Channelopathies and juvenile myoclonic epilepsy

"The shroud of ignorance surrounding idiopathic epilepsy is gradually being lifted. Epileptologists, particularly Gastaut and his colleagues in France and the German school led by Janz, have isolated a number of epileptic syndromes which allow a more precise diagnostic, prognostic, and therapeutic approach to the patient with seizures. It is as yet unclear if the syndromes delineate fundamentally different conditions. It is apparent, however, that not all patients fit into the described syndromes. An alternative approach is to view the epilepsies as a broad neurobiological continuum." (Berkovic et al., 1987). An increasing number of genes predisposing to idiopathic epilepsy have been identified over the last 10 years. Among these genes, mutations in four genes encoding for subunits of the γ-aminobutyric acid (GABA)A receptor appear to be an important cause of familial epilepsy. So far, the majority of these mutations have been associated with a dramatic decrease of GABA-evoked currents in recombinant receptors. Because GABA is the main inhibitory transmitter in the adult brain, it is generally believed that this loss of function would cause abnormal excitability of cortical neurons, thereby leading to clinical seizures. Although additional genetic mechanisms have been associated with juvenile myoclonic epilepsy (JME), impaired GABAA transmission appears to be central in the pathophysiology of familial idiopathic generalized epilepsy (IGE). Early description of clinical manifestations compatible with a benign form of myoclonic epilepsy was first reported in the French literature, notably by Herpin ("commotions épileptiques") (Herpin, 1867) and Rabot ("myoclonie épileptique") (Rabot, 1899). Lundborg also reported on a similar syndrome that he called "intermittierende myoklonische epilepsie" to differentiate from progressive myoclonus epilepsy (Lundborg, 1903). However, the first complete description of JME syndrome was reported by Janz and Christian who described an epilepsy syndrome that they named "impulsiv petit-mal" (Janz & Christian, 1957). In their original description, they observed that "epilepsy with impulsive petit mal appears around puberty and is characterized by myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. The disorder may be inherited and sex distribution is equal. Often there are generalized tonic-clonic seizures and, less often, infrequent absences. The seizures usually occur after awakening and are often precipitated by sleep deprivation. Interictal and ictal EEG [electroencephalography] have rapid, generalized, often irregular spike waves and polyspike waves; there is no close correlation between EEG spikes and jerks. Frequently, the patients are photosensitive. Response to appropriate drugs is good. The treatment will probably continue for the patient's lifetime." (Janz & Durner, 1997). Delgado-Escueta and Enrile-Bacsal later brought this syndrome to the attention of North American literature and emphasized that the syndrome was still underrecognized by clinicians and that myclonic jerks occurring in the morning are often overlooked by the affected individuals (Delgado-Escueta & Enrile-Bacsal, 1984). This author coined the contemporary appellation of this syndrome as "Juvenile myoclonic epilepsy of Janz." A strong genetic contribution to JME has been recognized in the early description of the syndrome (Delgado-Escueta & Enrile-Bacsal, 1984; Janz & Durner, 1997). Based on genetic epidemiology studies, it appears that classical IGE syndromes have complex genetic traits, probably caused by an interaction of several genetic variations and environmental factors (Annegers et al., 1982; Zara et al., 1995; Berkovic et al., 1998). However, over the last 10 years, there have been an increasing number of reports on rare forms of familial epilepsy syndromes where the mode of inheritance is clearly Mendelian. Specific genes causing these syndromes have been uncovered, confirming the existence of monogenic epilepsy syndromes (Gourfinkel-An et al., 2004; Turnbull et al., 2005). Most of these familial syndromes are autosomal dominant traits with reduced penetrance (Picard et al., 2000). We and others reported on monogenic forms of IGE that are associated with various mutations in genes encoding for voltage- and ligand-gated ion channels, including mutation in GABAA receptor