Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3.
OBJECTIVE
To report results of linkage analysis in a large family with autosomal dominant (AD) familial mesial temporal lobe epilepsy (FMTLE).


BACKGROUND
Although FMTLE is a heterogeneous syndrome, one important subgroup is characterized by a relatively benign course, absence of antecedent febrile seizures, and absence of hippocampal sclerosis. These patients have predominantly simple partial seizures (SPS) and infrequent complex partial seizures (CPS), and intense and frequent déjà vu phenomenon may be the only manifestation of this epilepsy syndrome. No linkage has been described in this form of FMTLE.


METHODS
We identified a four-generation kindred with several affected members meeting criteria for FMTLE and enrolled 21 individuals who gave informed consent. Every individual was personally interviewed and examined; EEG and MRI studies were performed on three affected subjects. DNA was extracted from every enrolled individual. We performed a genome-wide search using an 8 cM panel and fine mapping was performed in the regions with a multipoint lod score >1. We sequenced the highest priority candidate genes.


RESULTS
Inheritance was consistent with AD mode with reduced penetrance. Eleven individuals were classified as affected with FMTLE and we also identified two living asymptomatic individuals who had affected offspring. Seizure semiologies included predominantly SPS with déjà vu feeling, infrequent CPS, and rare secondarily generalized tonic-clonic seizures. No structural abnormalities, including hippocampal sclerosis, were detected on MRI performed on three individuals. Genetic analysis detected a group of markers with lod score >3 on chromosome 4q13.2-q21.3 spanning a 7 cM region. No ion channel genes are predicted to be localized within this locus. We sequenced all coding exons of sodium bicarbonate cotransporter (SLC4A) gene, which plays an important role in tissue excitability, and cyclin I (CCNI), because of its role in the cell migration and possibility of subtle cortical abnormalities. No disease-causing mutations were identified in these genes.


CONCLUSIONS
We report identification of a genetic locus for familial mesial temporal lobe epilepsy. The identification of a disease-causing gene will contribute to our understanding of the pathogenesis of temporal lobe epilepsies.
Hedera
P
P
Department of Neurology, Vanderbilt University, Nashville, TN 37232- 8552, USA. peter.hedera@vanderbilt.edu
Blair
M A
MA
Andermann
E
E
Andermann
F
F
D'Agostino
D
D
Taylor
K A
KA
Chahine
L
L
Pandolfo
M
M
Bradford
Y
Y
Haines
J L
JL
Abou-Khalil
B
B
D000328:Adult; D017668:Age of Onset; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D056749:Cyclin I; D016213:Cyclins / Q000235:genetics; D004252:DNA Mutational Analysis; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree
D001457:Anion Exchange Protein 1, Erythrocyte; C534756:CCNI protein, human; D056749:Cyclin I; D016213:Cyclins; C454201:SLC4A1 protein, human