Molecular bases and clinical spectrum of early infantile epileptic encephalopathies

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Abstract

Epilepsy can be a challenging diagnosis to make in the neonatal and infantile periods. Seizures in this age group may be due to a serious underlying cause that results in an epileptic encephalopathy. Early infantile epileptic encephalopathy (EIEE) is a progressive neurologic condition that exhibits concomitant cognitive and motor impairment, and is often associated with severe intellectual disability. This condition belongs to the group of age-dependent epileptic encephalopathies, and thus the clinical and electro-encephalographic features change with age as the central nervous system evolves. The molecular bases and the clinical spectrum associated with the early infantile epileptic encephalopathies continue to expand as new genetic discoveries are made. This review will highlight the molecular etiologies of early infantile epileptic encephalopathy, and the clinical and electro-encephalographic changes that take place in these epileptic phenotypes as the brain develops.

Highlights

► EIEE are usually refractory to multiple medications and often result in intractable seizures. ► These intractable seizures often result in devastated neurodevelopmental outcomes. ► EIEE are genetically heterogeneous with a broad molecular spectrum.

Section snippets

Overview

Epilepsy, and in particular intractable epilepsy in infancy, often results in an encephalopathic picture, known under these circumstances as an epileptic encephalopathy [8]. The infantile epileptic encephalopathies are a group of disorders described as “age-dependent epileptic encephalopathies”[1], [2]. These syndromes start with intractable epilepsy within the first few weeks to months of life (infantile), are marked by recurrent unprovoked seizures (epilepsy), and result in devastating global

Epilepsy

Epilepsy is defined as the tendency to have recurrent (two or more) unprovoked seizures without immediate cause [4]. This definition is used to differentiate the condition of epilepsy from either one single seizure or several provoked seizures. Provoked seizures may be caused by febrile seizures, tumor, trauma, or due to acute correctable metabolic disturbances. Febrile seizures are the most common type of reactive seizure, occurring between 5 and 6 months and 5–6 years. Febrile seizures follow

Neonatal seizures

Diagnosing neonatal seizures can be challenging due to a phenomenon known as electro-clinical dissociation [5]. In an adult or even child's brain, an electrical seizure impulse can start anywhere in the brain and, with the aid of well-myelinated pathways, be rapidly transmitted to the motor cortex, resulting in a clinically observable seizure. In contrast, the neonatal brain is not yet fully myelinated, and cannot efficiently propagate this electrical impulse away from its origin to the motor

Epileptic encephalopathies

While the effects of a single brief seizure on the brain may be controversial, prolonged or intractable seizures are more assuredly felt to have a detrimental effect on cognition and brain function [95]. The brain, further, may be affected via a shared mechanism by the underlying cause of the seizures [8], whether genetic, metabolic, post-infectious, brain structural, etc. The developing brain is particularly susceptible to the potentially severe effects of epilepsy. Epilepsy, especially

Infantile spasms

As can be expected given the “age-dependent” nature of infantile epileptic encephalopathies, many (though not all) patients who survive their early infantile epileptic encephalopathy evolve their seizure semiology and EEG pattern into infantile spasms (IS) [88]. Seventy-five percent of patients with Ohtahara syndrome (early infantile encephalopathy with burst-suppression pattern) progress to IS [16]. IS typically starts around 3–6 months of age and is characterized by clusters of flexors

Lennox–Gastaut

Whether or not medical therapy is effective, these age-dependent epileptic encephalopathies change as the child grows. IS may either be outgrown, or, if spasms persist, are called epileptic spasms. However, as 40–60% of patients with IS outgrow their spasms, they grow into Lennox–Gastaut syndrome (LGS) [1]. It should be noted that the risk of growing into LGS may be linked to the epilepsy of origin – that is, Ohtahara syndrome is felt to be more likely to evolve though IS all the way to LGS,

Examples of early infantile epileptic encephalopathies

As discussed above, early infantile epileptic encephalopathies exhibit intractable seizures which typically start in the first few weeks of life. The basic EEG pattern is that of burst-suppression. There are two main types of epileptic encephalopathy recognized by the ILAE – these are early infantile epileptic encephalopathy (EIEE) and early myoclonic encephalopathy (EME) [9]. They have similar EEG patterns (and thus have been argued to be variants of the same condition) but differ in their

EIEE1

Although EIEE has been found to be connected with central nervous systems malformations, single gene defects have been associated with EIEE. Aristaless-related homeobox gene (ARX) maps to Xp22. The ARX protein is a transcription factor expressed in the forebrain that plays an important role in the proliferation and differentiation of cerebral interneurons [14]. Seizures may start in the neonatal period [5]. Typically males can be affected although female carriers can be affected as well. The

EIEE2

EIEE2 is caused by mutations in CDKL5 which maps to Xp22.13. The gene encodes a phosphorylated protein with kinase activity that is a member of the Ser/Thr protein kinase family. The protein has a conserved serine-threonine kinase domain in the N-terminus and a C-terminus that regulates its catalytic activity and nuclear placement [17]. No correlation between sites of the mutations and clinical severity has been demonstrated [18]. This condition affects mostly girls and presents as an atypical

EIEE3

EIEE3 is caused by mutations in the SLC25A22 gene that maps to chromosome 11p15.5. This gene encodes a mitochondrial carrier (solute carrier family 25, mitochondrial carrier, glutamate, member 22) also known as GC1 (glutamate carrier 1), which is one of the two mitochondrial glutamate/H+ symporters. This protein catalyzes the cotransport of l-glutamate with hydrogen protons [26]. The expression of SLC25A22 has been demonstrated in areas of the central nervous system thought to contribute to the

