Early onset epileptic encephalopathy caused by novel compound heterozygous mutation of <i>WWOX</i> gene

Su, Tangfeng; Yan, Yu; Xu, Shan; Zhang, Ke; Xu, Sanqing

doi:10.1002/jdn.10013

Cited by 6 publications

(8 citation statements)

References 20 publications

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“…Comparing our findings with reported pathogenic variants causing WWOX-DEE, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] no region of the gene emerged as specific for being associated with WWOX-DEE. Furthermore, the two missense variants associated with the rarer, milder SCAR12 phenotype are situated in close proximity to WWOX-DEE variants: p.Gly372Arg in exon 9 and p.Pro47Thr in exon 2.…”

Section: Genetic Variantssupporting

confidence: 68%

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

et al. 2023

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Objective WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX‐DEE), also known as WOREE (WWOX‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival. Methods We studied 13 patients from 12 families with WWOX‐DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan–Meier method. Results All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day–10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo‐occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p‐value = .0085, log‐rank test). Significance Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

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Section: Genetic Variantssupporting

confidence: 68%

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

et al. 2023

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“…Whole exome sequencing (WES) was performed by the WuXi NextCODE Genomics, Shanghai, China (CLIA Lab ID: 99D2064856) using a previously described protocol (Su et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations

Yan

et al. 2022

Molec Gen & Gen Med

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Background:The human dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene encodes a large subunit of the cytoplasmic dynein complex. DYNC1H1 mutations are associated with various neurological diseases involving both the peripheral and central nervous systems. Methods: The clinical characteristics and genetic data of an infant carrying the de novo DYNC1H1 variant identified by trio exome sequencing were analyzed. Patients with epilepsy with DYNC1H1 mutations were summarized by reviewing the literature. Results: We first identified an infant presenting with epileptic spasms harboring a de novo missense mutation in DYNC1H1 (c.874C>T; p. Arg292Trp), once reported in an adult case, and further summarized another 54 patients with seizures or epilepsy caused by DYNC1H1 pathogenic variants in the literature. Refractory epilepsy, intellectual disability, and cortical developmental malformations are crucial characteristics of patients with developmental and epileptic encephalopathy (DEE) caused by DYNC1H1 variants. Notably, epileptic spasms in this case were resistant to multiple anti-seizure medications, corticosteroids, ketogenic diet, and vagus nerve stimulation treatment. The child also showed cortical gyrus malformation and global developmental delay. Conclusion: DYNC1H1 variants can cause infantile developmental and epileptic encephalopathy, in which Arg292Trp is a mutation hotspot of the DYNC1H1 gene. Epileptic seizures in this type of DYNC1H1-related DEE are mostly resistant to multiple antiepileptic strategies and need to explore optimized treatments.

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“…WOREE is characterized by early‐onset drug‐resistant seizures that lead to severe EE [7]. Focal seizures, focal to bilateral tonicclonic seizures, and epileptic spasms were reported in a recent review of 59 patients with WOREE syndrome [8]. In this article, we report on nine additional patients with homozygous pathogenic mutations in the WWOX gene who presented with WOREE syndrome.…”

mentioning

confidence: 89%

Epilepsy in patients with WWOX‐related epileptic encephalopathy (WOREE) syndrome

Baradie

Mir

Alsaif

et al. 2022

Epileptic Disorders

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Objective. Epileptic encephalopathy (EE) is difficult to diagnose and manage. It can be caused by a variety of disorders, and its aetiology may guide management and prognosis. The human gene for WW domain-containing oxidoreductase (WWOX) has been associated with epileptic encephalopathy, which presents in infancy with seizures, psychomotor delay, microcephaly, and optic atrophy. Methods. We report nine patients with WWOX-related EE from six families. We provide detailed descriptions of clinical presentations, imaging findings, neurophysiological manifestations, and related mutations. Whole-exome sequencing (WES) was used to identify the mutations in the WWOX gene. Results. We established correlations between genotype and phenotype in our cases and previously reported cases. Significance. Our data support previously reported findings regarding WWOXrelated EE, indicating the importance of the human WWOX gene in brain development and the association between WWOX mutations and EE. Our study also highlights the power of WES, particularly in clinically challenging cases.

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Early onset epileptic encephalopathy caused by novel compound heterozygous mutation of WWOX gene

Cited by 6 publications

References 20 publications

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations

Epilepsy in patients with WWOX‐related epileptic encephalopathy (WOREE) syndrome

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