Medicine (Austin & Northern Health) - Research Publications

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Start date: 2012 × End date: 2012 × Author: DAHL, HANS-HENRIK × Author: Berkovic, Samuel ×

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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.
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    Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage
    Smith, KR ; Damiano, J ; Franceschetti, S ; Carpenter, S ; Canafoglia, L ; Morbin, M ; Rossi, G ; Pareyson, D ; Mole, SE ; Staropoli, JF ; Sims, KB ; Lewis, J ; Lin, W-L ; Dickson, DW ; Dahl, H-H ; Bahlo, M ; Berkovic, SF (CELL PRESS, 2012-06-08)
    We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.