Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12

Morales-Corraliza, Jose; Gómez-Garre, Pilar; Sanz, Raúl; Fernando, Daniel; Gutierrez-Delicado, Eva; Serratosa, Joan

doi:10.1111/j.1528-1167.2010.02680.x

Cited by 15 publications

(13 citation statements)

References 14 publications

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“…Affected individuals respond well to antiepileptic drugs and have no brain lesions. Causative mutations have not been found for FPEVF [47]–[51]. Although the clinical features in our dogs resemble the characteristics of human FPEVF, the most significant region in dogs is ∼10 Mb from the strongest association signal in human patients.…”

Section: Discussionmentioning

confidence: 56%

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

et al. 2012

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Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10−10, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10−8, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10−11, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.

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Section: Discussionmentioning

confidence: 56%

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

et al. 2012

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“…14 One notable difference was a high rate of drug resistance (78%) in the patients with DEPDC5 mutation in comparison with the one-third classically reported in previous cohorts of ADNFLE families. [21][22][23] The occurrence of both diurnal and nocturnal seizures recalls frontal lobe seizures in FFEVF families, in which seizures emanate from different cortical regions among family members. 3,8 Among the 4 DEPDC5-positive ADNFLE families of the present study, 60% of the patients, all of whom were drug resistant, experienced rare diurnal seizures.…”

Section: Resultsmentioning

confidence: 99%

DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy

et al. 2014

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“…One of these clusters, in which all hubs had 55 gene-gene links, comprised: i) the genes encoding the voltage-gated potassium (KCNMA1) and sodium (SCN3B) channels [30], [31]; ii) SLC32A1, a gene coding for a vesicular GABA transporter [32]; iii) D4S234E, alias NEEP21, which codes for a protein with a pivotal role in the hippocampal recycling and internalization of AMPA-receptors [33], [34]; iv) LPPR4, a gene involved in the modulatory control of hippocampal excitability, preventing hyperexcitability in glutamaergic neurons [35]; v) SLC2A3, alias GLUT3, the main neuronal glucose-transporter [36]; vi) YWHAH, a candidate gene for autosomal dominant familial partial epilepsy with variable foci [37], which codes for a neural protein that mediates signal transduction by binding to phosphoserine-containing proteins [38], [39] and vii) MYT1L, a zinc finger gene involved in the recruitment of histone deacetylase to regulate neural transcription [40].…”

Section: Resultsmentioning

confidence: 99%

Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy

et al. 2011

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BackgroundProlonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). In order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal FindingsDNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/SignificanceCA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions.

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Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12

Cited by 15 publications

References 14 publications

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy

Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy

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