Abstract

Voltage-gated calcium channels support an array of fundamental biological processes in various systems. In the brain, they determine neuronal responses to stimulation, dendritic properties, neuronal firing mode, and synaptic release. They also regulate multiple critical developmental processes, including neuronal proliferation, migration, connectivity, and structural activity-dependent plasticity. For these reasons, mutations in voltage-gated calcium channels result in a variety of neurological disorders displaying epilepsy as a core feature. This chapter summarizes the molecular, cellular, and network mechanisms by which mutations in high-voltage-activated calcium channels result in epilepsy, with a particular focus on Ca_V1.2 (CACNA1C), Ca_V1.3 (CACNA1D), Ca_V2.1 (CACNA1A), and Ca_V2.3 (CACNA1E)-associated disorders.

Introduction

Calcium ions are key regulators of a range of fundamental biological processes, including cellular proliferation, migration, survival, signaling, and secretion, and system-specific function such as muscle contraction, cardiac rhythmicity, and gut motility. Calcium ions also act as secondary messengers during signal transduction, triggering activity-regulated gene transcription while supporting a range of enzymatic reactions in response to specific stimuli. In the brain, calcium ions are essential for neuronal proliferation, survival, migration, axonal guidance, synapse formation and pruning, and synaptic transmission and plasticity, as detailed in this review. Disruption of calcium homeostasis thus results in a range of neurological disorders, often with epilepsy as a core symptom, together with systemic and autonomic manifestations. This chapter provides an overview of genetic epilepsies associated with mutations in high-voltage-activated (HV) voltage-gated calcium channels (VGCC) genes, while discussing some of the underlying disease mechanisms based on findings in relevant cellular and rodent models.

Voltage-Gated Calcium Channels: An Overview

VGCCs are multisubunit complexes composed of an alpha (α) pore-forming subunit and a combination of auxiliary subunits (Fig. 46–1A). Each α subunit is encoded by a different gene and determines the fundamental properties of the encoded channel (Fig. 46–1B). VGCCs are divided between high-voltage-activated (HVA) and low-voltage-activated (LVA) channels, reflecting their different behavior in response to changes in membrane potential (Fig. 46–1B; see reviews: Perez-Reyes, 2003; Catterall et al., 2005, 2020). Specific subtypes of VGCCs also differ in their biophysical properties, gating kinetics, and in their sensitivity to different pharmacological agents and toxins. HVA channels include Ca_V1 channels (Ca_V1.1 to Ca_V1.4) that mediate L-type currents, activate at depolarized potentials (≈–40 to –30 mV), inactivate slowly, and thus produce prolonged Ca²⁺ transients, blocked by 1,4-dihydropyridine (DHP). HVA channels also include Ca_V2 channels that mediate P/Q-type currents (Ca_V2.1), N-type currents (Ca_V2.2), and R-type currents (Ca_V2.3), also activated by depolarization but displaying more rapid inactivation than L-type currents. These channels are respectively inhibited by ω-Agatoxin-IVA, ω-Conotoxin-GVIA, and nickel (NiCl₂), or the tarantula toxin SNX 482 (Mintz et al., 1992; Williams et al., 1992, 1994; Soong et al., 1993; McDonough et al., 1997; Newcomb et al., 1998). By contrast, Ca_V3 channels are LVA. They activate following depolarizations at more hyperpolarized potentials, display low-amplitude brief currents, are insensitive to DHP but highly sensitive to nickel (Tsien et al., 1988, Soong et al., 1993; see review: Perez-Reyes, 2003).

Figure 46–1.

General overview of voltage-gated calcium channels. A. Voltage-gated calcium channels (VGCC) are composed of a α1 pore-forming subunit, together with various auxiliary subunits. (Inspired from Catterall and Few, 2008). B. Phylogenetic tree illustrating (more...)

