Neonatal Seizures: An Overview of Genetic Causes and Treatment Options

Abstract

Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called ‘Neonatal Epilepsies’. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and ‘Ohtahara syndrome’ (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.

Human cerebral organoids — a new tool for clinical neurology research

“…The second use of organoids to study disease is to investigate the mechanisms that underlie development of diseases with a known cause. For example, many monogenetic diseases have been identified, including early infantile epileptic encephalopathies 112 , 113 , neurocutaneous syndromes 114 , lysosomal storage disorders 115 and neurodegenerative disorders 116 , but the link between developmental processes and phenotypes often remains poorly understood. Organoids can be used to dissect the mechanisms of pathogenic mutations in human tissue (Fig.…”

Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families

“…In most cases, seizures increase in frequency and become refractory to standard anti-epileptic medications. Affected individuals have profoundly impaired psychomotor development with poor head control, limited or no ability to walk, spastic quadriplegia, and poor or absent speech ( Spoto et al, 2021 ). In this article, we report Saudi families with a heterozygous stop-gain and a novel missense variants in exon 5 of the STXBP1 gene.…”

KCNQ2-Related Neonatal Epilepsy Treated With Vitamin B6: A Report of Two Cases and Literature Review

“…This clinical entity often occurs within the first 2 weeks of life and is characterized by tonic/clonic early-onset seizures with apneic episodes and autonomic manifestations. Generally, it presents a self-limiting course for weeks/months with a regular neurodevelopmental outcome (2)(3)(4).…”

“…Amounting evidence arising from innovative genetic testing, and particularly next-generation sequencing (NGS) techniques, has revealed that different pathogenic variants of the same gene are responsible for several epileptic phenotypes; in particular, KCNQ2-related neonatal epileptic encephalopathy (NEE) contributed to expanding the spectrum of KCNQ2-related epilepsies (5). This is a severe phenotype, with an onset during the first days of life of intractable seizures (usually focal tonic), variably evolving into seizure freedom or a worsening/relapsing of the epileptic attacks over time, and an inevitable, though variable, adverse neurodevelopmental outcome (4)(5)(6). The electroencephalogram (EEG) may show a burst-suppression pattern or multifocal epileptiform abnormalities with background attenuation.…”

“…The electroencephalogram (EEG) may show a burst-suppression pattern or multifocal epileptiform abnormalities with background attenuation. This phenotype is mostly due to de novo missense variants of KCNQ2 causing a dominant-negative effect leading to a loss or a reduction of the M-current (a slow activating non-inactivating potassium current modulating the resting membrane potential) and less commonly to a gain of function effect, but not to a loss of function (haplo-insufficiency) (4,(7)(8)(9).…”