Genetic and Biologic Classification of Infantile Spasms

Abstract

Infantile spasms are an age-dependent epilepsy that are highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems have focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with the 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 more likely to have infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children with these genetic associations with infantile spasms also have phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. We therefore also propose a biologic classification of the genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on that data. The two best described pathways of pathogenesis are abnormalities in the gene regulatory network of GABAergic forebrain development, and abnormalities in molecules expressed at the synapse. We intend for these genetic and biologic classifications to be flexible, and hope that they will encourage much needed progress in syndrome recognition, clinical genetic testing, and ultimately the development of new therapies that target specific pathways of pathogenesis.

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…Such groups include metabolic diseases [5], cytomegalovirus infection [6], cryptogenic group of infantile spasms [7] and tuberous sclerosis (TS) [8]. The number of genes associated with infantile spasms are rapidly increasing (ARX, CDKL5, FOXG, GRIN1, GRIN 2A, MAGI, MEF2C, SLC25A22, SPTANI, STXBP1 and 15q11q13) [9], therefore genetic therapy might be possible in the future.…”

Epileptic Syndromes With Possible Immunological Mechanisms (Rasmussen Encephalitis, FIRES, West Syndrome, Landau-Kleffner Syndrome)

“…Yayınlara göre West sendromu ile ilişkili genler ARX, CDKL5, SLC25A22, SPTAN1, PLCβ1, MAGI2 ve PNKP'dir. [72] Gün geçtikçe yeni mutasyonlar tanımlanmaya devam etmektedir. Fakat şimdiye kadar tanımlanan bu mutasyonların çoğu Dravet sendromu dışında sadece küçük hasta gruplarını içermekte ve tüm infantil spazm ve West sendro- [90] CHARGE; kolobama, nazal konka atrezisi, büyüme ve gelişme geriliği, genital ve üriner sistem anormallikleri, kulak anormallikleri ve sağırlık (Coloboma, Atresia, Choanae, Genital, Ear).…”

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

“…The most frequent genetic causes of IS are mutations in TSC1 (about 9% of all IS/WS patients, OMIM#191100), CDKL5, ARX and STXBP1 genes, as well as multiple genomic imbalances, the commonest being Pallister-Killian syndrome (tetrasomy 12p; OMIM#601803) and 1p36 deletion (OMIM#607872). [7][8][9][10][11][12][13] These and other genetic causes such as genes encoding proteins involved in inborn errors of metabolism were recently reviewed in Paciorkowski et al 14 IS/WS also occur with a lower prevalence as a feature of other genetic diseases, such as Down syndrome. 14 This heterogeneity often impedes the identification of the etiology of IS/WS within the clinical practice.…”

“…[7][8][9][10][11][12][13] These and other genetic causes such as genes encoding proteins involved in inborn errors of metabolism were recently reviewed in Paciorkowski et al 14 IS/WS also occur with a lower prevalence as a feature of other genetic diseases, such as Down syndrome. 14 This heterogeneity often impedes the identification of the etiology of IS/WS within the clinical practice. 15 Despite early clinical diagnosis and appropriate treatment, prognosis remains a major concern with frequent intellectual deficiency (75-90%) and recurrence of seizures later in life (50-60%).…”