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.
"" 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). "
"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 ; whereas mutations in the ST3GAL3 cause nonsyndromic autosomal recessive ID . Recently, Crane J. and collaborators , using linkage analysis study, suggested DLGAP3 as a candidate gene for Tourette syndrome. "
[Show abstract][Hide abstract] 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.
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.
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.
This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries.
BMC Medical Genetics 07/2014; 15(1):79. DOI:10.1186/1471-2350-15-79 · 2.08 Impact Factor
"Direct sequencing of candidate genes combined with a functional study of the abnormal genes products in vitro has met some success in identifying GGE-AS’s susceptibility genes (12). These factors include mutations of the Cav3.2 and GABRB3 gene (the gene encoding the gamma-aminobutyric acid receptor subunit beta-3 protein) in patients with CAE (13, 14) and mutations of SLC2A1 (the gene encoding the glucose transporter protein type 1) in early-onset absence epilepsy (under 4 years of age) (15, 16). Moreover, copy number variants have been found to play an important role in the patients with epilepsies (17, 18). "
[Show abstract][Hide abstract] ABSTRACT: The thalamic relay neurons, reticular thalamic nucleus, and neocortical pyramidal cells form a circuit that sustains oscillatory burst firing, and is regarded as the underlying mechanism of absence seizures. T-type calcium channels play a key role in this circuit. Here, we review the role of T-type calcium channel genes in the development of absence seizures, and emphasize gain or loss of function mutations, and other variations that alter both quantity and quality of transcripts, and methylation status of isoforms of T-type calcium channel proteins might be of equal importance in understanding the pathological mechanism of absence seizures.
Frontiers in Neurology 05/2014; 5:45. DOI:10.3389/fneur.2014.00045
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