a benign course with seizures disappearing before the age of 20. However, half of our sample with a history of epilepsy continued to have seizures after the age of 20. We reviewed the EEG reports of 18 of the 24 individuals (aged between 13 and 63 years) including all six individuals with epilepsy. We had 32 EEG recordings from 18 subjects, with nine people having more than one recording at different points. The EEG showed a definite improvement in only five individuals. Three individuals who had serial recordings (one with epilepsy) showed no significant changes over time and the EEG of one subject with epilepsy deteriorated. The most common abnormal EEG findings were rhythmic theta activity (50%) and a slowing of background activity (28%). There were no characteristic features in the sleep EEGs performed on four subjects. The possible implications of these preliminary findings are discussed.
Age-related changes of cortical excitability in subjects with sleep- enhanced centrotemporal spikes: A somatosensory evoked potential study
2000, Clinical Neurophysiology
Middle-latency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) have been reported in subjects with benign childhood epilepsy with centrotemporal spikes (BECT) and in normal children, which usually show significant age-related changes. However, the mechanisms by which age modifies the appearance of centrotemporal spikes and giant SEPs in these children, are not known. The characteristics of SEPs were studied in a group of 18 subjects (10 males and 8 females, aged 7.1–17.2 years) with sleep-enhanced centrotemporal spikes, with or without BECT and the results were compared with those obtained from a group of age-matched normal controls. Giant SEPs were recorded in 6 subjects and, in 3 of these, EEG spikes evoked by hand tapping were obtained also. No subjects with giant SEPs were found in subjects older than 12 years, and an age-related decrease in amplitude of giant SEPs as this age approached was observed. Moreover, at repeated SEP recordings, a clear trend towards a more important reduction in amplitude of giant SEPs over the temporal and parietal than over the central regions was evident. The study of EEG spikes evoked by hand tapping showed a striking similarity between the averaged evoked spikes and the main negative component of giant SEPs. It was also possible to observe that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5–15 ms. Our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related modifications which can be interpreted in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present.

View all citing articles on Scopus

¹: Correspondence should be addressed to: Dr. Kluger; Neuropediatric Department; Behandlungszentrum Vogtareuth; Krankenhausstraße 20; D-83569 Vogtareuth, Germany.

View full text

Case reportEpilepsy and fragile X gene mutations

Abstract

The Lancet

Cell

A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases

Am J Hum Genet

A study of the physical, behavioral, and medical phenotype, including anthropometric measures, of females with fragile X syndrome

Am J Develop Child Dis

Transmitting males and carrier females in fragile X-revisited

Am J Med Genet

Neurobehavioural effects of the fragile X premutation in adult women: A controlled study

Am J Hum Genet

Epilepsy and fragile X syndrome: A follow-up study

Am J Med Genet

Case report
Epilepsy and fragile X gene mutations