Dissecting the genetic basis of myoclonic‐astatic epilepsy

Abstract

Summary Herman Doose first described the generalized childhood epilepsy syndrome of myoclonic astatic epilepsy (MAE) in 1970, attributing a genetic cause from this first description. However, although the International League Against Epilepsy (ILAE) defined criteria for MAE in 1989, the diagnostic boundaries of the syndrome continue to be debated. Moreover, 40 years since Doose's first description of MAE, although a genetic predisposition is acknowledged and many studies have demonstrated familial aggregation of seizures within MAE families, the actual genetic determinants of MAE still remain unknown. Although initially thought to be within the same spectrum as severe myoclonic epilepsy of infancy, the exclusion of SCN1A mutations in non‐generalized epilepsy with febrile seizures plus (GEFS+) MAE cases has confirmed the genetic distinction of MAE. In this critical review, we shall trace the historical evolution of concepts around MAE and its distinction from Lennox‐Gastaut syndrome, review the described phenotypic features of MAE from updated studies that will allow its distinction from other overlap epilepsy syndromes, review the evidence of genetic influences and clues for genetic heterogeneity, and discuss strategies that may be helpful in elucidating the etiology of MAE in light of current genetic techniques.

Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?

“…3 The cause of MAE has yet to be determined. However, high incidence of epilepsy in patients' family 1,2,4,5 and a higher prevalence among patients' relatives (200 times higher than in the general population) 2 suggest a genetic basis. Some genes have been linked to sporadic cases of MAE: SLC2A1, SLC6A1, CHD2, SCN1A, GABRG2, SCN2A, CACNA1H, SYNGAP1 and SCN1B.…”

CHD2 mutations are a rare cause of generalized epilepsy with myoclonic–atonic seizures

“…Later on, a few studies highlighted familial history for epilepsy in up to 32% of affected children [1][2][3]. During the last years, several mutations in SCN1A, SCN1B, GABRG2, and SLC2A1 genes have been reported in single cases of MAE [4,5]. However, in the large majority of patients, a genetic cause remains elusive.…”

Neuropsychological functioning and developmental outcomes in childhood epileptic encephalopathy

“…There is one report of monozygotic twins both with epilepsy, but discordant for EM-AS. This finding, along with other family studies, suggests a familial susceptibility to generalized seizures with a separate factor affecting the expression [39,40]. Although there is strong evidence for a genetic basis, as with many epilepsies the findings are heterogeneous and often the findings represent a small portion of cases analyzed.…”

“…There is a strong familial component to Doose syndrome, leading to exploration of genetic causes of the disorder that may improve treatment and outcome. In a recent review, Tang and Pal [39] summarized evidence for a genetic basis underlying Doose syndrome coming from twin studies, family studies, and gene mutation analyses. There is a high co-incident occurrence of generalized seizures in families of children with EM-AS (approximately 1/3), although multiple family members with EM-AS is rare.…”