Epilepsy With Myoclonic Atonic Seizures: Why Is the Yield of Genetic Testing for a “Presumed Genetic” Epilepsy Low?

Nickels, Katherine C.

doi:10.1177/1535759720948890

Cited by 3 publications

(2 citation statements)

References 8 publications

(22 reference statements)

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“…A normal development prior to seizure onset is historically considered a diagnostic criterium for the diagnosis of MAE, but the phenotypic boundaries of this syndrome remain debated. 54 In a recent study on the genetic etiology of MAE, more than 20% of patients did have developmental delay prior to seizure onset. 8 This feature is indeed inherent to the concept of DEE, which acknowledges that the neurodevelopmental impairment of these patients is not solely related to frequent epileptic activity but is also a direct result of the underlying gene dysfunction.…”

Section: Discussionmentioning

confidence: 99%

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

Manivannan

Roovers

Smal

et al. 2021

Brain

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FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homolog of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype Myoclonic Atonic Epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental epileptic encephalopathy, and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental epileptic encephalopathies associated with a spectrum of neonatal to childhood onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental epileptic encephalopathy cases.

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Section: Discussionmentioning

confidence: 99%

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

Manivannan

Roovers

Smal

et al. 2021

Brain

View full text Add to dashboard Cite

show abstract

“…Of note, two patients in our study were diagnosed with MAE. A normal development prior to seizure onset is historically considered a diagnostic criterium for the diagnosis of MAE, but the phenotypic boundaries of this syndrome remain debated 64 . In a recent study on the genetic etiology of MAE, more than 20% of patients did have developmental delay prior to seizure onset 8 .…”

Section: Discussionmentioning

confidence: 99%

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

Manivannan

Roovers

Smal³

et al. 2021

Preprint

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FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment, both through the control of the cell cycle and through its multiple functions in post-mitotic neurons. In this study, the evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood-onset generalized epilepsy, intellectual disability, mild ataxia, and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. Along with a recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay, and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases.

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Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures

Caraballo

Valenzuela

Fortini³

et al. 2023

Epilepsy & Behavior

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Epilepsy With Myoclonic Atonic Seizures: Why Is the Yield of Genetic Testing for a “Presumed Genetic” Epilepsy Low?

Abstract: [Box: see text]

Cited by 3 publications

References 8 publications

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures

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