According to the World Health Organization, more than 50 million people worldwide have epilepsy, and about 5 million new cases are reported annually. According to other data, the number of patients exceeds 70.000.000, highlighting the relevance of this condition. Studies of developmental epileptic encephalopathies leading to early disability are particularly relevant. About 900 gene mutations associated with different types of epilepsy have been identified so far. One of the prominent «channelopathy genes» representatives is KCNT1, coding the largest subunit of the sodium-activated potassium channel, KNa1.1. Its mutations are associated with many neurological disorders, such as leukodystrophy, leukoencephalopathy, West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, focal epilepsy, and multifocal epilepsy. A clinical case of a typical course of KCNT1-associated epilepsy with early onset (in the first half of life), focal and asynchronous paroxysms, psychomotor retardation, and drug resistance is presented. The effectiveness of the anticonvulsants used and the nature of pharmacological resistance were analyzed. The applicability of four «Drug Resistance Hypotheses» to this case is shown: genetic, since the pathogenesis of this particular case is based on a change in the properties of potassium channels; a change in the sensitivity of the anticonvulsant targets explains the intermittent (according to Schmidt and Löscher) nature of resistance. The «Neural Networks Hypothesis» is illustrated by the change of encephalographic indicators from multifocal epileptiform activity with an intact background to pronounced dysrhythmia with periods of the «burst-suppression» pattern after several months. All these features, combined, refer to the «Intrinsic Severity» hypothesis by Rogawski and Johnson, since the child's disease was initially severe due to the intensity and frequency of epileptic seizures. As a result, a conclusion was made about the complexity of the refractoriness formation mechanisms, even in cases with a simple and understandable pathogenesis of channelopathy. По данным Всемирной организации здравоохранения, эпилепсией страдают более 50 млн человек во всем мире и ежегодно около 5 млн человек узнают об этом диагнозе. По другим данным, число больных превышает 70 млн, что определяет и долго еще будет определять актуальность любого материала по этой тематике. Особенно актуальны исследования эпилептических энцефалопатий развития, приводящих к ранней инвалидизации. В настоящее время насчитывают около 900 генов, различные мутации которых объясняют появление различных типов эпилепсий. Одним из ярких представителей «генов каналопатий» является KCNT1, детерминирующий самую большую субъединицу активируемого натрием калиевого канала — KNa1.1. Мутации в нем ассоциированы с большим количеством неврологических расстройств, таких как лейкодистрофия, лейкоэнцефалопатия, синдром Веста, синдром Отахары, ранняя миоклоническая энцефалопатия, фокальная эпилепсия и мультифокальная эпилепсия. Приведен клинический случай типичного течения KCNT1-ассоциированной эпилепсии с ранним, в 1-м полугодии жизни, дебютом, фокальными и асинхронными пароксизмами, задержкой психомоторного развития и фармрезистентностью. Проведен анализ эффективности применявшихся противоэпилептических препаратов (ПЭП) и природы фармакологической резистентности. Показана применимость к данному случаю четырех гипотез фармакорезистентности: генетической; поскольку патогенез данного конкретного случая основан на изменении свойств калиевых каналов, изменением чувствительности «целей» воздействия ПЭП, т.е. «целевой» гипотезой объясняется интермиттирующий характер резистентности. Гипотезу «нейронных сетей» иллюстрирует динамика энцефалографических показателей от мультифокальной эпилептиформной активности при неизмененном фоне до выраженной дизритмии с периодами паттерна «burst-supression» по прошествии нескольких месяцев. Все упомянутые особенности, объединяясь, относятся к гипотезе «внутренней серьезности» Rogavski и Johnson, поскольку заболевание ребенка изначально отличалось тяжестью за счет интенсивности и частоты эпилептических приступов. В итоге делается вывод о сложности механизмов формирования рефрактерности даже в случаях с простым и понятным патогенезом каналопатии.

Developmental and epileptic encephalopathy (DEE) is epilepsy related to developmental impairment that may be caused by both the underlying etiology (developmental encephalopathy) and superimposed epileptic activity (epileptic encephalopathy). The origin of DEE and the causes of its variations remain unknown. Owing the lack of clarity regarding the role of genetic variables in DEE, we conducted a scoping review to qualitatively identify the genes most important in the development of DEE to provide an up-to-date review. We searched all published studies related to the genetic factors of DEE. The identified publications were screened and selected by the authors on basis of on inclusion and exclusion criteria and assessed for methodological quality. Eighteen articles were included. The extracted data included age of onset, sex, gene mutations and inheritance (e.g. nucleotide change, protein change, and family testing), clinical manifestation, electroencephalogram, imaging, medication, and outcomes. A total of 18 studies were included in this scoping review. The most frequently reported gene variants were STXBP1 in Ohtahara Syndrome, SLC1A2 in Early Myoclonic Encephalopathy (EME), CDKL5 in West Syndrome, SCN1A in Dravet Syndrome, and KCNT1 in Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Each gene was associated with distinct electroclinical features, including differences in age of onset, seizure type, EEG patterns, and developmental outcomes. While genotype and phenotype associations were heterogeneous, certain variants showed consistent patterns indicative of more severe disease courses. This review identified key gene variants commonly associated with early-onset DEE in infants, particularly STXBP1, SLC1A2, CDKL5, SCN1A, and KCNT1, each linked to unique clinical presentations and outcomes. These findings support the clinical utility of next-generation sequencing (NGS) for early diagnosis and tailored treatment planning in DEE. Understanding genotype-phenotype correlations may enhance prognostication and highlight potential avenues for targeted therapy in future research.

Drug-resistant epilepsy is seen in patients with inborn errors of metabolism and metabolic dysfunction in neurons is crucial to brain disorders associated with psychomotor impairment. Diagnostic rates of metabolic causes of developmental and epileptic encephalopathy (DEE) using next generation sequencing have been rarely studied in literature. A prospective hospital study was carried out in 384 children with DEE, who underwent genetic testing. Metabolic disorders were evaluated with biochemical blood/urine assays and when required CSF estimations performed. A total of 154 pathogenic/likely pathogenic variants in 384 children were identified. Out of 384 children, 89 were clinically suspected to have probable or possible metabolic disorders. Pathogenic/likely pathogenic variants in metabolic genes were identified in 39 out of 89 (43.8 %) and promising VUS in 28 (31.4 %). These included variants for progressive myoclonus epilepsies (21; 53.8 %), DEE with focal/multifocal seizures (8; 20.5 %), generalized epilepsy (5;12.8 %), early myoclonic encephalopathy (2; 5.1 %), LGS (1; 2.6 %) and West syndrome (2; 5.1 %). Our cohort demonstrates for the first time from the Indian subcontinent that identification of metabolic variants can guide investigations and has therapeutic implications in patients with variable DEE phenotypes. A high utility is noted with regard to diagnosis and prognostication, given the low yield of available biochemical tests, indicating cost-effectiveness of this approach.

Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.

To study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients. Two hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0-3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non-progressive disorders, infantile spasms, Doose syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments. Abnormal neurotransmitter values were identified in 68 (33%) patients. 5-Hydroxyindoleacetic acid (5-HIAA) deficit was the most prevalent alteration (91%). Low CSF 5-HIAA levels were significantly higher in 1- to 3-year-old children. A negative significant correlation was found between 5-HIAA levels and epilepsy duration before CSF study (Spearman's ρ=-0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5-HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills. A considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy. 5-Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.