Clinical and Molecular Profile of Infantile-Onset Pharmaco-Resistant Epilepsy in Iraqi Children

Abstract

Background

Identifying the underlying genetic etiology of epilepsy and neurodevelopmental disorders can greatly inform clinical management from diagnosis to treatment to genetic counseling about prognosis. The aim of the study was to establish the genetic/molecular diagnosis in children presenting to two children hospitals in Baghdad, with infantile-onset epilepsy.

Methods

Twenty-nine Iraqi children with infantile-onset epilepsy, defined as epilepsy with onset in the first year of life, presenting between April 2018 and June 2021, were included in this prospective study.

Results

An overall molecular diagnostic rate of 65.5% (in 19/29 subjects) was achieved. Of the subjects with molecular diagnosis, 74% (14/19 subjects) were diagnosed by clinical exome sequencing and 26% (5/19 subjects) were diagnosed by the epileptic encephalopathy panel. Single nucleotide variants were detected in 95% (18/19 subjects) while copy number variants accounted for 5% of the cohort (1/19 subjects). Thirteen subjects (68%) had known pathogenic or likely pathogenic variants in the following genes: SCN1B, SCN1A, ALG13, STXBP1, TBC1D24, PRUNE1, ALDH7A1, PCDH19, SCN8A, and SLC13A5. Six patients (32%) had novel variants potentially explaining the phenotype in the following known genes: SYNJ1, SLC25A22, SCN2A, KCNT1, CACNA1A, and PLPBP. Half (9/19; 47%) of the molecularly diagnosed cases had therapeutic implications.

Conclusion

This is the first study to characterize the genotypic and phenotypic spectrum of infantile-onset drug-resistant epilepsy in children from Iraq. Our study demonstrates a high molecular yield with genetic heterogeneity and predominance of autosomal recessive mode of inheritance.

Keywords

infantile - epilepsy - pharmaco-resistant

Authors' Contributions

N.W.S. and N.M. contributed to the conceptualization of the manuscript. N.W.S. and A.K.A. contributed to data collection. N.W.S. wrote the original draft. D.M. critically reviewed the manuscript.

