Developmental Epileptic Encephalopathy Research Articles

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features

A biallelic nonsense variant of the potassium channel tetramerization domain-containing protein 3 gene (KCTD3) [c.1192C>T; p.R398*] was identified in a patient with developmental epileptic encephalopathy with distinctive features and brain structural abnormalities. The patient showed isodisomy of chromosome 1, where KCTD3 is located, and the father was heterozygous for the same variant. Based on these findings, paternal uniparental disomy was considered to cause the biallelic involvement of KCTD3.

Genetic epilepsy-digging in for gold: a case series on diagnostic genetic testing in epilepsy

Developmental epileptic encephalopathy (DEE) is a group of ictal and interictal epileptiform disorders (clinical and encephalographic) associated with severe cognitive and behavioural impairments according to the classification and terminology criteria of the international league against epilepsy (ILAE). Less than half of the genetic etiologies have been identified, even though DEEs are genetically heterogenous. Hence, genetic diagnoses of childhood neurological disorders are important as well as challenging. This research aims at determining the diagnostic utility of genetic testing (whole exome sequencing) in heterogeneous group of childhood DEEs. Here, we present the case series of 5 children who have had at least 1 episode of seizure during their lifetime associated with developmental delay and a definite genetic etiology. In view of an unrecognised aetiology, parents were counselled for a genetic evaluation. Genetic test reports showed pathogenic gene variation for epilepsy. Even though intervention would be mostly be the same, genetic aetiology helped us in prognosticating and improving the family’s outlook towards the disease condition. Hence it is desirable to identify genetic variations in all possible childhood epilepsy cases as it has the potential to improve family planning, aid the prognosis, and start specific interventions and also helps to save time in selecting appropriate anti-epileptic drugs.

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling. To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022. Phenotypic features associated with diagnostic genetic results. Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported. A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses. These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

Myoclonic Status Epilepticus in TBC1D24-Related Developmental/Epileptic Encephalopathy (DEE).

Myoclonic Status Epilepticus in TBC1D24-Related Developmental/Epileptic Encephalopathy (DEE).

A Rare Cause of Developmental Epileptic Encephalopathy: D-Bifunctional Protein Deficiency with a Novel Pathogenic Variant

Abstract Peroxisomal disorders are rare causes of severe neonatal encephalopathies. Here we report a two-month old infant with refractory neonatal seizures evaluated with first-step metabolic screening in the neonatal intensive care unit. The screening did not indicate the inborn error of metabolism. In a series of electroencephalography (EEG) studies, multifocal epileptic discharges and electroclinic seizures were observed, suggesting epileptic encephalopathy. The analysis of plasma very-long-chain fatty acids indicated a peroxisomal disorder. Then a next-generation DNA sequencing panel of epileptic encephalopathy provided a D-Bifunctional Protein Deficiency (D-BP) with a novel mutant gene. The epilepsy panels with next-generation DNA sequencing, after the primarily metabolic screening for the differential diagnosis of early infantile epileptic encephalopathy, provide guidance for a definitive diagnosis. Next-generation genetic studies are essential in identifying subtypes of peroxisomal disorders because they have similar very-long-chain fatty acid levels and dysmorphic findings.

The genetic landscape of developmental and epileptic encephalopathy with spike-and-wave activation in sleep

ObjectiveEpileptic Encephalopathy / Developmental Epileptic Encephalopathy with spike-and-wave activation in sleep (EE/DEE-SWAS) is defined as an epilepsy syndrome characterized by neurodevelopmental regression temporally related to the emergence of significant activation of spike-wave discharges in EEG during sleep. The availability of genetic testing has made it evident that monogenic and chromosomal abnormalities play an aetiological role in the development of EE/DEE-SWAS. We sought to review the literature to better understand the genetic landscape of EE/DEE-SWAS. MethodsIn this systematic review, we reviewed cases of EE/DEE-SWAS associated with a genetic aetiology, collecting information related to the underlying aetiology, onset, management, and EEG patterns. ResultsOne hundred and seventy-two cases of EE/DEE-SWAS were identified. Genetic causes of note included pathogenic variants in GRIN2A, ZEB2, CNKSR2 and chromosome 17q21.31 deletions, each of which demonstrated unique clinical characteristics, EEG patterns, and age of onset. Factors identified to raise suspicion of a potential genetic aetiology included the presentation of DEE-SWAS and onset of SWAS under the age of five years. Treatment of EE/DEE-SWAS due to genetic causes was diverse, including a combination of anti-seizure medications, steroids, and other clinical strategies, with no clear consensus on a preferred or superior treatment. Data collected was significantly heterogeneous, with a lack of consistent use of neuropsychology testing, EEG patterns, or use of established clinical definitions. ConclusionsUniformity concerning the new definition of EE/DEE-SWAS, guidelines for management and more frequent genetic screening will be needed to guide best practices for the treatment of patients with EE/DEE-SWAS.

Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes.

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Generation of a human iPSC line (ZJSHDPi001-A) from peripheral blood mononuclear cells of a patient with Developmental epileptic encephalopathy-47 carrying FGF12 gene mutation (c.334G > A)

Developmental epileptic encephalopathy-47 (DEE47) is a nervous system disease characterized by the onset of intractable seizures that appear the first days or weeks after birth. FGF12 is the disease-causing gene of DEE47 that encodes a small cytoplasm protein, which is a member of the fibroblast growth factor homologous factor (FGF) family. The FGF12-encoded protein interacts with the cytoplasmic tail of voltage-gated sodium channels to enhance the voltage dependence of rapid inactivation of sodium channels in neurons. This study used non-insertion Sendai virus transfection to establish the induced pluripotent stem cells(iPSCs)line with FGF12 mutation. The cell line was obtained from a 3-year-old boy carrying the c.334G > A heterozygous mutation in the FGF12 gene. This iPSC line could facilitate the investigations of pathogeneses of complex nervous system diseases such as developmental epileptic encephalopathy.

Arginase deficiency-An unheralded cause of developmental epileptic encephalopathy.

Arginase deficiency, which leads to hyperargininaemia is a rare urea cycle disorder caused by a mutation in the ARG1 gene. It is an under-recognized cause of pediatric developmental epileptic encephalopathy, with the key coexistent clinical features being developmental delay or regression and spasticity. Detection of ARG1 gene mutation on genetic testing is the confirmatory diagnostic test. However, elevated levels of plasma arginine and low plasma arginase level can be considered as biochemical markers for diagnosis. We present two cases of arginase deficiency with genetically confirmed ARG1 mutation in one and biochemical confirmation in both. As the spectrum of epilepsy in arginase deficiency has been less explored, we attempted to elucidate the novel electroclinical features and syndromic presentations in these patients. Informed consent was obtained from families of patients. Electroclinical diagnosis was consistent with Lennox Gastaut syndrome (LGS) in the first patient while the second patient had refractory atonic seizures with electrophysiological features consistent with developmental and epileptic encephalopathy. Though primary hyperammonaemia is not a consistent feature, secondary hyperammonaemia in the setting of infectious triggers and drugs like valproate (valproate sensitivity) has been well described as also observed in our patient. In the absence of an overt antecedent in a child with spasticity and seizure disorder, with a progressive course consistent with a developmental epileptic encephalopathy, arginase deficiency merits consideration. Diagnosis often has important therapeutic implications with respect to dietary management and choice of the appropriate antiseizure medications.

KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties.

Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.

Clinical Factors Related to Outcomes in Pediatric Epilepsy Surgery: Insight into Predictors of Poor Surgical Outcome.

Successful surgery for drug-resistant pediatric epilepsy can facilitate motor and cognitive development and improve quality of life by resolution or reduction of epileptic seizures. Therefore, surgery should be considered early in the disease course. However, in some cases, the estimated surgical outcomes are not achieved, and additional surgical treatments are considered. In this study, we investigated the clinical factors related with such unsatisfactory outcomes.We reviewed the clinical data of 92 patients who underwent 112 surgical procedures (69 resection and 53 palliation procedures). Surgical outcomes were assessed according to the postoperative disease status, which was classified as good, controlled, and poor. The following clinical factors were analyzed in relation to surgical outcome: sex, age at onset, etiology (malformation of cortical development, tumor, temporal lobe epilepsy, scar, inflammation, and non-lesional epilepsy), presence of genetic cause, and history of developmental epileptic encephalopathy. At a median of 59 (30-81.25) months after the initial surgery, the disease status was good in 38 (41%), controlled in 39 (42%), and poor in 15 (16%) patients. Among the evaluated factors, etiology exhibited the strongest correlation with surgical outcomes. Tumor-induced and temporal lobe epilepsy were correlated with good, whereas malformation of cortical development, early seizure onset, and presence of genetic cause were correlated with poor disease status. Although epilepsy surgery for the patients who present with the latter factors is challenging, these patients demonstrate a greater need for surgical treatment. Hence, development of more effective surgical options is warranted, including palliative procedures.

