GM3 Synthase Deficiency

Infantile spasms are an uncommon and serious form of epilepsy in infants. Our studies identified two Amish families with children with a severe infantile-onset epilepsy syndrome  (GM3 synthase deficiency) associated with developmental delay and blindness. Both families had multiple affected cases suggesting that the cause may be genetic. Using samples from these children we were able to show that a gene was responsible and that it was likely to be the same gene in both families, located on chromosome 2. Sequence analysis of the genes in this region led us to identify a mutation in the SIAT9, which encodes the GM3 synthase enzyme.

GM3 synthase is a key enzyme for the synthesis the ‘complex gangliosides’, a group of molecules crucial for normal brain development. Mutations in other genes involved in the breakdown of gangliosides had been shown before. However the discovery of mutations in GM3 synthase was particularly important because it showed for the first time that mutations in the synthesis of these molecules can also cause inherited disorders. Our most recent studies are now investigating other forms of infantile seizures for abnormalities in ganglioside synthesis, as well as examining the precise role of GM3 in cells in culture with the aim of one day developing a possible treatment option.