Important structure-function principles are shared between VGCCs and inform our understanding of the functional impact of various disease-causing mutations (see reviews: Catterall, 2000, Catterall et al., 2005, 2017, 2020; Campiglio and Flucher, 2015). The α subunit contains four homologous domains (labeled I to IV), each composed of six trans-membranous helical segments (S1–S6; Fig. 46–1C). The S5 and S6 segments of each domain form the ionic pore, which is lined by charged amino acids that determine the channels’ affinity for Ca²⁺ ions. The S5 to S6 loops of each domain interact to form the pore entry and the selectivity filter. The S4 segments are voltage sensors. Their outward movement upon depolarization drives conformational changes that open the channel pore. Mutations involving this voltage-sensitive motif tend to impact voltage activation threshold. Fast voltage-dependent channel inactivation occurs through movement of the inter-domain DII-DIII linker loop toward the channel pore, contacting the cytoplasmic ends of the S4–S6 segments. Disease-associated variants in these regions often impact channel inactivation and result in a functional gain-of-function (GoF) effect. A slower inactivation process has also been described, involving secondary messengers and modulation by G protein–coupled receptors (Pietrobon, 2010). Accessory subunits interact with the α subunit (Fig. 46–1A) and regulate channel assembly, trafficking, membrane targeting, and gating properties (Lacinova, 2005; Campiglio and Flucher, 2015).

Different VGCCs usually coexist within a single neuron to control various important biological processes in the dendrites, soma, and nerve terminals (Fig. 46–1D). For instance, different HVA VGCCs mediate synaptic release from a single neuron, with coexpression of different VGCCs often occurring within single release sites (Mintz et al., 1995; Wu et al., 1999; Eltes et al., 2017), although not in all cell types (Yamamoto and Kobayashi, 2018). This suggests that, in many neuronal populations, the loss of one VGCC may be partly compensated by the upregulation of other VGCCs. However, different VGCCs show different efficacy in controlling neurotransmitter release, reflecting their relative position with regard to the active zone: Ca_V2.1 channels are tightly bound to presynaptic structural elements in the active zone, while Ca_V2.3 channels tend to be localized further away from the release sites (Sheng et al., 1994; Mintz et al., 1995; Rettig et al., 1996; Wu et al., 1999; Rozov et al., 2001). Their different gating kinetics, binding to intracellular regulators (calmodulin, G protein–coupled receptors) and post-translational processes result in different plasticity rules, such that synaptic transmission that relies on Ca_V2.1 channels is characterized by short-term facilitation following repeated stimulations, while its loss (and its functional compensation by other HVA channels) results in short-term depression (see review: Catterall et al., 2013). Interestingly, individual release sites from a single neuron, which connect to different cellular targets, typically rely almost exclusively on one type of VGCC in a target-specific manner (Markram et al., 1998; Zaitsev et al., 2007; Rossignol et al., 2013; Eltes et al., 2017) and thus display different short-term synaptic plasticity rules (Reyes et al., 1998; Koester and Johnston, 2005; Eltes et al., 2017; Yamamoto and Kobayashi, 2018), which provide target-specific VGCC modulation at individual synapses (Eltes et al., 2017). Thus, even if the loss of function of a particular α subunit induces a functional compensation by other VGCCs, the different biophysical properties of specific α subunits render them not entirely interchangeable, resulting in functional deficits that are often cell type or network specific, as detailed below.

The functional diversity of VGCCs is further expanded by alternative splicing, which results in the production of multiple different α subunit isoforms, with specific cell type, tissue type, and age-dependent expression patterns (Rettig et al., 1996; Sakurai et al., 1996; Khan et al., 1998; Pereverzev et al., 1998, 2022; Grabsch et al., 1999, Schramm et al., 1999, Mitchell et al., 2002; Striessnig et al., 2006; Ernst and Noebels, 2009; Sinnegger-Brauns et al., 2009; Lipscombe and Andrade, 2015). Thus, some disease-associated mutations that affect selected isoforms result in cell-type-specific and tissue-specific pathological outcomes, in an age-dependent fashion.

The current chapter focuses on the implication of HVA VGCCs in epilepsy, with a particular focus on L-type (Ca_V1.2 and Ca_V1.3), P/Q-type (Ca_V2.1), and R-type (Ca_V2.3) VGCCs, given the wealth of recent data implicating these channels in various human epilepsy syndromes. Readers are referred to other extensive reviews concerning the important roles of LVA channels and various auxiliary subunits in epilepsy (Perez-Reyes, 2003; Cain and Snutch, 2012; Campiglio and Flucher, 2015; Lory et al., 2020; Weiss and Zamponi, 2020).