Clinical features of 6 children with uridine-responsive developmental epileptic encephalopathy 50 caused by CAD gene variants

Objective: To analyze the clinical features of children with uridine responsive developmental epileptic encephalopathy 50 (DEE50) caused by CAD gene variants. Methods: A retrospective study was conducted on 6 patients diagnosed with uridine-responsive DEE50 caused by CAD gene variants at Beijing Children's Hospital and Peking University First Hospital from 2018 to 2022. The epileptic seizures, anemia, peripheral blood smear, cranial magnetic resonance imaging (MRI), visual evoked potential (VEP), genotype features and the therapeutic effect of uridine were descriptively analyzed. Results: A total of 6 patients, including 3 boys and 3 girls, aged 3.5(3.2,5.8) years, were enrolled in this study. All patients presented with refractory epilepsy, anemia with anisopoikilocytosis and global developmental delay with regression. The age of epilepsy onset was 8.5 (7.5, 11.0) months, and focal seizures were the most common seizure type (6 cases). Anemia ranged from mild to severe. Four patients had peripheral blood smears prior to uridine administration, showing erythrocytes of variable size and abnormal morphology, and normalized at 6 (2, 8) months after uridine supplementation. Two patients suffered from strabismus, 3 patients had VEP examinations, indicating of suspicious optic nerve involvement, and normal fundus examinations. VEP was re-examined at 1 and 3 months after uridine supplementation, suggesting significant improvement or normalization. Cranial MRI were performed at 5 patients, demonstrating cerebral and cerebellar atrophy. They had cranial MRI re-examined after uridine treatment with a duration of 1.1 (1.0, 1.8) years, indicating significant improvement in brain atrophy. All patients received uridine orally at a dose of 100 mg/(kg·d), the age at initiation of uridine treatment was 1.0 (0.8, 2.5) years, and the duration of treatment was 2.4 (2.2, 3.0) years. Immediate cession of seizures was observed within days to a week after uridine supplementation. Four patients received uridine monotherapy and were seizure free for 7 months, 2.4 years, 2.4 years and 3.0 years respectively. One patient achieved seizure free for 3.0 years after uridine supplementation and had discontinued uridine for 1.5 years. Two patients were supplemented with uridine combined with 1 to 2 anti-seizure medications and had a reduced seizure frequency of 1 to 3 times per year, and they had achieved seizure free for 8 months and 1.4 years respectively. Conclusions: The clinical manifestations of DEE50 caused by CAD gene variants present a triad of refractory epilepsy, anemia with anisopoikilocytosis, and psychomotor retardation with regression, accompanied by suspected optic nerve involvement, all of which respond to uridine treatment. Prompt diagnosis and immediate uridine supplementation could lead to significant clinical improvement.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Trends in COA Use and Regulatory Acceptance for Epileptic Encephalopathy and Developmental Epileptic Encephalopathy Indications (P13-1.006)

