Review ArticleGenes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotype
Introduction
Early-onset epileptic encephalopathies are severe disorders in which cognitive, sensory, and motor development is impaired by recurrent clinical seizures or prominent interictal epileptiform discharges during the neonatal or the early infantile periods [1]. Several studies elucidated the pathogenic role of genetic mutations involved in the synaptogenesis, pruning, neuronal migration and differentiation, neurotransmitter synthesis and release, structures, and functions of membrane receptors and transporters [2], [3].
We review the genes more frequently associated with early-onset epileptic encephalopathies and their associated phenotypes (Table 1).
Section snippets
Aristaless-Related Homeobox Gene (ARX, Online Mendelian Inheritance in Man Number 300382)
The Aristaless-related homeobox gene maps to Xp22.13 and includes five coding exons. The Aristaless-related homeobox protein contains the paired/Q50 homeodomain, the Aristaless preserved domain, octapeptide and acidic domains, four polyalanine tracts, and three nuclear localization sequence motifs [4].
The Aristaless-related homeobox gene acts as both a transcriptional repressor and activator in an incompletely characterized biochemical cascade, and modulates cerebral development and patterning
Cyclin-Dependent Kinase-Like 5 (CDKL5, Online Mendelian Inheritance in Man Number 300203)
The cyclin-dependent kinase-like 5 gene maps to Xp22 and contains 20 coding exons. The related protein is a large, serine-threonine kinase of 1030 amino acids, including a preserved serine-threonine kinase domain in the N-terminal, and a C-terminal zone that regulates its catalytic activity and nuclear placement [25].
Cyclin-dependent kinase-like 5 is part of an incompletely characterized cascade. A recent study seems to rule out a previous hypothesis that cyclin-dependent kinase-like 5 protein
Solute Carrier Family 25, Member 22 (SLC25A22, Online Mendelian Inheritance in Man Number 609302)
The solute carrier family 25, member 22 gene maps to 11p15.5, contains nine encoding exons, and encodes for a mitochondrial glutamate/H+ symporter [39]. Molinari et al. [40] identified a missense mutation (p.Pro206Leu) in the SLC25A22 gene in four consanguineous Arab infants with early myoclonic epilepsy (early infantile epileptic encephalopathy 3, Online Mendelian Inheritance in Man number 609304). In the same study, the authors did not identify any mutation in the coding zone of the solute
Syntaxin Binding Protein 1 (STXBP1, Online Mendelian Inheritance in Man Number 602926)
The syntaxin binding protein 1 (STXBP1, or Munc18) gene maps to 9q341, and includes 20 exons. Syntaxin binding protein 1 modulates the release of synaptic vesicles through specific interactions with syntaxin A (Stx1a) and with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. An open conformation of syntaxin 1A that promotes the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex and subsequent vesicular release, and a
Nonerythrocytic α-Spectrin-1 (SPTAN1, Online Mendelian Inheritance in Man Number 182810)
The nonerythrocytic α-spectrin-1 gene maps to 9q33-q34, and encodes for a filamentous cytoskeletal protein that regulates the stability of axonal structure [48].
Saitsu et al. [48] recently described de novo heterozygous nonerythrocytic α-spectrin-1 gene mutations in three unrelated patients, previously reported by Tohyama et al. [49], with drug-resistant seizures, hypsarrhythmia, mental retardation, spastic quadriplegia, and progressive microcephaly (early infantile epileptic encephalopathy 5,
Phospholipase Cβ1 (PLCβ1, Online Mendelian Inheritance in Man Number 607120)
The phospholipase Cβ1 (PLCβ1) gene maps to 20p12.3, and encodes for an enzyme that is involved in cellular signaling through the production of inositol 1,4,5 triphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. Kurian et al. [50] described a homozygous loss-of-function 0.5-Mb deletion, including the promoter and exons 1, 2, and 3 of phospholipase Cβ1, in a single male infant who developed tonic seizures and then infantile spasms. The same authors excluded a linkage to the
Membrane-Associated Guanylate Kinase Inverted-2 Gene (MAGI2, Online Mendelian Inheritance in Man Number 606382)
Membrane-associated guanylate kinase inverted-2 maps to 7q11.23-q21.1, and encodes for a scaffolding enzyme interacting with different presynaptic and postsynaptic receptors (including the N-methyl-d-aspartic acid receptor) [51].
Marshall et al. described a hemizygous 1.4-Mb deletion encompassing membrane-associated guanylate kinase inverted-2 gene in 15 of 16 patients with infantile spasms, whereas the same mutation was absent in 11 of 12 controls without a history of seizures [51].