L-Type VGCCs in Epilepsy

L-Type Ca_V1.2 Channels: CACNA1C-Associated Disorders in Humans

Ca_V1.2 channels are expressed broadly in the brain, including in the cortex, hippocampus, amygdala, thalamus, and cerebellum (Splawski et al., 2004). They are also expressed in multiple other organs, including the heart, blood vessels, eyes, developing digits, smooth muscles, lymph nodes, and pancreas (Splawski et al., 2004). Therefore, de novo missense mutations in the CACNA1C gene have been associated with a multisystemic disorder called Timothy syndrome (MIM 601005), which includes life-threatening cardiac arrhythmias (long QT syndrome, second degree AV bloc and ventricular fibrillation), cardiac structural malformations (patent ductus arteriosus, ventricular septal defects, Tetralogy of Fallot), dysmorphic traits (syndactyly, low-set ears, flat nasal bridge, receding upper jaw, small displaced teeth), intermittent hypoglycemia, immune deficiency, and a range of neurocognitive deficits (intellectual deficiency and/or autism spectrum disorder) (Reichenbach et al., 1992; Splawski et al., 2004; see reviews: Napolitano et al., 1993; Bidaud and Lory, 2011; Franklin and Laubham, 2021). Notably, close to a quarter of children with Timothy syndrome develop epilepsy (Splawski et al., 2004). Timothy-syndrome-associated mutations typically induce a GoF effect, mostly through a deficit of channel voltage-dependent fast inactivation (Splawski et al., 2004; Barrett and Tsien, 2008), often with a leftward shift of activation toward more hyperpolarized potentials (Dick et al., 2016), resulting in persistent calcium “window” currents, calcium overload, and cellular toxicity (Splawski et al., 2004).

More recently, missense CACNA1C mutations have been reported in patients with isolated neurological symptoms, without the classical cardiac or systemic manifestations of Timothy syndrome (Rodan et al., 2021; Fig. 46–2A). Nonsense truncating variants or intragenic deletions typically present with autism, intellectual deficiency, or isolated language delay (Firth et al., 2011; Quintela et al., 2017; Mio et al., 2020; Rodan et al., 2021). By contrast, de novo missense variants give rise to severe early-onset epileptic encephalopathies, with developmental delay, hypotonia, ataxia, intellectual disability, and/or autism spectrum disorders (Firth et al., 2011; Iossifov et al., 2014; Rodan et al., 2021). Although not all children with de novo missense variants develop epilepsy, the majority do (≈70% of cases) (Rodan et al., 2021). CACNA1C-associated epilepsies include focal or generalized seizure disorders, as well as severe early-onset epileptic encephalopathies (West syndrome, neonatal epileptic encephalopathies), often evolving toward Lennox-Gastaut syndrome (Bozarth et al., 2018; Rodan et al., 2021). Electroencephalographic (EEG) findings are nonspecific, displaying focal or generalized epileptiform discharges, and brain imaging is usually unremarkable (Rodan et al., 2021).

Figure 46–2.

Ca_V1.2 and Ca_V1.3 L-type voltage-gated calcium channels. A. Schematic representation of selected CACNA1C mutations, color-coded according to their associated phenotypes. DEE, developmental epileptic encephalopathies; NDD, neurodevelopmental disorders, (more...)

The functional validation of four de novo missense variants associated with epilepsy revealed either a GoF effect (p.L614P and p.L657F), mostly through a shift of voltage-dependent activation toward more hyperpolarized potentials; or a loss-of-function (LoF) effect (p.L1408V), with reduced current density but unaltered gating kinetics (Rodan et al., 2021). Notably, one variant (p.L614R) had no clear impact on channel function, although this might reflect methodological differences in the associated subunits used to test this particular variant (Rodan et al., 2021). Other potential detrimental impacts leading to cellular toxicity, such as protein misfolding, mistargeting, intracellular accumulation, and ER stress, may contribute to the disease pathogenesis of specific variants (Bidaud and Lory, 2011), as demonstrated also for other VGCC disorders (Mezghrani et al., 2008; Jiang et al., 2019). To better appreciate these potential pathological mechanisms, testing of a larger sample of patient-derived mutations, preferably expressed in neurons, will likely be required (Rodan et al., 2021).

