The genetic landscape of developmental and epileptic encephalopathy with spike-and-wave activation in sleep

Freibauer, Alexander; RamachandranNair, Rajesh; Jain, Puneet; Jones, Kay S.; Whitney, Robyn

doi:10.1016/j.seizure.2023.06.017

Cited by 7 publications

(1 citation statement)

References 49 publications

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“…In addition to GRIN2A , genes associated with DEE‐SWAS to date include, in order of frequency, CNKSR2, ZEB2, KCNA2, KCNQ2, SLC9A6, SCN2A, KCNB1 , SLC6A1, WAC, TET3, KCND2, KCNA1, ATP1A3, MECP2, SERPINI, TUBA1A, CDKL5, KANSL1, ATN1 , SRPX2 , OPA3 , HIVEP2 (Freibauer et al., 2023; Kessi et al., 2018), IL1RAPL1 (Jiang et al., 2022), FRRS1L (Mir et al., 2023), CARS2 and RARS2 (Freibauer et al., 2023). The latter two are other nuclear genes encoding different mitochondrial aminoacyl‐tRNA synthetases, cysteinyl and argynil, respectively.…”

Section: Discussionmentioning

confidence: 99%

Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep

Licchetta,

Di Giorgi,

Santucci

et al. 2023

Molec Gen & Gen Med

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BackgroundBiallelic pathogenic variants in the mitochondrial prolyl‐tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy‐75 (DEE‐75, MIM #618437). This condition is typically characterized by early‐onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years.MethodsWe describe a patient with early‐onset DEE, consistently showing an EEG pattern of Spike‐and‐Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES).ResultsWES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2‐associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2.Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability.ConclusionThese findings widen the genetic heterogeneity of DEE‐SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2‐related DEE.

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Section: Discussionmentioning

confidence: 99%

Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep

Licchetta,

Di Giorgi,

Santucci

et al. 2023

Molec Gen & Gen Med

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ALDH18A1‐related hereditary spastic paraplegia and developmental and epileptic encephalopathy with spike‐wave activation in sleep: Expanding the clinical phenotype

Ferrara,

Cutillo,

Peterlongo

et al. 2024

Annals of the Child Neurology Society

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ObjectiveWe present the cases of two sisters, both harboring the same ALDH18A1 gene mutations, who presented with a complex clinical phenotype characterized by spastic paraparesis with ataxia, epileptic encephalopathy, severe psychomotor deficits, and behavioral abnormalities.MethodsCase description of two sisters with ALDH18A1 gene mutations.ResultsThe older patient, a 12‐year‐old girl, exhibited spastic paraparesis with ataxia, microcephaly, facial dysmorphisms, and severe intellectual disability, with an absence of verbal language. An electroencephalogram (EEG) revealed marked spike‐and‐wave activation during sleep (SWAS), although no clinically documented seizures were observed. The younger sister, who was 9 years old, displayed a similar clinical presentation, including spastic paraparesis with ataxia, microcephaly, dysmorphisms, however, she displayed slightly more severe intellectual deficits and polymorphic seizures. EEG revealed a SWAS pattern in this case. Magnetic resonance imaging scans in both cases showed only a thin corpus callosum. Whole exome sequencing unveiled the presence of two likely pathogenic variants in compound heterozygosity within the ALDH18A1 gene. Specifically, these variants included the splice site variant c.88 + 1c.88+1G>A of paternal origin and the variant c.1364c.1364T>C (p.Leu455Ser) of maternal origin. Both sisters displayed normal blood levels of ammonia, ornithine, citrulline, arginine, and other amino acids.InterpretationThese findings were compatible with ALDH18A1‐related HSP complicated with a clinical and EEG pattern reminiscent of DEE‐SWAS. We present the first report of DEE‐SWAS in ALDH18A1‐related HSP, expanding the clinical manifestations of this complex neurodevelopmental condition.

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Transorbital intraoperative electrocorticography-guided surgical resection for medically refractory developmental epileptic encephalopathy with spike-wave activation in sleep

Baumgartner,

Kessler,

Franco

et al. 2024

Epilepsy & Behavior Reports

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The genetic landscape of developmental and epileptic encephalopathy with spike-and-wave activation in sleep

Cited by 7 publications

References 49 publications

Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep

Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep

ALDH18A1‐related hereditary spastic paraplegia and developmental and epileptic encephalopathy with spike‐wave activation in sleep: Expanding the clinical phenotype

Transorbital intraoperative electrocorticography-guided surgical resection for medically refractory developmental epileptic encephalopathy with spike-wave activation in sleep

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