title: Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2.
abstract: We characterize a consanguineous Egyptian family with an autosomal recessively inherited familial cortical myoclonic tremor and epilepsy. We used multipoint linkage analysis to map the causative mutation to a 12.7 megabase interval within 1q31.3-q32.2 with a log of odds score of 3.6. For further investigation of the linked region in an efficient and unbiased manner, we performed exome sequencing. Within the suspected region we identified a homozygous single base pair deletion (c.503_503delG) leading to a frameshift in the coding region of the sixth exon of CNTN2 alias TAG-1 (p.Trp168fs), which segregated in the respective family. Many studies point towards an important role of the CNTN2 product contactin 2 in neuronal excitability. Contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, and another transmembrane protein called contactin associated protein-like 2 (CNTNAP2 alias CASPR2) are together necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. CNTN2 knockout mice were previously reported to suffer from spontaneous seizures and mutations in the CNTNAP2 gene have been described to cause epilepsy in humans. To further delineate the role of CNTN2 in patients with epilepsy, we sequenced the coding exons in 189 Caucasian patients with epilepsy. No recessive mutation was detected and heterozygote carriers of rare CNTN2 variants do not seem to be predisposed to epilepsy. Given the severity of the mutation and the proposed function of the gene, we consider this mutation as the most likely cause for cortical myoclonic tremor and epilepsy in this family.
authors.affiliation: Department of Clinical Neurology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. elisabeth.stoegmann@meduniwien.ac.at
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stogmann
authors.forename: Eva
authors.initials: E
authors.lastname: Reinthaler
authors.forename: Salwa
authors.initials: S
authors.lastname: Eltawil
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: El Etribi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Hemeda
authors.forename: Nevine
authors.initials: N
authors.lastname: El Nahhas
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Gaber
authors.forename: Amal
authors.initials: A
authors.lastname: Fouad
authors.forename: Sherif
authors.initials: S
authors.lastname: Edris
authors.forename: Anna
authors.initials: A
authors.lastname: Benet-Pages
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Eck
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pataraia
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Friedrich
authors.initials: F
authors.lastname: Zimprich
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
mesh_terms: D000328:Adult; D003241:Consanguinity; D058969:Contactin 2 / Q000235:genetics*; D004534:Egypt; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D014202:Tremor / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: C548674:CNTN2 protein, human; C403049:CNTNAP2 protein, human; D058969:Contactin 2; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins