Genetics and Extracellular Vesicles of Pediatrics Sleep Disordered Breathing and Epilepsy

Abstract

Sleep remains one of the least understood phenomena in biology, and sleep disturbances are one of the most common behavioral problems in childhood. The etiology of sleep disorders is complex and involves both genetic and environmental factors. Epilepsy is the most popular childhood neurological condition and is characterized by an enduring predisposition to generate epileptic seizures, and the neurobiological, cognitive, psychological, and social consequences of this condition. Sleep and epilepsy are interrelated, and the importance of sleep in epilepsy is less known. The state of sleep also influences whether a seizure will occur at a given time, and this differs considerably for various epilepsy syndromes. The development of epilepsy has been associated with single or multiple gene variants. The genetics of epilepsy is complex and disorders exhibit significant genetic heterogeneity and variability in the expressivity of seizures. Phenobarbital (PhB) is the most widely used antiepileptic drug. With its principal mechanism of action to prolong the opening time of the γ-aminobutyric acid (GABA)-A receptor-associated chloride channel, it enhances chloride anion influx into neurons, with subsequent hyperpolarization, thereby reducing excitability. Enzymes that metabolize pharmaceuticals including PhB are well known for having genetic polymorphisms that contribute to adverse drug-drug interactions. PhB metabolism is highly dependent upon the cytochrome P450 (CYP450) and genetic polymorphisms can lead to variability in active drug levels. The highly polymorphic CYP2C19 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and variants contribute significantly to adverse drug reactions and therapeutic failures. A limited number of CYP2C19 single nucleotide polymorphisms (SNPs) are involved in drug metabolism. Extracellular vesicles (EVs) are circular membrane fragments released from the endosomal compartment as exosomes are shed from the surfaces of the membranes of most cell types. Increasing evidence indicated that EVs play a pivotal role in cell-to-cell communication. Theses EVs may play an important role between sleep, epilepsy, and treatments. The discovery of exosomes provides potential strategies for the diagnosis and treatment of many diseases including neurocognitive deficit. The aim of this study is to better understand and provide further knowledge about the metabolism and interactions between phenobarbital and CYP2C19 polymorphisms in children with epilepsy, interplay between sleep, and EVs. Understanding this interplay between epilepsy and sleep is helpful in the optimal treatment of all patients with epileptic seizures. The use of genetics and extracellular vesicles as precision medicine for the diagnosis and treatment of children with sleep disorder will improve the prognosis and the quality of life in patients with epilepsy.

Keywords: CYP2C19; CYP45; GABA; GABARA; GABARB; GABARC; drug metabolism; epilepsy; exosomes; extracellular vesicles; metabolic function; pediatric; phenobarbital; sleep; sleep disorders.

Figure 1

Diagram illustrates the effects of sleep disorders and epilepsy treatment on γ-aminobutyric acid (GABA) receptors (A, B & C), CYP2C19 gene and drug metabolism.

Figure 2

Potential networks of GABA receptors and association with ion channels. Panel (A) is the GABA receptor A 1 (GABAR1) and gene networks of chloride transport genes. Panel (B) is GABA receptor B (GABRB1) and networks of potassium transport. Panel (C) is GABA receptor C (GABA-A) and networks of chloride transport.

Figure 3

Promoter regions of CYP2C19 transcripts in the human genome. As shown, there are three transcripts for CYP2C19 including CYP2C19-201 (ENST00000371321.3) composed of 1901 nucleotides and protein coding 490 amino acids (aa), CYP2C19-002 (ENST00000464755.1), composed of 2395 nucleotides and no protein coding, and CYP2C19-003 (ENST00000480405.1) composed of 1417 and no protein coding.

Figure 4

Gene network for the CYP2C19 gene and selected interacting protein using STRING software utilizing version 10.5. STRING is a biological database and web resource of known and predicted protein–protein interactions, and imports data from experimentally derived protein–protein interactions through literature curation. Furthermore, STRING also stores computationally predicted interactions using text mining of scientific texts, interactions computed from genomic features, and interactions transferred from model organisms based on orthology. All predicted or imported interactions are benchmarked against a common reference of functional partnership as annotated by KEGG (Kyoto Encyclopedia of Genes and Genomes).

Figure 5

Single nucleotide polymorphisms (SNPs) of the CYP2C19 gene was identified using the University of California, Santa Cruz (UCSC) genome Browser on Human (GRCh37/hg19) assembly from position 94,765,00 to 94,785,00 on chromosome 10.

Figure 6

Five single nucleotide polymorphisms (SNPs) of the CYP2C19 gene that are involved in drug metabolism. We identified two upstream and two downstream for each of those SNPs and their location in the gene sequence.

Figure 7

Diagram showing there is an urgent need for multiple disciplines to research children with sleep disorders and epilepsy to better understand the pathophysiology of the disease. This includes studying single nucleotide polymorphisms (SNPs), copy number variations (CNVs), transcriptomic mRNA, or the mRNA sequence, proteomics, circulating miRNA, microbiomes, and epigenetics. In addition, extracellular vesicles cargos which also contains DNAs, RNAs, miRNA and proteins.