Epilepsy Research 121 (2016) 47–54

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Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres

Review article

Genetics of reflex seizures and epilepsies in humans and animals Domenico Italiano a , Pasquale Striano b , Emilio Russo c , Antonio Leo c , Edoardo Spina a , Federico Zara d , Salvatore Striano e , Antonio Gambardella f,g , Angelo Labate f,g , Sara Gasparini f,h , Marco Lamberti a , Giovambattista De Sarro c , Umberto Aguglia f,g,h,∗ , Edoardo Ferlazzo f,g,h a

Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, Messina, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genova, Italy c Science of Health Department, School of Medicine, University of Catanzaro, Viale Europa, Catanzaro, Italy d Laboratory of Neurogenetics and Neurosciences, Department of Neurosciences, “G. Gaslini” Institute, Genova, Italy e Epilepsy Center, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy f Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Viale Europa, Catanzaro, Italy g Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Viale Europa, Catanzaro, Italy h Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy b

a r t i c l e

i n f o

Article history: Received 4 September 2015 Received in revised form 22 January 2016 Accepted 29 January 2016 Available online 2 February 2016 Keywords: Genes Photosensitivity Reading Startle Music Eating

a b s t r a c t Introduction: Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. This comprehensive narrative review focuses on the role of genetic determinants in humans and animal models of reflex seizures and epilepsies. Methods: References were mainly identified through MEDLINE searches until August 2015 and backtracking of references in pertinent studies. Results: Autosomal dominant inheritance with reduced penetrance was proven in several families with photosensitivity. Molecular genetic studies on EEG photoparoxysmal response identified putative loci on chromosomes 6, 7, 13 and 16 that seem to correlate with peculiar seizure phenotype. No specific mutation has been found in Papio papio baboon, although a genetic etiology is likely. Mutation in synaptic vesicle glycoprotein 2A was found in another animal model of photosensitivity (Fayoumi chickens). Autosomal dominant inheritance with incomplete penetrance overlapping with a genetic background for IGE was proposed for some families with primary reading epilepsy. Musicogenic seizures usually occur in patients with focal symptomatic or cryptogenic epilepsies, but they have been reported in rare genetic epilepsies such as Dravet syndrome. A single LGI1 mutation has been described in a girl with seizures evoked by auditory stimuli. Interestingly, heterozygous knockout (Lgi1+/− ) mice show susceptibility to sound-triggered seizures. Moreover, in Frings and Black Swiss mice, the spontaneous mutations of MASS1 and JAMS1 genes, respectively, have been linked to audiogenic seizures. Eating seizures usually occur in symptomatic epilepsies but evidences for a genetic susceptibility were mainly provided by family report from Sri Lanka. Eating seizures were also reported in rare patients with MECP2 duplication or mutation. Hot water seizures are genetically heterogeneous but two loci at chromosomes 4 and 10 were identified in families with likely autosomal dominant inheritance. Startle-induced seizures usually occur in patients with symptomatic epilepsies but have also been reported in the setting chromosomal disorders or genetically inherited lysosomal storage diseases.

Abbreviations: PRE, primary reading epilepsy; GRM8, metabotropic glutamate receptor 8; CHRM2, cholinergic-muscarinic type 2 acetylcholine receptor M2; IPS, intermittent photic stimulation; ADLTE, autosomal dominant lateral temporal epilepsy; AGS, audiogenic seizures; DBA/2J, Dilute Brown Agouti coat color; EL, EL/Suz; GEPRs, genetically epilepsy-prone rats; HWE, hot water epilepsy; KM, Krushinsky–Molodkina. ∗ Corresponding author at: Regional Epilepsy Centre, “Bianchi-Melacrino-Morelli” Hospital, Reggio Calabria, Italy. E-mail address: [email protected] (U. Aguglia). http://dx.doi.org/10.1016/j.eplepsyres.2016.01.010 0920-1211/© 2016 Elsevier B.V. All rights reserved.