genes (Baulac et al., 2001; Wallace et al., 2001; Cossette et al., 2002). GABAA receptors are ligand-gated chloride channels that mediate fast inhibition in the adult central nervous system (CNS). Their molecular structure comprises a heteropentameric protein complex assembled from 19 different classes of subunits (α1-6, β1-4, γ1-3, δ, ε, π, θ, and ρ1-2). So far, epilepsy-causing mutations have been identified in GABRA1 (Cossette et al., 2002; Maljevic et al., 2006), GABRG2 (Baulac et al., 2001; Wallace et al., 2001; Harkin et al., 2002; Kananura et al., 2002), GABRB3 (Tanaka et al., 2008), and GABRD (Dibbens et al., 2004), encoding respectively the α1, γ2, β3, and δ subunits. In vitro functional studies have revealed that the majority of these mutations result in a reduction of GABA-activated chloride currents (Macdonald et al., 2004). In at least two mutations in GABRG2 (p.Q351X, p.R43Q) (Harkin et al., 2002; Kang & Macdonald, 2004) and two mutations in GABRA1 (p.A322D, p.S326fs328X) (Krampfl et al., 2005; Maljevic et al., 2006), it has been shown that the reduction in the amplitude of GABA-evoked current was due to reduced surface expression of receptor protein, caused by retention of mutant receptors in the endoplasmic reticulum. In addition, epilepsy-causing mutations have been identified in the CLCN2 gene (Haug et al., 2003; D'Agostino et al., 2004), encoding the voltage-gated chloride channel ClC-2. Whole-cell patch-clamp recordings of recombinant ClC-2 channels harboring epilepsy-causing mutations did not yield detectable chloride currents, compatible with a loss of function (Haug et al., 2003). Because ClC-2 channels play an important role in maintaining low intracellular chloride concentration, it is expected that loss of function mutations involving CLCN2 will result in impaired chloride efflux and abnormal intracellular accumulation of chloride, which may eventually impair GABAergic neurotransmission in the brain. These latter findings are thus consistent with loss-of-function mutations found in at least four different subunits of the GABAa receptor for related epileptic syndromes. Taken together, these results suggest that there is impairment in the degree of inhibition mediated by GABAa receptors in the pathophysiology of the classical IGE with autosomal dominant inheritance. However, high genetic heterogeneity has been observed since the early linkage studies on JME (Greenberg et al., 2000). It is thus likely that additional ion channel genes will be involved in JME. Moreover, there is growing evidence that non–ion channel genes are also associated with the disease. Indeed, mutations in the EFHC gene have been recently associated with familial JME (Suzuki et al., 2004), whereas polymorphisms in BRD2 (Pal et al., 2003) and MAE (Greenberg et al., 2005) have been associated with JME with complex inheritance. The exact mechanisms by which these later gene variants are involved in the pathophysiology of JME remain to be determined. Whereas mutations in the EFHC gene are associated with classical JME only (Suzuki et al., 2004), mutations in most of the IGE genes identified so far (GABRA1, GABRG2, GABRD, and CLCN2) are rather associated with a variety of classical IGE phenotypes, including JME, juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and epilepsy with grand mal seizures on awakening (EGMA) (Table 1) (Baulac et al., 2001; Wallace et al., 2001; Cossette et al., 2002; Haug et al., 2003; Dibbens et al., 2004; Maljevic et al., 2006). Several observational studies previously proposed that these syndromes, although considered to be distinct entities in the current classification, rather represent a biologic continuum (Berkovic et al., 1987). So far, genotype–phenotype correlations, although from a limited number of families, further support this hypothesis. However, additional data will be needed to explore potential overlap between these various epileptic syndromes. Eventually, these findings should contribute to a revised, molecular-based classification of IGE. The author is supported by the CIHR, the FRSQ, and the Savoy Foundation. The author has no conflict of interest. Since the submission of the manuscript, a retraction of the work of Haug et al. (2003) has been published (Haug et al., 2009) which changes the genotype-phenotype correlations presented in Table 1.

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