EIEE4

EIEE4 is due to mutations and deletions in the STXBP1 gene on chromosome 9q34.1, and initially was reported to follow the typical epileptic encephalopathy progression [29]. STXBP1 encodes syntaxin binding protein 1 (STXBP1), which is an evolutionarily conserved protein expressed in neurons that acts as a regulator of the synaptic vesicular machinery and mediates a critical role in calcium-dependent neurotransmitter release from synaptic vesicles in neurons [30], [31], [32]. STXBP1 is involved

EIEE5

EIEE5 results from molecular alterations in the SPTAN1 gene. SPTAN1 encodes a nonerythocytic alpha spectrin protein that belongs to a family of widely distributed filamentous cytoskeletal proteins and that plays an important role modulating the stability of axonal structures [44]. In addition, this protein plays an essential role in the adequate myelination of the spinal cord and the motor nerves [45]. SPTAN1 mutations may be causative of infantile spasms, severe central hypomyelination, and

EIEE6

EIEE6, also known as Dravet syndrome or severe myoclonic epilepsy of infancy, is caused by mutations in the SCN1A gene [47]. This gene encodes the sodium channel neuronal type 1α subunit. This subunit, in addition to two smaller, auxiliary β-subunits, associate to form the voltage-gated sodium channel. The sodium channel neuronal type 1α subunit maps to 2q24.3 [48]. Several mutations in this gene have been found and they can either lead to a gain of function with heightened susceptibility to

EIEE7

EIEE7 is an autosomal dominant severe epileptic encephalopathy caused by mutations in the KCNQ2 gene. KCNQ2 encodes a voltage-gated K+-channel subunit that is characterized by six transmembrane regions, a pore region and a long cytoplasmic tail. A missense mutation affecting an amino acid residue in the fifth transmembrane domain of the KCNQ protein was detected in a proband who presented with EIEE. Seizures presented on day three of life and were refractory to treatment [22]. Serial EEGs

EIEE8

EIEE8 results from mutations in the cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9) [54]. ARHGEF9 encodes collybistin, a brain specific guanine nucleotide exchange factor for the Rho GTPase cell division cycle 42 [55]. This molecule is involved in the gephyrin-dependent clustering of postsynaptic glycine and γ-aminobutyric acid receptors at inhibitory postsynaptic sites [56], [57]. The first reported patient carrying an ARHGEF9 mutation was a male with severe

EIEE9

EIEE9 has been associated with mutations in the PCDH19 gene [62]. This gene maps to Xq22 and encodes protocadherin 19, a transmembrane protein that belongs to the protocadherin δ2 subclass of the cadherin superfamily that is highly expressed in neural tissues [60]. Although the precise function of this protein remains unknown, delta-protocadherins are thought to regulate calcium-dependent cell–cell adhesion and intervene in the modulation of neuronal connections during brain development [61].

EIEE10

Mutations in the PNKP gene are responsible for a phenotype that consists of microcephaly, early-onset intractable epilepsy, developmental delay and behavioral abnormalities (MCSZ). This autosomal recessive disorder has been mainly observed in individuals of Middle Eastern and European origin [68]. Patients did not exhibit developmental regression. Brain imaging studies revealed microcephaly but no structural abnormalities. In consanguineous families, the disease locus was mapped to 19q13.33.

EIEE11

Mutations in the SCN2A gene are responsible for EIEE11. Voltage-gated sodium channels are formed by α and β subunits. There at least four genes encoding four α subunits (SCN1A, SCN2A, SCN3A, and SCN8A) that are responsible for regulating sodium currents in the central nervous system and mutations in SCN2A are known to be associated with epilepsy [72]. Mutations in SCN2A are associated with a variety of epileptic phenotypes [73]. Three novel missense mutations in SCN2A affecting highly conserved

EIEE12

EIEE12 has been associated with the disruption of the PLCβ1 gene that maps to 20p12.3 and codes for an enzyme involved in a signaling pathway through the production of inositol 1,4,5 triphosphate [77]. The index case, born to consanguineous parents, presented with tonic seizures that eventually progressed to West syndrome. The epileptic phenotype evolved to refractory epilepsy associated with a regressive encephalopathy and failure to thrive. He was found to have a homozygous loss of function

SRGAP2 disruption

In addition to these twelve loci, EIEE has been recently associated with the disruption of the SRGAP2 gene encoding Slit-Robo Rho GTPase activating protein 2 [79]. The Slit-Robo signaling pathway regulates axonal guidance and neuronal migration [80]. The SRGAP proteins are involved in neuronal development since they induce neurite outgrowth and branching [81]. The patient presented with EIEE and profound developmental delay and harbored a de novo reciprocal translocation t(1; 9)(q32; q13) that

MEF2C disruption

Submicroscopic deletions of the 5q14.3 region have been described in patients with severe intellectual disability, stereotypic movements, epilepsy and cerebral malformations. Further studies pointed to the MEF2C haploinsufficiency as responsible for the phenotype. This gene plays a key role in early neurogenesis, neuronal migration and differentiation [92]. A female with a potential disruption of MEF2C and presenting with EIEE has been recently reported [93].

This patient exhibited EIEE, severe

Summary

A neonate who develops unprovoked seizures in the first few days to weeks of life will most likely have an EEG pattern that is consistent with EIEE, irrespective of the cause. The seizures are typically refractory to treatment, even with multiple anti-epileptic medications (phenobarbital, topiramate, zonisamide, levetiracetam, vigabatrin, as well as the ketogenic diet, pyridoxine, ACTH). These children for the most part will tend to have poor neurological outcomes. Although there are no current

Acknowledgments

Special thanks to Michele Blecher, NP, for editing assistance.

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