<h3>Objective:</h3> To investigate the landscape of clinical outcome assessments (COAs) used in epileptic encephalopathies (EEs) and developmental epileptic encephalopathies (DEEs). <h3>Background:</h3> EEs and DEEs are rare conditions characterized by difficult-to-treat seizures and intellectual or developmental disability. The heterogeneity of these conditions creates unique challenges for outcome measurement, particularly in clinical trials. To assess trends in the COA landscape, a targeted literature review was conducted to identify COAs used in EE and DEE clinical trials. <h3>Design/Methods:</h3> A search was conducted in ClinicalTrials.gov to identify interventional studies in EEs and DEEs. Findings were supplemented by searches in PubMed (titles/abstracts only), PROLABELS, and Food and Drug Administration (FDA) COA guidance materials, pairing EE/DEE and COA search terms when applicable. No limits on year of publication were applied. All results were reviewed, and relevant data were extracted and analyzed to identify trends in COA use. <h3>Results:</h3> The search identified 153 trials (ClinicalTrials.gov), 405 articles (PubMed), and 92 FDA drug labels (PROLABELS). Following screening, 105 trials, 26 article abstracts, and 19 labels met the criteria for data extraction. Excluding safety measures, 113 COAs were identified. Consistent with FDA guidance, seizure assessments and diaries were utilized most frequently, followed by clinician- or caregiver-rated global impression measures. Observer-reported outcomes and clinician-reported outcomes were more common than patient-reported outcomes. Approximately 25% of COAs were disease-specific. Additionally, common domains in COAs reviewed included cognition (n=22), motor functioning (n=14), multi-domains or quality of life (n=14), or communication (n=6). Several COAs utilized a global impression approach to assess within-patient change in domains, such as seizure severity or non-seizure concepts. <h3>Conclusions:</h3> Importantly, disease-specific measures, including global impression items intended to capture change in multiple domains, were identified. These findings may suggest that a disease-specific global impression approach is becoming increasingly common in these heterogeneous conditions to accompany seizure assessments and diaries. <b>Disclosure:</b> Ms. Graham has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of IQVIA. Dr. Batchelder has received personal compensation for serving as an employee of IQVIA. Dr. Gleeson has nothing to disclose. Ms. Buenfil has received personal compensation for serving as an employee of IQVIA. Ms. Kim has received personal compensation for serving as an employee of IQVIA. Dr. Meyers has received personal compensation for serving as an employee of IQVIA. Dr. Williams has received personal compensation for serving as an employee of IQVIA.

Epilepsy in Children

Childhood epilepsy is characterized by specific epilepsy syndromes that occur during each developmental age. These "age-dependent" epilepsy syndromes are clinically categorized into a self-limited epilepsy group with good prognosis and high prevalence rate and a pharmacoresistant epilepsy group with poor prognosis despite low prevalence rates. Many children develop pharmacoresistant epilepsy beginning in early infancy and progress to developmental epileptic encephalopathy, which is associated with intellectual, behavioral, and/or motor disabilities. These children do not show remission in epilepsy and are transitioned to the adult service and require comprehensive medical care.

Epilepsy in Dravet Syndrome—Current and Future Therapeutic Opportunities

Dravet Syndrome (DS) is a developmental epileptic encephalopathy characterized by drug-resistant seizures and other clinical features, including intellectual disability and behavioral, sleep, and gait problems. The pathogenesis is strongly connected to voltage-gated sodium channel dysfunction. The current consensus of seizure management in DS consists of a combination of conventional and recently approved drugs such as stiripentol, cannabidiol, and fenfluramine. Despite promising results in randomized clinical trials and extension studies, the prognosis of the developmental outcomes of patients with DS remains unfavorable. The article summarizes recent changes in the therapeutic approach to DS and discusses ongoing clinical research directions. Serotonergic agents under investigation show promising results and may replace less DS-specific medicines. The use of antisense nucleotides and gene therapy is focused not only on symptom relief but primarily addresses the underlying cause of the syndrome. Novel compounds, after expected safe and successful implementation in clinical practice, will open a new era for patients with DS. The main goal of causative treatment is to modify the natural course of the disease and provide the best neurodevelopmental outcome with minimum neurological deficit.

Acute effect of antiseizure drugs on background oscillations in Scn1a A1783V Dravet syndrome mouse model.

Dravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. Antiseizure medications (ASMs) for Dravet patients include valproic acid (VA) or clobazam (CLB), with or without stiripentol (STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. In addition to their effect on epileptic phenotypes, ASMs were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alterations in Dravet. Here, utilizing Dravet mice (DS, Scn1a A1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes. Compared to wild-type mice, background ECoG activity in DS mice had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, VA, CLB, or a combination of CLB + STP, caused, in most mice, a reduction in the frequency of interictal spikes, alongside an increase in the relative contribution of the beta frequency band. Conversely, CBZ and LTG increased the frequency of interictal spikes, with no effect on background spectral properties. Moreover, we uncovered a correlation between the reduction in interictal spike frequency, the drug-induced effect on the power of background activity, and a spectral shift toward higher frequency bands. Together, these data provide a comprehensive analysis of the effect of selected ASMs on the properties of background neuronal oscillations, and highlight a possible correlation between their effect on epilepsy and background activity.