Publikationsverlauf

Eingereicht: 26. Dezember 2024

Angenommen: 06. Juni 2025

Artikel online veröffentlicht:
11. August 2025

• References

• 1 Zhang Y, Kong W, Gao Y. et al. Gene mutation analysis in 253 Chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One 2015; 10 (11) e0141782
• 2 Zuberi SM, Wirrell E, Yozawitz E. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63 (06) 1349-1397
• 3 Berg AT, Coryell J, Saneto RP. et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatr 2017; 171 (09) 863-871
• 4 Calhoun JD, Carvill GL. Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. J Neurogenet 2018; 32 (04) 295-312
• 5 Arafat A, Jing P, Ma Y. et al. Unexplained early infantile epileptic encephalopathy in Han Chinese children: next-generation sequencing and phenotype enriching. Sci Rep 2017; 7: 46227
• 6 Wang J, Wen Y, Zhang Q. et al. Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome. Seizure 2019; 66: 26-30
• 7 Scheffer IE, Liao J. Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy”. Eur J Paediatr Neurol 2020; 24: 11-14
• 8 Nashabat M, Al Qahtani XS, Almakdob S. et al. The landscape of early infantile epileptic encephalopathy in a consanguineous population. Seizure 2019; 69: 154-172
• 9 Idris A, Alabdaljabar MS, Almiro A. et al. Prevalence, incidence, and risk factors of epilepsy in Arab countries: a systematic review. Seizure 2021; 92: 40-50
• 10 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 512-521
• 11 Fisher RS, Cross JH, D'Souza C. et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia 2017; 58 (04) 531-542
• 12 Rim JH, Kim SH, Hwang IS. et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics 2018; 11 (01) 6
• 13 Møller RS, Larsen LH, Johannesen KM. et al. Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 2016; 7 (04) 210-219
• 14 Helbig KL, Farwell Hagman KD, Shinde DN. et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 2016; 18 (09) 898-905
• 15 Mercimek-Mahmutoglu S, Patel J, Cordeiro D. et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 2015; 56 (05) 707-716
• 16 Nakayama J. Progress in searching for the febrile seizure susceptibility genes. Brain Dev 2009; 31 (05) 359-365
• 17 Blazekovic A, Gotovac Jercic K, Meglaj S. et al. Genetics of pediatric epilepsy: next-generation sequencing in clinical practice. Genes (Basel) 2022; 13 (08) 1466
• 18 Duan R, Saadi NW, Grochowski CM. et al. A novel homozygous SLC13A5 whole-gene deletion generated by Alu/Alu-mediated rearrangement in an Iraqi family with epileptic encephalopathy. Am J Med Genet A 2021; 185 (07) 1972-1980
• 19 Li T, Cheng M, Wang J. et al. De novo mutations of STXBP1 in Chinese children with early onset epileptic encephalopathy. Genes Brain Behav 2018; 17 (08) e12492
• 20 Shang KW, Zhang YH, Yang XL. et al. Clinical features and gene mutations in epilepsy of infancy with migrating focal seizures [in Chinese]. Zhonghua Er Ke Za Zhi 2016; 54 (10) 735-739
• 21 Poulat AL, Ville D, de Bellescize J. et al. Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability. Epilepsy Res 2015; 111: 72-77
• 22 Samanta D, Arya K. Electroclinical findings of SYNJ1 epileptic encephalopathy. J Pediatr Neurosci 2020; 15 (01) 29-33
• 23 Al Zaabi N, Al Menhali N, Al-Jasmi F. SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure. Mol Genet Genomic Med 2018; 6 (01) 109-113
• 24 Pisani F, Percesepe A, Spagnoli C. Genetic diagnosis in neonatal-onset epilepsies: back to the future. Eur J Paediatr Neurol 2018; 22 (03) 354-357
• 25 Wolff M, Brunklaus A, Zuberi SM. Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond. Epilepsia 2019; 60 (Suppl 03): S59-S67
• 26 Gardella E, Marini C, Trivisano M. et al. The phenotype of SCN8A developmental and epileptic encephalopathy. Neurology 2018; 91 (12) e1112-e1124
• 27 Barcia G, Fleming MR, Deligniere A. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44 (11) 1255-1259
• 28 Heron SE, Smith KR, Bahlo M. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012; 44 (11) 1188-1190
• 29 McTague A, Appleton R, Avula S. et al. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013; 136 (Pt 5): 1578-1591
• 30 McTague A, Nair U, Malhotra S. et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 2018; 90 (01) e55-e66
• 31 Martin HC, Kim GE, Pagnamenta AT. et al; WGS500 Consortium. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet 2014; 23 (12) 3200-3211
• 32 Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 2016; 99 (02) 287-298
• 33 Hu Y, Jiang H, Wang Q, Xie Z, Pan S. Identification of a novel nonsense mutation p.Tyr1957Ter of CACNA1A in a Chinese family with episodic ataxia 2. PLoS One 2013; 8 (02) e56362
• 34 Molinari F, Kaminska A, Fiermonte G. et al. Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet 2009; 76 (02) 188-194
• 35 Lemattre C, Imbert-Bouteille M, Gatinois V. et al. Report on three additional patients and genotype-phenotype correlation in SLC25A22-related disorders group. Eur J Hum Genet 2019; 27 (11) 1692-1700
• 36 Molinari F, Raas-Rothschild A, Rio M. et al. Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet 2005; 76 (02) 334-339
• 37 Cohen R, Basel-Vanagaite L, Goldberg-Stern H. et al. Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. Eur J Paediatr Neurol 2014; 18 (06) 801-805
• 38 Poduri A, Heinzen EL, Chitsazzadeh V. et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol 2013; 74 (06) 873-882
• 39 Giacomini T, Pisciotta L, Prato G. et al. Severe early-onset developmental and epileptic encephalopathy (DEE) associated with novel compound heterozygous pathogenic variants in SLC25A22: Case report and literature review. Seizure 2019; 70: 56-58
• 40 Striano P, Minassian BA. From genetic testing to precision medicine in epilepsy. Neurotherapeutics 2020; 17 (02) 609-615
• 41 D'Gama AM, Mulhern S, Sheidley BR. et al; Gene-STEPS Study Group, IPCHiP Executive Committee. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. Lancet Neurol 2023; 22 (09) 812-825