Genetic Studies in Patients and Families With Infantile Spasms

Genetic Studies in Patients and Families With Infantile Spasms

Infantile spasms (IIS), a characteristic epilepsy syndrome of infancy with often catastrophic developmental consequences, is known in some patients to have many different genetic, metabolic and structural etiologies. However, for most patients IIS is the only presenting clinical feature and the specific cause is unknown. Only two FDA approved pharmacologic treatments for IIS exist, Adrenocorticotropic hormone (ACTH) and vigabatrin. While vigabatrin may be the treatment of choice for Tuberous Sclerosis as a cause for IS, ACTH is the treatment of choice for all others. Unfortunately, a substantial number of patients may still not respond to ACTH and there is no a priori way that suggests which patients may be responders. This has led to the following key questions:

Can novel genetic analyses determine known genetic causes of IS with greater efficiency (more timely and cost-effective)? Can novel genetic analyses determine previously unknown disease modifying genes that predispose individuals to develop IS? Can novel genetic analyses elaborate genes and gene polymorphisms that favor ACTH responsiveness? Do these polymorphisms suggest strategies to improve ACTH responsiveness?

Primary Aim 1: Apply whole-exome sequencing to determine possible causes of cryptogenic IS and evaluate adding whole-exome sequencing to standard practice for determining causes of IS. Sub-aim 1: Determine the effectiveness of whole-exome sequencing in suggesting disease-modifying genes that may contribute to triggering IS.

Primary Aim 2: Determine genes, through whole-exome sequencing, that may play a role in determining ACTH responsiveness for IS. Sub-aim 2: Correlate genes or genetic factors (haplotypes) associated with ACTH responsiveness and disease modification.

Inclusion Criteria:

• Patient trios (both biological parents + patient with IIS = trio) with IIS retrospectively identified to have been treated with ACTH according to FDA-approved protocol (Table 1).
• Ability to provide informed consent (in case of severe to profound intellectual disability, consent provided by an legally authorized representative, as necessary)

Exclusion Criteria:

• IIS due to suspected or genetically proven tuberous sclerosis
• IIS but do not meet retrospective enrollment criteria (Table 1)
• Inability to complete consent process