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Multicenter Study
. 2023 Dec;8(4):1383-1404.
doi: 10.1002/epi4.12811. Epub 2023 Aug 25.

Landscape of genetic infantile epileptic spasms syndrome-A multicenter cohort of 124 children from India

Balamurugan Nagarajan  1 , Vykuntaraju K Gowda  2 , Sangeetha Yoganathan  3 , Indar Kumar Sharawat  4 , Kavita Srivastava  5 , Nitish Vora  6 , Rahul Badheka  6 , Sumita Danda  7 , Umesh Kalane  4 , Anupriya Kaur  8 , Priyanka Madaan  1   9 , Sanjiv Mehta  6 , Sandeep Negi  1 , Prateek Kumar Panda  4 , Surekha Rajadhyaksha  5 , Arushi Gahlot Saini  1 , Lokesh Saini  1   10 , Siddharth Shah  6 , Varunvenkat M Srinivasan  2 , Renu Suthar  1 , Maya Thomas  3 , Sameer Vyas  11 , Naveen Sankhyan  1 , Jitendra Kumar Sahu  1
Affiliations
Multicenter Study

Landscape of genetic infantile epileptic spasms syndrome-A multicenter cohort of 124 children from India

Balamurugan Nagarajan et al. Epilepsia Open. 2023 Dec.

Abstract

Objective: Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children.

Methods: Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed.

Results: Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy.

Significance: Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.

Keywords: developmental and epileptic encephalopathy; genetic West; genetic epileptic spasms; genetic infantile spasms.

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Conflict of interest statement

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Genetic spectrum of children with genetic IESS.
FIGURE 2
FIGURE 2
Distribution of single‐gene disorders causing genetic IESS.
FIGURE 3
FIGURE 3
Gene network diagram and its interactions among the genes observed in the study.
See this image and copyright information in PMC

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