By contrast, some missense CACNA1C mutations present with isolated cardiac phenotypes. For instance, GoF variants have been associated with long QT syndrome (Zhang et al., 2018), while nonsense variants have been associated Brugada syndrome and a risk of sudden death (Antzelevitch et al., 2007), although this is debated (Hosseini et al., 2018). Nonetheless, such system-specific effects may reflect the selective impact of specific variants on different tissue-specific isoforms (Snutch et al., 1991; Chin et al., 1992; Kim et al., 1992; Sinnegger-Brauns et al., 2004; Liao and Soong, 2010; Napolitano and Antzelevitch, 2011; Lipscombe and Andrade, 2015; Bozarth et al., 2018; Clark et al., 2020; Franklin and Laubham, 2021). However, some patients with epilepsy and CACNA1C variants display cardiac conduction disorders, warranting caution in monitoring for potential arrhythmias and a theoretical risk of SUDEP, as some missense variants may affect all channel isoforms (Rodan et al., 2021).

P/Q-Type Ca_V2.1 VGCC and Epilepsy

P/Q-Type Ca_V2.1 Channels: CACNA1A-Associated Disorders in Humans

Ca_V2.1 channels are expressed broadly in the brain, including in most neuronal populations of the cortex, hippocampus, striatum, amygdala, thalamus, and cerebellum (Westenbroek et al., 1995; Ludwig et al., 1997), as well as in the spinal cord and neuromuscular junctions (Westenbroek et al., 1998). CACNA1A mutations have thus been associated with multiple neurological disorders characterized by prominent motor manifestations, including acetazolamide-responsive episodic ataxia type II (EA2; MIM #108500) (Ophoff et al., 1996), degenerative spinocerebellar ataxia type 6 (SCA6; MIM # 183086) (Zhuchenko et al., 1997), and familial hemiplegic migraines type I (FHM1; MIM #141500) (Ophoff et al., 1996), as reviewed extensively elsewhere (Pietrobon, 2010). Patients with EA2 or FHM1 occasionally present with epilepsy, EA2 being typically associated with absence seizures (Rajakulendran et al., 2010) while FHM1 results in brain edema and focal seizures or status epilepticus following minor head trauma (Chan et al., 2008; Stam et al., 2009). Mechanistically, EA2 is classically associated with CACNA1A LoF mutations (Mantuano et al., 2010; Rajakulendran et al., 2010), while GoF mutations induce FHM1 (Tottene et al., 2009; Pietrobon, 2010), although some exceptions exist (Barrett et al., 2005; Cao and Tsien, 2005). By contrast, triplet expansions result in progressive ataxia (SCA6) with degenerative cerebellar atrophy, mostly due to the accumulation of misfolded protein and ensuing cytotoxic effects, rather than to the loss of Ca_V2.1 channel function (Mark et al., 2015).

More recently, heterozygous de novo or inherited CACNA1A nonsense mutations (stop gain, frameshift, splice mutations, deletions), causing a presumed LoF, have been associated with developmental epileptic encephalopathies, global developmental delay, limb hypotonia, nystagmus, congenital episodic and progressive ataxia, and cognitive-behavioral impairments ranging from attention deficits and learning disability to frank intellectual disability and/or autism spectrum disorder (Fig. 46–3A; Damaj et al., 2015; Lupien-Meilleur et al., 2021). Other nonepileptic events, such as paroxysmal tonic upward gaze deviation, are frequent and may be confused with focal seizures (Tantsis et al., 2016; Le Roux et al., 2021). Epilepsies associated with nonsense CACNA1A mutations usually start in the first 4 years of life, with absences, generalized tonic-clonic seizures, focal seizures, and/or febrile seizures, with rare instances of infantile spasms (Auvin et al., 2009; Damaj et al., 2015; Le Roux et al., 2021). These epilepsies are accompanied by pathological EEG patterns, including hypsarrhythmia, generalized 3 Hz spike-wave discharges, and slow background with multifocal spikes (Auvin et al., 2009; Damaj et al., 2015; Le Roux et al., 2021). There is a high degree of inter-individual phenotypic variability regarding seizure susceptibility, even with the same mutation. Indeed, in 16 individuals from 4 unrelated families with confirmed CACNA1A LoF variants, epilepsy was observed in 19% of individuals, while isolated febrile seizures occurred in another 40% of individuals (Damaj et al., 2015). Nonsense heterozygous CACNA1A variants otherwise present with isolated neurodevelopmental phenotypes without epilepsy, characterized by global delay, developmental and progressive ataxia, autism spectrum disorder, and/or cognitive impairments (Tonelli et al., 2006; Damaj et al., 2015; Travaglini et al., 2017).

