Abstracts

Rationale: Infantile spasms (IS) are a severe epilepsy syndrome that occurs in infants, characterized by spasms, hypsarrhythmia on EEG, and developmental regression. The etiology of IS is diverse, encompassing genetic, structural, metabolic, and unknown causes. Advances in genetic testing have facilitated the identification of various genetic mutations associated with IS, improving diagnosis and potentially guiding treatment. This systematic review aims to summarize the incidence of various genetic etiologies of IS as reported in different studies. The focus is on understanding the distribution of genetic mutations and syndromes, the methodologies used for genetic testing, and the percentage of patients identified with specific genetic causes. This comprehensive analysis of the genetic etiologies of IS has not been previously conducted.

Methods: A search was conducted using MEDLINE and EMBASE using the following terms: "infantile spasms," "etiology," "genetic." Additional studies were identified through manual review of study citations. The inclusion criteria were cross-sectional studies or case series using genetic analysis on >20 IS patients under 2 years of age. Some studies included all patients with IS, while others focused on subsets of patients with idiopathic, unknown etiology, cryptogenic IS, or those requiring a second opinion. This variation in study populations may affect the accuracy of reported incidence rates.


Results: A total of 14 studies met the inclusion criteria, encompassing 3,633 patients. Population sizes varied significantly, with the lowest sample size being 31 patients and the highest being 728 patients. Genetic testing methods varied, including whole-exome sequencing (WES), targeted gene panels, and karyotyping. The range in incidence of specific genetic syndromes was as follows: Tuberous Sclerosis Complex (TSC2) 16.8%, Epileptic Encephalopathy (STXBP1) 0.9% to 12%, Rett Syndrome (CDKL5) 0.5% to 11.1%, Dravet Syndrome (SCN1A) 0.9% to 9%, X-Linked Lissencephaly (ARX) 0.9% to 6.7%, Chromosomal abnormalities 6%, KCNB1 Encephalopathy 0.5% to 4.4%, DEPDC5-Related Epilepsy 0.5% to 4.4%, SCN3A Encephalopathy 0.7% to 3.2%, SCN2A Encephalopathy 0.7% to 3.2%, Tuberous Sclerosis Complex (TSC1) 0.9% to 2.8%, KCNQ2 Encephalopathy 0.5% to 2.2%, AARS-Related Epilepsy 0.5% to 2.2%, WDR45-Related Epilepsy 0.5% to 2.2%.


Conclusions: This review highlights the genetic heterogeneity of IS and the estimated incidence of significant contributing genetic mutations. Genetic testing in the workup of IS can reveal pathology that clinical evaluation, imaging, and metabolic screening may miss. The variability in the incidence rates suggests a need for standardized genetic testing protocols to ensure consistency and accuracy in diagnosis. A considerable proportion of IS cases with a genetic etiology are associated with tuberous sclerosis, encephalopathy, and chromosomal anomalies, emphasizing the need for comprehensive genetic screening. This approach could uncover additional genetic mutations and provide a more complete understanding of the genetic landscape of IS.


Funding: No funding was received in support of this abstract.