Autosomal Dominant Frontal Lobe Epilepsy Research Articles

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function.

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

New Genes for Epilepsy–Autism Comorbidity

AbstractSimilar genetic abnormalities have been demonstrated for epilepsy and autism spectrum disorder (ASD). Genetic syndromes, such as fragile X syndrome and tuberous sclerosis, also have high rates of comorbidity with epilepsy and ASD. Furthermore, next-generation sequencing has identified common genetic abnormalities in epilepsy and ASD, and recurrent de novo gene alterations can be recognized as mutations if there is sufficient evidence for pathogenicity. Such mutations occur in SCN2A and GRIN2B. SCN2A encodes the α2 subunit of the Nav1.2 neuronal voltage-gated Na+ channel, which is mutated in several genetically mediated epilepsies. GRIN2B encodes a subtype of the N-methyl-D-aspartate glutamate receptor and is mutated in epileptic encephalopathies, which often present with features of ASD. In addition, KCNT1 encodes the Na+-dependent K+ channel known as Slack. Mutations in KCNT1 produce several epilepsy phenotypes, including autosomal dominant frontal lobe epilepsy, which often includes features of ASD. Slack also has an intracellular fragile X mental retardation protein-binding domain, which is significant in its relationship with intellectual disabilities. Furthermore, DEPDC5 mutations produce autosomal dominant familial focal epilepsy with variable foci and may contribute to ASD. DEPDC5 encodes a regulator of the mechanistic target of rapamycin (mTOR) pathway, which is also affected by tuberous sclerosis mutations, suggesting that “mTORopathy” may underlie both epilepsy and ASD. Mutations in PCDH19 also produce an epilepsy syndrome that exclusively affects heterozygous females and is associated with ASD. The genetic similarities between ASD and epilepsy provide insight into the pathological molecular mechanisms of both conditions and therefore may be useful for understanding clinical outcomes.

Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2

BackgroundThe genetic understanding of primary familial brain calcification (PFBC) has increased considerably in recent years due to the finding of causal genes like SLC20A2, PDGFRB and PDGFB. The phenotype of PFBC is complex and has as of yet been poorly delineated. The most common clinical presentations include movement disorders, cognitive symptoms and psychiatric conditions. We report a family including two sisters with brain calcifications due to a variant in SLC20A2 and generalized tonic-clonic seizures as the principal phenotypic trait. MethodsThe affected siblings underwent whole exome sequencing and candidate variants and cosegregation in the family were validated by Sanger sequencing. ResultsBoth siblings and their asymptomatic father were heterozygous for a variant in SLC20A2. The siblings also had a variant in CHRNB2, a known epilepsy gene associated with autosomal dominant frontal lobe epilepsy, which they had inherited from the mother. ConclusionsTo our knowledge, the reported siblings represent the third and fourth subjects with confirmed SLC20A2 variants exhibiting epilepsy as a phenotypic trait. Our findings support seizures as part of the phenotypic spectrum of SLC20A2-related PFBC. However, the present phenotype may also result from additional genetic influence, such as the identified missense variant in CHRNB2.

Animal models for autosomal dominant frontal lobe epilepsy: on the origin of seizures

Autosomal dominant frontal lobe epilepsy (ADNFLE) can be caused by mutations in either the α4 or β2 subunit of the neuronal nicotinic Ach receptor. In vitro expression studies in Xenopus oocytes or human embryonic kidney cells have been proven to be valuable tools for the characterization of these mutations, but they do not fully resemble the situation in vivo. Compared with them, animal models have the advantage that the functional consequences of a given mutation can be studied in the complex context of an intact living organism. Recent transgenic and knock-in animal models and their valuable contributions to our current understanding of ADNFLE epileptogenesis are discussed in this article. Several of the mouse and rat models support the hypothesis that ADNFLE mutations cause seizures mainly by increasing GABAergic inhibition, and a conditional knock-in mouse model adds early embryonal structural changes as another possible pathogenetic mechanism.

Malignant autosomal dominant frontal lobe epilepsy with repeated episodes of status epilepticus: successful treatment with vagal nerve stimulation

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a familial partial epilepsy syndrome characterized by seizures suggesting a frontal lobe origin occurring predominantly during sleep. Up to a third of patients may have refractory seizures, with repeated episodes of status epilepticus, intellectual disability of variable degree and psychiatric disturbances. We report a patient with ADNFLE, refractory seizures and repeated episodes of life-threatening convulsive status epilepticus who underwent prolonged video-EEG monitoring and was implanted with a vagal nerve stimulator. At 3.5 years of follow-up, a decrease of more than 80% in seizure frequency was achieved, episodes of status were completely controlled and he displayed improved mood and alertness. Vagal nerve stimulation may be considered as therapy for patients with refractory epilepsies of genetic cause, as well as repeated status epilepticus.