Figure 46–3.

Ca_V2.1 P/Q-type voltage-gated calcium channels. A. Schematic representation of selected published CACNA1A mutations, color-coded according to their associated phenotype. DEE, developmental epileptic encephalopathy; EA2, episodic ataxia type II; FHM1, (more...)

By contrast, rare cases of recessive biallelic inheritance of a nonsense variant have been described, including four babies with a homozygous variant (p.Arg932*) who presented with early-onset epileptic encephalopathy and premature death within the first 3–6 months of life, and two siblings with compound heterozygous variants (p.Trp1439Arg/p.Ala158Thr fs*6) who developed severe epileptic encephalopathy, progressive neurodegeneration, brain atrophy, optic nerve atrophy, and early lethality (Reinson et al., 2016; Arteche-Lopez et al., 2021). Thus, the homozygous LoF of CACNA1A consistently results in epilepsy, with a severe neurodegeneration phenotype.

Interestingly, some de novo missense mutations have been associated with a drastically more severe phenotype than seen in patients with heterozygous nonsense variants (Fig. 46–3A). These missense variants induce an early-onset developmental epileptic encephalopathy (DEE type 42, MIM# 617106), characterized by severe refractory epilepsy starting in the first few days or months of life, accompanied by profound developmental delay, regression, progressive ataxia and cerebellar atrophy, nystagmus, spasticity, and severe cognitive deficits (moderate to severe intellectual deficiency, severely restricted language abilities) (Myers et al., 2016; Hamdan et al., 2017; Jiang et al., 2019; Le Roux et al., 2021). These patients present with complex seizure disorders, combining myoclonic seizures, epileptic spasms, atypical absences, tonic seizures, tonic-clonic seizures, atonic drop attacks, status epilepticus, and febrile seizures, often reminiscent of Lennox-Gastaut syndrome (Myers et al., 2016; Hamdan et al., 2017; Jiang et al., 2019; Le Roux et al., 2021; Niu et al., 2022). These epilepsies tend to be highly refractory to medical therapies, vagus nerve stimulation, or the ketogenic diet, with some responses to antiepileptic drugs with calcium channel blocking activity (topiramate or valproic acid), and anecdotal reports of benefits from the sodium channel blocker lamotrigine or the L-type VGCC blocker verapamil (Byers et al., 2016; Jiang et al., 2019; Le Roux et al., 2021; Niu et al., 2022). Brain imaging typically reveals progressive brain atrophy, with preferential atrophy of the vermis and cerebellar hemispheres (Jiang et al., 2019; Le Roux et al., 2021), although unilateral cerebral atrophy following prolonged focal status epilepticus has been reported (Niu et al., 2022). Altogether, de novo missense CACNA1A variants underlie ≈1% of cases of severe developmental epileptic encephalopathies in large cohorts of patients, suggesting that it is an important contributor to severe early-onset human epilepsies (Myers et al., 2016; Hamdan et al., 2017). Further, they exacerbate the epilepsy phenotype in patients with SCN1A-related Dravet syndrome (Ohmori et al., 2013).

