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

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. 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. 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). 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.

Oliver KL ，Trivisano M ，Mandelstam SA ，De Dominicis A ，Francis DI ，Green TE ，Muir AM ，Chowdhary A ，Hertzberg C ，Goldhahn K ，Metreau J ，Prager C ，Pinner J ，Cardamone M ，Myers KA ，Leventer RJ ，Lesca G ，Bahlo M ，Hildebrand MS ，Mefford HC ，Kaindl AM ，Specchio N ，Scheffer IE ... -  《-》

[Genotype and phenotype of WWOX gene related developmental and epileptic encephalopathy].

Wang T ，Cheng MM ，Liu WW ，Tan QZ ，Liu CH ，Yang Y ，Yang XL ，Zhang YH ... -  《-》

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature.

Piard J ，Hawkes L ，Milh M ，Villard L ，Borgatti R ，Romaniello R ，Fradin M ，Capri Y ，Héron D ，Nougues MC ，Nava C ，Arsene OT ，Shears D ，Taylor J ，Pagnamenta A ，Taylor JC ，Sogawa Y ，Johnson D ，Firth H ，Vasudevan P ，Jones G ，Nguyen-Morel MA ，Busa T ，Roubertie A ，van den Born M ，Brischoux-Boucher E ，Koenig M ，Mignot C ，DDD Study ，Kini U ，Philippe C ... -  《-》

A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay.

Johannsen J ，Kortüm F ，Rosenberger G ，Bokelmann K ，Schirmer MA ，Denecke J ，Santer R ... -  《-》

Late infantile epileptic encephalopathy: A distinct developmental and epileptic encephalopathy syndrome.

Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Kacker S ，Phitsanuwong C ，Oetomo A ，Nordli DR Jr ... -  《-》