Nocturnal Frontal Lobe Epilepsy

Nocturnal frontal lobe epilepsy (NFLE) is a condition primarily characterized by seizures occurring exclusively or predominantly during sleep, the semiology of which suggest a frontal lobe origin and, more specifically, the involvement of the orbitofrontal or mesial frontal regions. It is usually considered as a relatively benign and homogeneous epileptic syndrome, the neuropsychological impact of which should be minimal. However, several issues complicate this view. 1. NFLE is rather a heterogeneous disorder which includes both sporadic and familial forms, various seizure types, and drug resistance in about 30% of patients. 2. The frontal origin of seizures has rarely been demonstrated, and mainly relies on the presence of ictal signs suggestive of frontal lobe epilepsy, but which might only reflect the propagation of ictal discharges of extrafrontal origin. 3. NFLE-like seizures were recently found to be associated with temporobasal cortical dysplasia, or an insular epileptogenic zone, including one patient with autosomal dominant frontal lobe epilepsy (ADNFLE). 4. No study has yet specifically evaluated the neuropsychological profile of patients with NFLE. Available data suggest that behavioral problems and mental retardation might be associated with ADNFLE, especially when it is related to a mutation of the nicotinic receptor subunits. Conversely, the majority of NFLE patients does not seem to present with gross cognitive disturbance, even though many of these patients complain of chronically disrupted sleep and daytime sleepiness. Further research is warranted in this field, keeping in mind that the neural networks underlying NFLE remain poorly known and might primarily involve extrafrontal brain regions in some patients.

Increased Sensitivity of the Neuronal Nicotinic Receptor α2 Subunit Causes Familial Epilepsy with Nocturnal Wandering and Ictal Fear

Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.

Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus

ABSTRACT Alternative methods, for the treatment of medically refractory epileptic patients, who cannot be treated by resective surgery, such as chronic deep brain neurostimulation, are under development. Such methods have been used in the cerebellum, various thalamic nuclei, and in the caudate nucleus. In Grenoble, encouraged by the suppressive effects of pharmacological or electrical inhibition of the STN on different types of seizure in animal models of epilepsy, and by our experience with STN high frequency stimulation (HFS) in patients with movement disorders, we have evaluaded the high frequency stimulation of the subthalamic nucleus (STN HFS). STN HFS was performed in five patients suffering from medically intractable seizures and considered unsuitable for resective surgery. A 67% to 80% reduction in seizure frequency was observed in three patients, with a partial symptomatic epilepsy of the central region. An additional patient suffering from severe myoclonic epilepsy (Dravet syndrome) also responded to STN HFS, with a weaker reduction of seizure frequency. The fifth patient who suffered from an autosomal dominant frontal lobe epilepsy with insulo‐frontal seizures did not show any improvement. These results suggest that stimulation of STN could be a promising treatment for patients with drug‐resistant epilepsy who would not benefit from conventional surgery.

Idiopathic familial temporal lobe epilepsy with febrile convulsions

Efforts to duplicate the genetic and molecular breakthroughs of autosomal dominant frontal lobe epilepsy have lead to increased interest in familial temporal lobe epilepsy. In this report we describe three kindreds. The epilepsy syndrome described manifests after the teenage years and was generally mild and treatment responsive. The predominant seizure types were simple and complex partial seizures, typical of mesial temporal onset. Some family members had febrile convulsions only and others had epilepsy without preceding febrile convulsions. Three patients had both febrile convulsions and temporal lobe epilepsy. High-resolution quantitative and qualitative MRI was normal. The syndrome in these three kindreds is distinct from temporal lobe epilepsy due to mesial temporal sclerosis and febrile convulsions and is probably a form of idiopathic localization related epilepsy. Its relation to other familial temporal lobe epilepsy phenotypes is discussed.

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EpilepsiaVolume 38, Issue 6 p. 739-740 Free Access Reply Marco Zucconi, Marco Zucconi Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorLuigi Ferini-Strambi, Luigi Ferini-Strambi Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorDaniele Bizzozero, Daniele Bizzozero Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorSalvatore Smirne, Salvatore Smirne Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorAlessandro Oldani, Alessandro Oldani Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this author Marco Zucconi, Marco Zucconi Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorLuigi Ferini-Strambi, Luigi Ferini-Strambi Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorDaniele Bizzozero, Daniele Bizzozero Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorSalvatore Smirne, Salvatore Smirne Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this authorAlessandro Oldani, Alessandro Oldani Sleep Disorders Center University of Milano School of Medicine Istituto ScientiJico H San Raffaele Milan, ItalySearch for more papers by this author First published: 03 August 2005 https://doi.org/10.1111/j.1528-1157.1997.tb01248.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal lobe epilepsy misdiagnosed as sleep disorder. Lancet 1994; 343: 515– 7. 2 Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant frontal lobe epilepsy. Nature Genet 1995; 11: 201– 3. 3 Oldani A, Zucconi M, Asselta R, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome, 1997 (in press). 4 Zucconi M, Oldani A, Ferini-Strambi L, Smirne S. Nocturnal paroxysmal arousals with motor behaviors during sleep: frontal lobe epilepsy or parasomnia J Clin Neurophysiol 1997 (in press). 5 Roger J, Bureau M, Dravet C, Deifuss FE, Perret A, Wolf P. Epileptic syndromes in infancy, childhood and adolescence, 2nd ed. London : John Libbey, 1992. 6 Plazzi G, Tinuper P, Montagna P, Provini F, Lugaresi E. Epileptic nocturnal wanderings. Sleep 1995; 18: 749– 56. Volume38, Issue6June 1997Pages 739-740 ReferencesRelatedInformation