Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency

Epilepsy Research Centre, Neuroscience Building, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia.
Neurology (Impact Factor: 8.29). 08/2010; 75(5):432-40. DOI: 10.1212/WNL.0b013e3181eb58b4
Source: PubMed


Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1 mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy.
This family study analyses the phenotypes in 2 kindreds segregating SLC2A1 mutations identified through probands with early-onset absence epilepsy. One comprised 9 individuals with mutations over 3 generations; the other had 6 individuals over 2 generations.
Of 15 subjects with SLC2A1 mutations, epilepsy occurred in 12. Absence seizures were the most prevalent seizure type (10/12), with onset from 3 to 34 years of age. Epilepsy phenotypes varied widely, including idiopathic generalized epilepsies (IGE) with absence (8/12), myoclonic-astatic epilepsy (2/12), and focal epilepsy (2/12). Paroxysmal exertional dyskinesia occurred in 7, and was subtle and universally undiagnosed prior to molecular diagnosis. There were 2 unaffected mutation carriers.
GLUT1 deficiency is an important monogenic cause of absence epilepsies with onset from early childhood to adult life. Individual cases may be phenotypically indistinguishable from common forms of IGE. Although subtle paroxysmal exertional dyskinesia is a helpful diagnostic clue, it is far from universal. The phenotypic spectrum of GLUT1 deficiency is considerably greater than previously recognized. Diagnosis of GLUT1 deficiency has important treatment and genetic counseling implications.

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    • "Moreover, numerous additional presentations have been reported: choreoathetosis (Friedman et al., 2006), alternating hemiplegia (Rotstein et al., 2009), and intermittent ataxia/dystonia and migraine (De Giorgis and Veggiotti, 2013). Otherwise, a broader spectrum of epilepsy syndromes have been recognized including early-onset absence epilepsy (EOAE) beginning before age 4 years (Arsov et al., 2012a; Mullen et al., 2010; Suls et al., 2009), idiopathic generalized epilepsy (Arsov et al., 2012b; Striano et al., 2012), myoclono-astatic epilepsy (Mullen, 2011), focal seizures (Wolking et al., 2014) and infantile spasms (Pong et al., 2012). To date, no consensual classification of GLUT1DS on clinical grounds exists: some authors distinguish classic and non classic phenotypes, others split the disorder into (a) classic and complex phenotypes with intellectual disability (ID) in combination with epilepsy or a movement disorder, (b) " epilepsy-dominant " phenotype with seizures as the main symptom with or without movement disorders but without ID, and (c) " movement-disorder-dominant " phenotype without ID, nor seizures (Leen et al., 2014). "
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    ABSTRACT: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia).
    No preview · Article · Aug 2015 · European journal of medical genetics
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    • "" Genetic Absence Epilepsy Rats from Strasbourg " (GAERS) and WAG/Rij rats are the two most widely used animal models for absence epilepsy (Danober et al., 1998; van Luijtelaar and Coenen, 1986). Moreover numerous gene mutations and copy number variants associated with absence epilepsy, and partly introduced in mouse models, have been found, affecting a heterogeneous group of molecular structures, for instance P/Q and T-Type calcium channels (Chen et al., 2003; Fletcher et al., 1996; Jouvenceau et al., 2001; Powell et al., 2009), voltage-gated sodium channels (Audenaert et al., 2003; Papale et al., 2009), glutamate receptors (Bertaso et al., 2008; Beyer et al., 2008), the GLUT1 glucose transporter (Mullen et al., 2010; Suls et al., 2009), the GABA(A) receptor (Dibbens et al., 2009; Johnston et al., 2014; Kananura et al., 2002; Maljevic et al., 2006; Wallace et al., 2001) and others (Jiang et al., 2012; Muhle et al., 2011). "
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    ABSTRACT: Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2(R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43 mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Neurobiology of Disease
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    • "Heterozygous mutations in the GLUT1/SLC2A1 gene, occurring de novo or inherited as an autosomal dominant trait, result in cerebral energy failure and a clinical condition termed GLUT1-deficiency syndrome (GLUT1-DS). Clinical features usually comprise motor developmental delay and intellectual disability, seizures with infantile onset, deceleration of head growth often resulting in acquired microcephaly, and a movement disorder with ataxia, dystonia, and spasticity [41]; whereas mutations in the ST3GAL3 cause nonsyndromic autosomal recessive ID [42]. Recently, Crane J. and collaborators [43], using linkage analysis study, suggested DLGAP3 as a candidate gene for Tourette syndrome. "
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    ABSTRACT: Background Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development delay/intellectual disability and congenital malformation in East Africa. Methods Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent’s 180 K microarray platform. Results Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances. Conclusion This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries.
    Full-text · Article · Jul 2014 · BMC Medical Genetics
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