Genotype-phenotype correlations of STXBP1 pathogenic variants and the treatment choices for STXBP1-related disorders in China

BackgroundWe aimed to analyze the genotype-phenotype correlations of STXBP1 pathogenic variants, prognostic factors and the treatment choices in a case-series of STXBP1-related disorders from China.MethodsThe clinical data and genetic results of the children diagnosed with STXBP1-related disorders at Xiangya hospital from 2011 to 2019 were collected retrospectively, and analyzed. We divided our patients into groups for comparison purposes: patients with missense variants and nonsense variants, patients who are seizure-free and not seizure-free, patients with mild to moderate intellectual disability (ID) and severe to profound global developmental delay (GDD).ResultsNineteen patients were enrolled: 17 (89.5%) unrelated and 2 (10.5%) familial. Twelve (63.2%) were females. Developmental epileptic encephalopathy (DEE) was observed in 18 (94.7%) patients and ID alone in 1 (5.3%) individual. Thirteen patients (68.4%) had profound ID/GDD, 4 (23.53%) severe, 1 (5.9%) moderate and 1 (5.9%) mild. Three patients (15.8%) with profound ID died. A total of 19 variants were detected: pathogenic (n = 15) and likely pathogenic (n = 4). Seven were novel variants: c.664-1G>-, M486R, H245N, H498Pfs*44, L41R, L410del, and D90H. Of the 8 previous reported variants, 2 were recurrent: R406C and R292C. Anti-seizure medications were used in combinations, and 7 patients became seizure-free, and most of them achieved seizure freedom within the first 2 years of life irrespective of the type of the mutation. Effective medications for the seizure-free individuals included adrenocorticotropic (ACTH) and/or levetiracetam and/or phenobarbital and/or sodium valproate and/or topiramate and/or vigabatrin and/or nitrazepam. There was no correlation between the types of pathogenic variants and the phenotypes.ConclusionOur case-series showed that there is no genotype-phenotype correlation in patients with STXBP1-related disorders. This study adds 7 novel variants which expand the spectrum of STXBP1-related disorders. Combinations of levetiracetam and/or sodium valproate and/or ACTH and/or phenobarbital and/or vigabatrin and/or topiramate and/or nitrazepam were more often associated with seizure freedom in our cohort within 2 years of life.

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

Genetic and clinical variations of developmental epileptic encephalopathies

ABSTRACT Objective The concept of ‘developmental and epileptic encephalopathy (DEE)’ recognises that in infants presenting with severe early-onset epilepsy, neurodevelopmental comorbidity may be attributable to both the underlying cause and to adverse effects of uncontrolled epileptic activity. There is no direct genotype – phenotype correlation in DEEs. This study aimed to report the genetic and phenotypic differences in patients with DEE. Methods Genetic evaluations of the patients were performed due to epilepsy combined with developmental delay, epileptic encephalopathy, motor deficits, autistic features, or cognitive impairment. Patients were assessed for demographic characteristics, medical history, family history, psychomotor development, seizure control interventions, electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings. Results This study included 20 children aged 0–16 years who were diagnosed as having DEE.The types of DEE detected in our study were DEE 2, 4, 6B, 7, 11, 26, 30, 33, 35, 42, 58, 62, and 67.Status epilepticus was recorded in only DEE7. The most common EEG abnormality was multifocal epileptic discharges (35%,) followed by burst-suppression patterns in patients with neonatal-onset seizures. Thirteen of the children were aged over 2 years, two (15%) were non-ambulatory and six (46%) were non-verbal. MRI scans were normal in 80% of the patients. Refractory epilepsy seen in 33% of cases.De-novo mutation, microcephaly and dysmorphic findings accompany resistant seizures and are associated with poor prognosis Discussion For patients with movement disorders, developmental delay, autism, and ID with or without epilepsy in any period of their life, next-generation sequencing is the only diagnostic technique available, with genetic analysis often being the only diagnostic method.