Genetic and biologic classification of infantile spasms

Infantile spasms constitute an age-dependent epilepsy, highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with recent discoveries of mutations in genes in key pathways of central nervous system development in patients with infantile spasms. Children with certain genetic syndromes are much likelier to manifest infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children demonstrating genetic associations with infantile spasms also manifest phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. Therefore we propose a biologic classification of genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on those data. The two best described pathways of pathogenesis involve abnormalities in the gene regulatory network of gamma-aminobutyric acidergic forebrain development and abnormalities in molecules expressed at the synapse. These genetic and biologic classifications are flexible, and they should encourage much needed progress in syndrome recognition, clinical genetic testing, and the development of new therapies targeting specific pathways of pathogenesis.