Polynucleotide Kinase 3′-Phosphatase (PNKP, Online Mendelian Inheritance in Man Number 605610)
The polynucleotide kinase 3′-phosphatase gene encodes for an enzyme that is involved in DNA repair networks and maps to 19q13.33. Through a genome-wide linkage analysis in seven consanguineous families, Shen et al. associated mutations in this gene with an autosomal recessive syndrome involving early-onset, drug-resistant seizures, microcephaly, developmental delay, and behavioral disorders [53].
Sodium Channel Neuronal Type 1α Subunit (SCN1A, Online Mendelian Inheritance in Man Number 182389)
Voltage-gated sodium channels present a large, multimeric α-subunit and two smaller, auxiliary β-subunits. The sodium channel neuronal type 1α subunit belongs to a family of nine genes encoding for α subunits. The sodium channel neuronal type 1α subunit maps to 2q24.3, and is expressed in nine isoforms (Nav1.1-Nav1.9) [54].
More than 600 sodium channel neuronal type 1α subunit mutations have been discovered [55]. In sodium voltage channels, they can promote both a gain of function, resulting in
Protocadherin 19 (PCDH19, Online Mendelian Inheritance in Man Number 300460)
The protocadherin 19 gene maps to Xq22, and encodes for a transmembrane protein that controls calcium-dependent cell-cell adhesion. Protocadherin 19 may be involved in specific synaptic connections and transmissions [66].
Dibbens et al. reported on protocadherin 19 mutations in seven families with “epilepsy and mental retardation limited to females” (Online Mendelian Inheritance in Man number 300088) [67]. Hines et al. described two protocadherin 19 mutations in three cases of female mental
Pyridoxamine 5-Prime-Phosphate Oxidase (PNPO, Online Mendelian Inheritance in Man Number 603287)
Pyridoxamine 5-prime-phosphate oxidase is an enzyme that produces pyridoxal 5-prime-phosphate in the pathway of activation of pyridoxine (an important cofactor in neurotransmitter synthesis). Its encoding gene maps to 17q21.32, and contains seven exons [72].
Mills et al. [72] defined homozygous missense, splice site, and stop codon pyridoxamine 5-prime-phosphate oxidase gene mutations in five preterm infants from three families with parental consanguinity, low Apgar scores, perinatal respiratory
The Role of Genetic Workups in the Diagnostic Approach to Early-Onset Epileptic Encephalopathies
The diagnostic workup of early-onset epileptic encephalopathies remains a challenge because of frequent difficulties in defining etiologies. Acquired structural abnormalities, such as hypoxic-ischemic insults and isolated cortical malformations, represent the most common causes of epileptic encephalopathy in infancy, and they should be excluded in the first diagnostic steps [73].
Specific tests for the abovementioned genes should always be performed:
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In newborns or infants with epileptic spasms,
Conclusions
Genetic knowledge about early epileptic encephalopathies has revolutionized the diagnostic approach to these disorders, and an increasing number of gene mutations have been related to their pathogenesis. In the future, a more detailed classification of epileptic encephalopathic genotypes will improve the accuracy of risk assessment and genetic counseling. Moreover, all these developments could yield unexpected therapeutic applications such as gene therapy or antiepileptic drugs “tailored” to
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2020, Epilepsy ResearchCitation Excerpt :Recent advances in genetics, especially the advent of next generation sequencing, have shown that a wide range of genetic variations can be associated with EOEE-BS.( Axeen and Olson, 2018; Martin et al., 2014; Mastrangelo, 2015; Mastrangelo and Leuzzi, 2012; Olson et al., 2017; Pavone et al., 2012; Wang et al., 2017) These genes encode ionic channels (SCN2A, SCN8A, KCNQ2, KCNT1)(AlSaif et al., 2019; Gardella et al., 2018; Kato et al., 2013; Kojima et al., 2018; Ohba et al., 2015; Saitsu et al., 2012a), proteins related to synaptic vesicle release (NECAP1, STXBP1, SPTAN1)(Mizuguchi et al., 2019; Nicita et al., 2015; Ortega-Moreno et al., 2016), proteins associated with intra/inter-cellular signal transduction (DOCK7, GNAO1, CASK, CDKL5)(Bai et al., 2019; Bernardo et al., 2019; Saitsu et al., 2016, 2012b; Talvik et al., 2015), membrane receptors of neurotransmitters (GRIN2A, GRIN2B, GABRA1)(Endele et al., 2010; Kodera et al., 2016; Smigiel et al., 2016; Yuan et al., 2014), and intracellular transporters (SLC25A22, SZT2)(Cohen et al., 2014; Pizzino et al., 2018). Actually, about 60 % of patients diagnosed with EOEE-BS without structural malformations were reported to be associated with pathogenic genetic abnormalities, indicating that genetic variants could be the major etiological factor related to EOEE-BS.(
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