Medicine (Austin & Northern Health) - Research Publications

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Author: Berkovic, Samuel × Author: Damiano, John × Author: Scheffer, Ingrid × End date: 2013 × Start date: 2012 × Type: Journal Article ×

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    Mutations in TNK2 in Severe Autosomal Recessive Infantile Onset Epilepsy
    Hitomi, Y ; Heinzen, EL ; Donatello, S ; Dahl, H-H ; Damiano, JA ; McMahon, JM ; Berkovic, SF ; Scheffer, IE ; Legros, B ; Rai, M ; Weckhuysen, S ; Suls, A ; De Jonghe, P ; Pandolfo, M ; Goldstein, DB ; Van Bogaert, P ; Depondt, C (WILEY, 2013-09)
    We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients.
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    GRIN2A mutations cause epilepsy-aphasia spectrum disorders
    Carvill, GL ; Regan, BM ; Yendle, SC ; O'Roak, BJ ; Lozovaya, N ; Bruneau, N ; Burnashev, N ; Khan, A ; Cook, J ; Geraghty, E ; Sadleir, LG ; Turner, SJ ; Tsai, M-H ; Webster, R ; Ouvrier, R ; Damiano, JA ; Berkovic, SF ; Shendure, J ; Hildebrand, MS ; Szepetowski, P ; Scheffer, IE ; Mefford, HC (NATURE PUBLISHING GROUP, 2013-09)
    Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.
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    Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency
    Arsov, T ; Mullen, SA ; Damiano, JA ; Lawrence, KM ; Huh, LL ; Nolan, M ; Young, H ; Thouin, A ; Dahl, H-HM ; Berkovic, SF ; Crompton, DE ; Sadleir, LG ; Scheffer, IE (WILEY-BLACKWELL, 2012-12)
    Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.