Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

Population-based study of rare epilepsy incidence in a US urban population.

OBJECTIVE: This study was undertaken to estimate incidence of rare epilepsies and compare with literature. METHODS: We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010-2014). We estimated cumulative incidence and compared with literature. RESULTS: Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox-Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic-atonic seizures (1 in 34 100), Sturge-Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike-and-wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan-McDermid syndrome, myoclonic epilepsy with ragged-red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. SIGNIFICANCE: We estimated the incidence of rare epilepsies using population-based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted.

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

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.

EEG and clinical characteristics of neonatal parechovirus encephalitis.

RATIONALE: Human parechoviruses (HPeVs) are single -stranded ribonucleic (RNA) viruses belonging to the picornaviridae family with characteristics similar to enteroviruses. They either cause mild respiratory and gastrointestinal or no symptoms in older children and adults but can be a major cause of central nervous system (CNS) infection in the neonatal period and demonstrate a seasonal predilection. Starting in March 2022, we saw eight patients with polymerase chain reaction (PCR) proven HPeV encephalitis with seizures and some electroencephalographic (EEG) features raising concerns for neonatal genetic epilepsy. Although cerebrospinal fluid (CSF) and imaging findings have been previously described, there is little emphasis on seizure presentation and EEG findings of HPeV in the literature. We wish to highlight the EEG and seizure semiology of HPeV encephalitis that may mimic a genetic neonatal epilepsy syndrome. METHODS: Retrospective chart review of all neonates seen at Children's Health Dallas, UTSW Medical Center between 03/18/2022-06/01/2022 with HPeV encephalitis. RESULTS: Term neonates (postmenstrual age 37-40 weeks) presented with a variable combination of fever, lethargy, irritability, poor oral intake, erythematous rash, and focal seizures. One patient with a single episode of limpness and pallor did not undergo EEG due to a low suspicion for seizures. CSF indices were normal in all patients. EEG was abnormal in all patients where performed (n = 7). EEG features included dysmaturity (7/7, 100 %); excessive discontinuity (6/7, 86 %); excessive asynchrony (6/7, 86 %); multifocal sharp transients (7/7, 100 %). Focal/multifocal seizures were captured in 6/7 (86 %); tonic in 3/7 (42 %) and described as migrating in 2 patients. Subclinical seizures were noted in 6/7 (86 %) with status epilepticus in 5/7 (71 %) patients. In 2/7 (28 %) the EEG showed a burst suppression pattern with poor state variation and voltages of < 5-10 uV/mm during the inter-burst intervals. Repeat EEG (3-11 days post initial EEG) showed improvement in 3 of 4 patients. No patient had ongoing seizures beyond day two of admission (22.5 h after EEG initiation). MRI showed extensive restricted diffusion in the supratentorial white matter, thalami, and less frequently the cortex, mimicking imaging findings of a metabolic or hypoxic-ischemic encephalopathy (7/8). Seizures responded within 36 h of presentation to treatment with acute bolus doses of medications. One patient died due to diffuse cerebral edema and status epilepticus. Six patients had a normal clinical exam at discharge. All patients started on maintenance antiseizure medication (ASM) were sent home on either a single medication or two medications (phenobarbital and levetiracetam) with plans to wean phenobarbital after discharge. CONCLUSIONS: HPeV is a rare cause of seizures and encephalopathy in neonates. Prior studies have emphasized specific patterns of white matter injury on imaging. We demonstrate that HPeV also commonly presents with clonic or tonic seizures with or without apnea and often subclinical multifocal and migrating focal seizures that could mimic a genetic neonatal epilepsy syndrome. Interictal EEG shows a dysmature background with excessive asynchrony, discontinuity, burst-suppression pattern, and multifocal sharp transients. However, we note that 100 % of patients responded quickly to standard ASM, and did not have seizures after hospital discharge- a factor that can help distinguish it from a genetic epilepsy syndrome.

Neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis: A case report with a novel missense variant of SCN1A.

Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype-genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.