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. 2024 Dec:123:17-25.
doi: 10.1016/j.seizure.2024.09.021. Epub 2024 Oct 10.

Therapeutic implications of etiology-specific diagnosis of early-onset developmental and epileptic encephalopathies (EO-DEEs): A nationwide Turkish cohort study

Seda Kanmaz  1 , Hasan Tekgul  2 , Hulya Kayilioglu  3 , Yavuz Atas  2 , Pinar Ozkan Kart  4 , Nihal Yildiz  4 , Hakan Gumus  5 , Kursad Aydin  6 ; Turkish Epistep Concortium
Collaborators, Affiliations

Therapeutic implications of etiology-specific diagnosis of early-onset developmental and epileptic encephalopathies (EO-DEEs): A nationwide Turkish cohort study

Seda Kanmaz et al. Seizure. 2024 Dec.

Abstract

Objective: To evaluate the etiology-specific diagnosis of early-onset developmental epileptic encephalopathies (EO-DEEs) in a nationwide Turkish cohort to determine the implications for therapeutic management.

Methods: The cohort comprised 1450 patients who underwent EO-DEE. The utility of genetic testing was assessed with respect to the initial phases of next generation sequencing (NGS) (2005-2013) and the current NGS era (2014-2022). A predefined four-stepwise diagnostic model was evaluated using cost-effectiveness analysis. The diagnostic and potential therapeutic yields of the genetic tests were subsequently determined.

Results: Gene-related EO-DEEs were identified in 48.3 % (n = 701) of the cohort: non-structural genetic (62.6 %), metabolic genetic (15.1 %), and structural genetic (14.1 %). The most common nonstructural genetic variants were SCN1A (n = 132, 18.8 %), CDKL5 (n = 30, 4.2 %), STXBP1 (n = 21, 2.9 %), KCNQ2 (n = 21, 2.9 %), and PCDH19 (n = 17, 2.4 %). The rate of ultra-rare variants (< 0.5 %) was higher in the NGS era (52 %) than that in the initial phase (36 %). The potential therapeutic yields with precision therapy and antiseizure drug modification were defined in 34.5 % and 56.2 % in genetic-EO-DEEs, respectively. The diagnostic model provided an etiology-specific diagnosis at a rate of 78.7 %: structural (nongenetic) (31.4 %), genetic (38.5 %), metabolic (6.1 %), and immune-infectious (2.8 %). Based on a cost-effectiveness analysis, the presented diagnostic model indicated the early implementation of whole-exome sequencing for EO-DEEs.

Significance: In the present cohort, the higher rate (48.3 %) of gene-related EO-DEE diagnoses in the NGS era provides a potential therapeutic management plan for more patients.

Keywords: Early-onset developmental epileptic encephalopathies; Genetic testing; Precision medicine; Stepwise diagnostic model.

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Conflict of interest statement

Declaration of competing interest There are no conflicts of interest that require disclosure by any of the authors. This article does not contain any pertinent financial information that the authors are required to disclose. This manuscript does not receive any external funding.

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