A number sign (#) is used with this entry because of evidence that myoclonic-atonic epilepsy (MAE) is caused by heterozygous mutation in the SLC6A1 gene (137165) on chromosome 3p25.

Myoclonic-atonic epilepsy (MAE) is an autosomal dominant disorder characterized by onset of absence and myoclonic seizures in early childhood. Patients have delayed development before the onset of seizures and show varying degrees of impaired intellectual development following seizure onset (summary by Carvill et al., 2015).

Carvill et al. (2015) reported 8 patients, including a mother and daughter, with early-onset myoclonic-atonic epilepsy following early developmental delay. The median age of seizure onset was 30.5 months (range, 12-38 months). All patients had absence seizures, including 4 with eyelid myoclonia. All patients also had drop attacks, which were myoclonic-atonic in 4 and atonic in the other 4. Electroencephalogram (EEG) showed generalized spike-wave patterns in all, as well as a photoparoxysmal response in 4. Three patients had remission of the seizures during childhood, whereas 5 had ongoing seizures. All patients had mildly to severely impaired intellectual development, including 6 patients who had autistic features. More variable additional features included tremor, scoliosis, ataxia, and dysarthria.

In 7 patients, including a mother and daughter, with myoclonic-atonic epilepsy, Carvill et al. (2015) identified 6 different heterozygous mutations in the SLC6A1 gene (see, e.g., 137165.0001-137165.0005). One additional patient had a heterozygous deletion of chromosome 3p25 that included part of the SLC6A1 gene. Four of the mutations and the deletion occurred de novo; 1 affected child inherited the mutation from an affected mother, and another affected child inherited the mutation from an unaffected mother who was somatic mosaic for the mutation. Functional studies of the variants were not performed, but Carvill et al. (2015) postulated that the mutations resulted in a loss of function and disrupted GABA transport from the extracellular space into the presynaptic terminal. The mutations were found by direct sequencing of the SLC6A1 gene in 2 cohorts: the first 4 mutations were found in 4 of 569 individuals with epileptic encephalopathies, and the remaining 2 mutations were found in 2 of 75 individuals with MAE. Overall, SLC6A1 mutations occurred in 6 (4%) of 160 probands with MAE, suggesting that mutations in this gene result in a specific epilepsy syndrome.

Cope et al. (2009) found that Slc6a1-knockout mice developed spike-wave discharges characteristic of absence seizures (see, e.g., ECA1, 600131). The activation of peri- or extrasynaptic GABA receptors by ambient GABA causes a persistently active, or tonic, inhibitory current. Extrasynaptic GABA-A receptors in thalamocortical neurons contain the delta subunit (GABRD; 137163). In an established rat model of absence epilepsy with spontaneous spike-wave discharges called GAERS (genetic absence epilepsy rats from Strasbourg), Cope et al. (2009) found increased tonic current amplitude at thalamocortical GABA-A receptors beginning at postnatal day 17 compared to controls. Similarly increased tonic GABA-A receptor activation was observed in other mouse strains of absence epilepsy, including stargazer and lethargic mice, but not in tottering mice. Increased tonic inhibition was due to compromised GABA uptake by the GABA transporter GAT1 in the thalamus. Blockade or knockout of GAT1 in normal animals induced absence-like seizures. Mice without thalamic GABA-A receptors were resistant to pharmacologically induced seizures. Overall, these results showed that enhanced extrasynaptic GABA-A receptor activation in the thalamus may underlie absence seizures.