Cortical and Subcortical Network Dysfunction in a Female Patient With NEXMIF Encephalopathy

Cioclu, Maria Cristina; Coppola, Antonietta; Tondelli, Manuela; Vaudano, Anna Elisabetta; Giovannini, Giada; Krithika, S.; Iacomino, Michele; Zara, Federico; Sisodiya, Sanjay M.; Meletti, Stefano

doi:10.3389/fneur.2021.722664

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…The proband of Family EEM_05 had a frameshift deletion in NEXMIF (NM_001008537: c.2171delG, p.Ser724fs) that was absent in gnomAD. As described, 32 she had drug‐resistant epilepsy starting at the age of 9 years with recurrent episodes of prolonged nonconvulsive status epilepticus characterized by mydriasis, EM, and reduced responsiveness to environmental stimuli. She also had mild ID and was thus classified as having EEM+.…”

Section: Resultsmentioning

confidence: 95%

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Coppola,

Krithika,

Iacomino

et al. 2023

Epilepsia

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ObjectiveEpilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure‐induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM.MethodsWe studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM− (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder).ResultsWe identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM− subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM− an established association. Burden analysis did not identify any single burdened gene or gene set.SignificanceOur results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene–disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM− and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM− remains to be elucidated.

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Section: Resultsmentioning

confidence: 95%

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Coppola,

Krithika,

Iacomino

et al. 2023

Epilepsia

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“…10,11 There has been an increased understanding of the role of genetics in EEM, with cases of EEM related to mutations in RORB, SYNGAP1, KCNB1, NAA10, COL6A3, KIAA2022, CHD2, NIPA1, APC2, and SLC2A1. 2,[12][13][14][15][16][17][18][19][20][21][22] There has also been the recognition that patients with EEM and underlying genetic mutations may also have an intellectual disability. There was no consensus about performing genetic testing in every patient with EEM among the panelists.…”

Section: Discussionmentioning

confidence: 99%

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel

Smith,

Wirrell,

Andrade

et al. 2023

Epilepsia

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ObjectiveThe objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis.MethodsAn international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM.ResultsThere was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic–clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug‐resistant epilepsy.SignificanceThis international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

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“…Brain MRI does not usually show major anomalies [40,41]. Advanced neuroimaging techniques have revealed brain structural and functional changes, especially in the visual pericalcarine cortex and in the middle frontal gyrus, which are involved in several visuo-motor function and therefore in epilepsy phenotypes with visual sensitivity and eyelid myoclonia [141].…”

Section: Nexmifmentioning

confidence: 99%

X-Linked Epilepsies: A Narrative Review

Bernardo,

Cuccurullo,

Rubino

et al. 2024

IJMS

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X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype–phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

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Cortical and Subcortical Network Dysfunction in a Female Patient With NEXMIF Encephalopathy

Cited by 4 publications

References 29 publications

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel

X-Linked Epilepsies: A Narrative Review

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