Epilepsy, Idiopathic Generalized, Susceptibility To, 12

A number sign (#) is used with this entry because susceptibility to idiopathic generalized epilepsy-12 (EIG12) is conferred by heterozygous mutation in the SLC2A1 gene (138140) on chromosome 1p34.

Allelic disorders with overlapping features include GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), and dystonia-9 (DYT9; 601042).

For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669).

Clinical Features

Suls et al. (2009) identified heterozygous mutations in the SLC2A1 gene in 4 (12%) of 34 patients with early-onset absence epilepsy before age 4 years. CSF glucose levels were not available from any of the patients. One of the patients had no additional abnormalities and normal development. However, clinical review of these patients after diagnosis showed that 3 had mild to moderate mental retardation, 2 had mild ataxia, and 1 had myoclonus and exercise-induced paroxysmal dyskinesia. None had microcephaly. Two patients inherited missense mutations from parents with later-onset absence epilepsy.

Mullen et al. (2010) reported significant intrafamilial clinical variability in 2 unrelated families with SLC2A1 mutations: 1 with 9 mutation carriers spanning 2 generations and the other with 6 mutation carriers spanning 2 generations. Of 15 patients with SLC2A1 mutations, 12 had epilepsy, most commonly absence epilepsy, with onset between ages 3 and 34 years. Eight patients had idiopathic generalized epilepsies with absence seizures, 2 had myoclonic-astatic epilepsy, and 2 had focal epilepsy. Seven patients had subtle paroxysmal exertional dyskinesia as the only manifestation, and 2 mutation carriers were unaffected. Only 3 of 15 patients had mild intellectual disabilities. Mullen et al. (2010) emphasized the phenotypic overlap with common forms of idiopathic generalized epilepsy.

Striano et al. (2012) reported a large Italian family in which 9 individuals spanning 3 generations had various forms of epilepsy. The age at seizure onset ranged from early childhood to 23 years. All had generalized seizures, mainly typical absence seizures, and EEG showed regular, symmetric discharges of 3 to 3.5 Hz spike wave complexes. Seizures typically remitted 2 to 5 years after onset, although 1 patient later developed juvenile myoclonic epilepsy. Most showed a favorable response to pharmacologic treatment. None of the patients had other neurologic manifestations, including movement disorders.

In a European population-based study of epilepsy types associated with GLUT1, Larsen et al. (2015) identified SLC2A1 mutations in 5 (10%) of 50 patients with absence epilepsy and in 1 (2.7%) of 37 patients from a group with epilepsies, intellectual disability, and/or movement disorders. Five mutations occurred de novo and 1 was inherited from an affected mother. Five patients had absence epilepsy, including 1 with epilepsy with myoclonic absences, and 1 had focal epilepsy. Seizure onset ranged from 6 weeks to 5 years of age, and 5 of the 6 patients had mild to moderate intellectual disability. Four patients became seizure-free on a ketogenic diet. SLC2A1 mutations were not found in 120 patients with myoclonic astatic epilepsy. The report confirmed the association between SLC2A1 mutations and early-onset absence epilepsy.

Inheritance

The transmission pattern of idiopathic generalized epilepsy in the family reported by Striano et al. (2012) was consistent with autosomal dominant inheritance and incomplete penetrance (67%).

Molecular Genetics

Suls et al. (2009) reported a 28-year-old woman with early-onset absence epilepsy at age 3 years and generalized tonic-clonic seizures at age 7. She had normal intelligence and remission of seizures with medication at age 7. CSF glucose levels were not available. Genetic analysis identified a heterozygous mutation in the SLC2A1 gene (138140.0020). The findings indicated that SLC2A1 mutations may contribute to relatively mild forms of epilepsy.

In 1 of 95 families with EIG, Striano et al. (2012) identified a heterozygous missense mutation in the SLC2A1 gene (R232C; 138140.0019). All 8 living patients with seizures in this family carried the mutation, which was also found in 4 healthy adult family members, yielding a penetrance of 67%. In vitro functional studies showed that the mutant protein was expressed at the cell surface but had mildly decreased glucose uptake (70%) compared to wildtype. The findings suggested that GLUT1 deficiency is a rare cause of typical EIG, and also expanded the phenotypic spectrum associated with mutations in the SLC2A1 gene.

By direct sequencing of the SLC2A1 gene, Arsov et al. (2012) identified variants not previously reported in databases of normal human genetic variation in 9 of 504 probands from Israel and Australia with idiopathic generalized epilepsy and in 1 of 470 controls (p = 0.02). All variants occurred at highly conserved residues, but in vitro functional expression studies in Xenopus oocytes indicated variable effects. Three variants (see, e.g., R458W, 138140.0021 and N411S, 138140.0022) caused a marked decrease in glucose transport, 4 variants caused a mild reduction in glucose transport, and 2 variants, including the 1 identified in the control individual, had no effect on glucose transport; the effect of the remaining variant could not be determined. Segregation with incomplete penetrance in families was observed for 2 of the variants that had a marked effect on protein function; the third variant occurred de novo. In contrast, segregation was not strong for variants with mild functional effects: several carriers of the mild variants were unaffected, 1 homozygous carrier was unaffected, and 1 affected individual did not carry a variant. Arsov et al. (2012) concluded that variants in the GLUT1 gene, particularly those with mild functional effects, may act as susceptibility alleles that contribute to the multifactorial etiology of EIG in about 1% of cases.