Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients

Federica Provini,Paolo Tinuper,Giovanni Crichiutti,Giuseppe Plazzi,Antonio Gambardella,Eleonora Briatore,Carla Marini,Francesca Bisulli,Tommaso Pippucci,Raffaella Minardi,Aglaia Vignoli,Stefano Meletti,Margherita Santucci,Amedeo Bianchi,Lucio Giordano,Pasquale Striano,Sara Baldassari,Barbara Mostacci,Robertino Dilena

doi:10.1016/j.seizure.2019.11.009

Abstract

PurposeGenetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome. MethodsWe selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines. ResultsWe included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD).We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD. ConclusionsThe overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.

Highlights

Sleep-related hypermotor epilepsy (SHE), previously Nocturnal Frontal Lobe Epilepsy (NFLE), is characterized by hypermotor seizures arising predominantly from sleep
We identified three pathogenic variants in CHRNA4 (2.9 %, confidence intervals (CI): 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic
In 17 (16.5 %) the abnormalities were consistent with focal cortical dysplasia (FCD), confirmed by histopathology in four (3.9 %)

Summary

Introduction

Sleep-related hypermotor epilepsy (SHE), previously Nocturnal Frontal Lobe Epilepsy (NFLE), is characterized by hypermotor seizures arising predominantly from sleep. The first gene for SHE, CHRNA4 (Cholinergic Receptor Nicotinic Alpha 4 Subunit MIM *118504), was identified in 1995 by linkage analysis in a large pedigree showing an autosomal dominant pattern of transmission (ADSHE). For about two decades no further genetic determinants of SHE have been identified. Since 2012, the application of generation sequencing (NGS) technologies allowed to study nuclear pedigrees not suitable for linkage analysis, or even sporadic cases, leading to the identification of four additional main genes: KCNT1 (Potassium Sodium-Activated Channel Subfamily T Member 1, MIM *608167) [3], DEPDC5 (DEP Domain Containing 5, MIM *614191) [4], NPRL2 (NPR2like Protein, MIM *607072) [5] and NPRL3 (Nitrogen Permease Regulator-like 3, MIM *600928) [6]

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Conclusion