CACNA1A epilepsy-associated missense mutations are distributed across all domains of the Ca_V2.1 protein, particularly on the cytoplasmic ends of the S5–S6 segments, on the S4 segment of DIII and IV, and on the DII-III linker loop (Fig. 46–3A), regions involved in voltage-dependent activation and inactivation (Hans et al., 1999; Luvisetto et al., 2004; Catterall et al., 2020). Notably, the DII-DIII cytoplasmic linker loop includes the synaptic protein interaction site (“synprint”), at which various presynaptic proteins involved in vesicular release (SNAP-25 and syntaxin) interact with the α1 subunit, linking Ca_V2.1 channels to the synaptic release machinery (Rettig et al., 1996). Mutations in this region would thus be expected to impair synaptic release mechanisms.

The functional investigation of four epileptic encephalopathy-associated de novo missense variants revealed that both GoF and dominant-negative LoF mechanisms result in similar clinical phenotypes, with severe early-onset developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome (Jiang et al., 2019). Two of the studied variants (p.A713T and p.V1396M) resulted in GoF effects, with facilitated voltage-dependent activation (hyperpolarization shift of voltage activation curves), steeper activation curves, a significant delay of channel inactivation, and an increased current density, together with predicted conformational changes on 3D modeling likely mediating these alterations in gating (Fig. 46–3B; Jiang et al., 2019). This was in stark contrast with the effects of a nearby FHM1-associated mutation (p.V714A), characterized by an increased current density and a steeper activation curve, but with intact voltage dependency of activation and inactivation kinetics (Fig. 46–3C; Jiang et al., 2019). Thus, the alteration in channel gating properties likely contributes to the severity of the overall phenotype in patients with GoF mutations causing epileptic encephalopathy compared to those inducing a FHM1 phenotype.

By contrast, two other epileptic encephalopathy- associated de novo missense variants (p.G230V and p.I1357S) resulted in reduced current density, suggesting a LoF effect. These variants also resulted in a mistargeting of the α1 subunit to the plasma membrane, leading to aberrant accumulations in intracytoplasmic inclusions, which may be cytotoxic (Jiang et al., 2019). Notably, when coexpressed with wild-type α1 subunits, mutant α1 subunits sequestered wild-type subunits in these intracellular inclusions, suggesting a dominant- negative (DN) LoF effect (Fig. 46–3D; Jiang et al., 2019). Such DN-LoF mutations are expected to result in greater functional consequences than nonsense heterozygous LoF mutations (haploinsufficiency), since they prevent proper targeting of the wild-type allele to the membrane, resulting in a net decrease of channel expression at the cell surface, while also causing cellular toxicity through pathological accumulation of misfolded proteins, as observed in SCA6-associated mutations (Mark et al., 2015). The cellular and network mechanisms by which both GoD and DN-LoF mutations induce such similar clinical phenotypes will need to be investigated using clinically relevant mouse models expressing epilepsy-associated missense variants.

Furthermore, the characterization of larger patient cohorts may ultimately help identify phenotypic differences between these two functional classes of missense variants, which may ultimately help guide future therapies designed to target specific LoF or GoF mechanisms. For instance, early motor signs, such as tremors, myoclonus, and jitteriness in the first postnatal days, are observed in babies with GoF mutations (Le Roux et al., 2021), likely reflecting enhanced synaptic release at the neuromuscular junctions. Future natural evolution studies may help pinpoint other clinical markers suggesting a GoF or a DN- LoF effects in patients with de novo missense CACNA1A variants.

R-Type Ca_V2.3 Channels: CACNA1E-Associated Epilepsy

CACNA1E-Associated Disorders in Humans

Ca_V2.3 channels are expressed broadly in the brain (Soong et al., 1993; Williams et al., 1994; Day et al., 1996; de Borman et al., 1999; Lin et al., 1999), as well as in the peripheral nervous system, cardiac myocytes, sperm, kidneys, pancreas, and gastrointestinal tract (Vajna et al., 1998; Grabsch et al., 1999; Weiergraber et al., 2000; Mitchell et al., 2002). At least six isoforms have been described, with different age-dependent, tissue-specific, and cell-type-specific differences in expression patterns (Pereverzev et al., 1998, 2002; Grabsch et al., 1999; Mitchell et al., 2002). CACNA1E-associated disorders described to date present with prominent neurological and musculoskeletal symptoms, without frank systemic manifestations, potentially reflecting the tissue-selective roles of specific isoforms.

