Recently defined epileptic encephalopathy related to WWOX gene mutation: six patients and new mutations

Havalı, Cengiz; Ekici, Arzu; Dorum, Sevil; Görükmez, Özlem; Topak, Ali

doi:10.1080/01616412.2021.1932173

Cited by 3 publications

(15 citation statements)

References 12 publications

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“…individuals by Havali et al (2021) and Piard et al (2019) All WWOX variants in these five patients are predicted to be null, consistent with the proposed mechanism of WOREE syndrome. The missense p.Gln230Pro variant located in the catalytic short chain dehydrogenase/reductase (SDR) domain of WWOX was reported in patients with epileptic encephalopathy (Johannsen et al, 2018;Weisz-Hubshman et al, 2019).…”

Section: Discussionsupporting

confidence: 75%

“…These findings are in stark contrast with the data from a cohort reported by Piard et al in which only 6% of the subjects manifested growth retardation and 20% of the subjects presented microcephaly (≤ −3 SD; Piard et al, 2019). On the other hand, Havali et al reported in their cohort the head circumferences of all six patients were < 3SD (Havali et al, 2021).…”

Section: Discussionmentioning

confidence: 90%

“…Even though facial dysmorphism was reported in 12 of 20 (60%) individuals by Havali et al (2021) and Piard et al (2019), it had been suggested that patients with WOREE syndrome manifest characteristic dysmorphic features including round, coarse face with full cheeks and thick eyebrows. In contrast, none of our patients showed distinctive facial features.…”

Section: Discussionmentioning

confidence: 98%

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Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Chong

Cao

Fung

et al. 2022

American J of Med Genetics Pt A

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WWOX biallelic loss‐of‐function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX‐related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 98%

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Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Chong

Cao

Fung

et al. 2022

American J of Med Genetics Pt A

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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: 70%

“…As discussed further below, we have shown that mortality risk correlates with WWOX genotype, whereby the presence of at least one missense variant increases 5-year survival probability from <50% to >75%. Respiratory complications are the most frequently reported cause of death, 11,12,15,23 although one of our patients died of possible SUDEP. Alternate causes of death in the literature included status epilepticus 7 and obstructive cardiomyopathy.…”

Section: Discussionmentioning

confidence: 66%

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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Neuroimaging features of WOREE syndrome: a mini-review of the literature

Battaglia,

Scorrano,

Spiaggia

et al. 2023

Front. Pediatr.

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The WWOX gene encodes a 414-amino-acid protein composed of two N-terminal WW domains and a C-terminal short-chain dehydrogenase/reductase (SDR) domain. WWOX protein is highly conserved among species and mainly expressed in the cerebellum, cerebral cortex, brain stem, thyroid, hypophysis, and reproductive organs. It plays a crucial role in the biology of the central nervous system, and it is involved in neuronal development, migration, and proliferation. Biallelic pathogenic variants in WWOX have been associated with an early infantile epileptic encephalopathy known as WOREE syndrome. Both missense and null variants have been described in affected patients, leading to a reduction in protein function and stability. The most severe WOREE phenotypes have been related to biallelic null/null variants, associated with the complete loss of function of the protein. All affected patients showed brain anomalies on magnetic resonance imaging (MRI), suggesting the pivotal role of WWOX protein in brain homeostasis and developmental processes. We provided a literature review, exploring both the clinical and radiological spectrum related to WWOX pathogenic variants, described to date. We focused on neuroradiological findings to better delineate the WOREE phenotype with diagnostic and prognostic implications.

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Recently defined epileptic encephalopathy related to WWOX gene mutation: six patients and new mutations

Cited by 3 publications

References 12 publications

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

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

Neuroimaging features of WOREE syndrome: a mini-review of the literature

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