A rare form of familial epilepsy has been linked to a mutation in a gene that is normally involved in the production of gangliosides in the brain, according to new research published in Nature Genetics. Gangliosides are glycolipids that contain sialic acid and are found in almost all cells, but are especially abundant in the central nervous system. Abnormalities in their degredation are usually associated with lysosomal storage disorders, but, so far, their role in the brain has not been well characterized. This new work indicates that they are crucial for neuronal stability.

Inherited epilepsies are thought to account for ∼40% of cases. A small proportion of these are related to single gene defects, several of which have been shown to encode ion channels. Simpson et al. have identified a different mechanism underlying inherited epilepsy in two branches of a large family with an autosomal recessive form of epilepsy who were connected through a fifth-generation common ancestor. Eight surviving individuals were affected with severe epilepsy that began in the first year of life, and involved generalized tonic clonic (grand mal) and partial seizures. The onset of epilepsy was accompanied by a marked decline in motor and verbal development, as well as severe visual impairments.

Genome-wide linkage analysis showed that all affected children shared a single region of homozygosity on chromosome 2 that was not found in unaffected siblings or parents. A nonsense mutation (C694T) in the gene SIAT9 was identified by high-throughput sequencing, and it was shown that this mutation abolishes the activity of GM3 synthase. GM3 synthase triggers the first step in the production of central nervous system gangliosides by transferring a sialic acid residue to lactosylceramide to form GM3, the main ganglioside in human plasma. Disrupting the activity of GM3 synthase therefore prevents the formation of GM3 and other important gangliosides.

Biochemical analyses showed that GM3 and its derivatives were completely absent in the affected members of the family; in addition, they had elevated levels of its immediate precurser, lactosylceramide. It is not clear, however, whether the condition is due to reduced GM3 levels or to elevated lactosylceramide levels or a combination of both. Nevertheless, this research highlights a novel mechanism that might, in the future, help us to understand other forms of epilepsy. Moreover, the involvement of the ganglioside-formation pathway in epilepsy indicates that these glycolipids might be important for neuronal stability.