De novo missense CACNA1E variants have been associated with a severe early-onset developmental and epileptic encephalopathy (DEE 69, MIM618285), characterized by neonatal or early infantile seizure onset, with profound global developmental delay, severe axial hypotonia, spastic quadriplegia, congenital joint contractures, movement disorders, and macrocephaly (Helbig et al., 2018). Hyperkinetic movement disorders, including dystonia and chorea, appear to be prominent early signs of the disease (Helbig et al., 2018; Ortiz Cabrera et al., 2021). Although the majority of children with de novo CACNA1E missense variants develop epilepsy (described in 45%–87% of patients) (Helbig et al., 2018; Heyne et al., 2018), others display a range of neurodevelopmental deficits, including global delay, developmental regression, autism spectrum disorder, and/or intellectual disability without epilepsy (Helbig et al., 2018; Heyne et al., 2018; Royer-Bertrand et al., 2021). There is considerable inter-individual phenotypic variability, even with the same mutations (Royer-Bertrand et al., 2021). Notably, nearly 40% of nonepileptic patients with de novo CACNA1E missense variants display pathological epileptiform activity on EEG, potentially reflecting a greater susceptibility to seizures (Royer-Bertrand et al., 2021). CACNA1E-associated epilepsies are complex seizure disorders, often starting with epileptic spasms, with subsequent combinations of myoclonic, tonic, atonic, focal motor, or focal with impaired consciousness and generalized tonic-clonic seizures (Helbig et al., 2018). EEG recordings typically show severely perturbed brain rhythms, with multifocal spike discharges, slow spike-wave discharges, hypsarrhythmia, and/or continuous spike and wave in slow-wave sleep (CSWS) (Helbig et al., 2018). Brain imaging is often unremarkable or reveals nonspecific brain atrophy (Helbig et al., 2018).

Mechanistically, the majority of published de novo CACNA1E missense variants are localized on the cytoplasmic portion of the S6 segments in domains I–IV (Fig. 46–4A), regions involved in channel activation (Raybaud et al., 2006, 2007; Royer-Bertrand et al., 2021), together with the DII S4–S5 linker (Wall-Lacelle et al., 2011). Most described variants induce GoF effects on Ca_V2.3 channels, through combinations of facilitated voltage-dependent activation (hyperpolarization shift of voltage activation curves), slower fast inactivation, and increased current density (Fig. 46–4B; Helbig et al., 2018). These findings are clinically relevant as 50% of patients with CACNA1E-related epilepsy display partial or full seizure control with topiramate (Helbig et al., 2018), a known Ca_V2.3 channel blocker (Kuzmiski et al., 2005). De novo LoF mutations (frameshift or indel) have also been described in patients with epilepsy, global developmental delay, and major speech impairments, although the overall phenotype is milder than that caused by GoF missense variants (Helbig et al., 2018). Nonetheless, in large control populations (GnomAD database), CACNA1E haploinsufficiency appears to be poorly tolerated (pLI score = 1.0) (Lek et al., 2016). Thus, as in CACNA1A-associated disorders, both GoF and LoF variants in CACNA1E have been associated with epilepsy, although GoF variants induce more severe disorders.

Figure 46–4.

Ca_V2.3 R-type voltage-gated calcium channels. A. Schematic representation of selected published CACNA1E mutations, color-coded according to their associated phenotype. DEE, developmental epileptic encephalopathy; NDD, neurodevelopmental disorders, including (more...)

Conclusions

In summary, HVA VGCCs are essential for a range of physiological processes regulating dendritic and somatic excitability, burst-firing mode, synaptic release, and structural plasticity, required for optimal brain function. They are also critical for multiple fundamental neurodevelopmental processes, including neuronal proliferation, migration, dendritic development, and structural plasticity. Thus, mutations affecting HVA calcium channels result in multiple neurological disorders, including various types of severe early-onset developmental epileptic encephalopathies. Novel cellular and animal models are shedding light on the underlying pathological mechanisms. Furthermore, new models carrying patient-derived mutations will be required to explore these disease mechanisms and to test novel therapies.

Acknowledgments

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