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Discussion: The genetic background of reflex seizures and epilepsies is heterogeneous and mostly unknown with no major gene identified in humans. The benefits offered by next-generation sequencing technologies should be merged with increasing information on animal models that represent an useful tool to study the mechanism underlying epileptogenesis. Finally, we expect that genetic studies will lead to a better understanding of the multiple factors involved in the pathophysiology of reflex seizures, and eventually to develop preventive strategies focused on seizure control and therapy optimization. © 2016 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 3.1. Photosensitivity in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 3.2. Animal models of photosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Primary reading epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Musicogenic seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Eating seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Hot water seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Startle-induced seizures in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 8.1. Animal models of audiogenic seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

1. Introduction Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. Frequently, reflex seizures occur in association with spontaneous seizures, and are considered as “seizure types” (Engel, 2001). The term of reflex epilepsy is traditionally applied to rare conditions in which all, or almost all seizures are provoked by one specific stimulus (Wolf and Koepp, 2012). Currently, only Idiopathic Photosensitive Occipital Lobe Epilepsy, primary reading epilepsy (PRE), Startle Epilepsy and other Visual Sensitive Epilepsies are recognized as specific reflex epileptic syndromes (Engel, 2001). Actually, despite their rarity, reflex seizures and reflex epilepsies have been described in almost all epileptic syndromes. Thus, this chapter includes conditions very heterogeneous both for clinical and etiological point of view. Effective stimuli, electro-clinical features, proposed classifications and pathophysiological mechanisms of reflex seizures and epilepsies have been reviewed elsewhere (Ferlazzo et al., 2005; Striano et al., 2012; Italiano et al., 2014). Multimodal investigations of cerebral function (Koepp et al., 2016) indicate that ictogenic mechanisms in reflex epilepsies largely depend from the excitation of functional anatomic networks normally serving highly complex physiological functions that are genetically determined or regulated in humans and animals (Rakic et al., 1994). Therefore, we reviewed the literature on the role of genetic determinants in reflex seizures and epilepsies. In most of these conditions such as photosensitivity, the role of a genetic predisposition is evident. However, the involvement of genetic determinants in other reflex seizures and epilepsies, in particular in PRE, eating seizures, hot water seizures and in some cases of musicogenic and startle-induced seizures, will also be reviewed. 2. Review of the literature Medical publications concerning genetics of human and animal models of reflex seizures and epilepsies were reviewed. References were identified by searches of PubMed with the terms “genetics” in various combination with “reflex seizures”, “reflex epilepsies”, “photosensitivity”, “photoparoxysmal response”, “intermittent

photic (or light) stimulations”, “reading”, “language”, “startle”, “eating”, “hot water”, “Papio Papio”, “animal models”. Articles were also identified through searches of the authors’ own files. Selection criteria were novelty, importance, originality, quality and relevance to the scope of this review. 3. Results The main genetic findings in humans and animal models of reflex seizures and epilepsies are summarized in Tables 1 and 2. 3.1. Photosensitivity in humans Seizures triggered by visual stimuli occur in up to 10% of epilepsies in childhood and in 5% of adult patients with epilepsy (Kasteleijn-Nolst Trenité, 1989). Photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in response to intermittent photic stimulation (IPS). Photosensitivity can occur in several epilepsy syndromes, the most frequent association being with idiopathic generalized epilepsies (IGE), especially with juvenile myoclonic epilepsy (JME) (Gambardella et al., 1996; Kasteleijn-Nolst Trenité et al., 2013). Photosensitivity is also common in some symptomatic generalized epilepsies such as Unverricht–Lundborg disease, Lafora disease and in many unsolved cases of progressive myoclonus epilepsies (Ferlazzo et al., 2007, 2014; Franceschetti et al., 2014; Muona et al., 2015). The occurrence of giant evoked responses to low flash frequencies and even single flashes of light is a diagnostic clue of late infantile and adult forms of neuronal ceroid lipofuscinosis (KasteleijnNolst Trenité et al., 2005). Nevertheless, it is well known that the prevalence of PPR in relatives of PPR-positive subjects is independent of the underlying seizure disorder (Davidson and Watson, 1956; Stephani et al., 2004; Waltz and Stephani, 2000). Indeed, PPR often segregates independently of epilepsy phenotype indicating that they represent different entities (Doose and Gerken, 1973). Family and twin studies provided unequivocal evidence that PPR is genetically determined (Stephani et al., 2004). The inheritance

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Table 1 Main genetic findings in reflex seizures and epilepsies of humans. Reflex seizure type

References

Inheritance

Identified loci or genes

Photosensitivity

Davidson and Watson (1956) Doose et al. (1969) Herrlin (1960) Jeavons and Harding (1975) Waltz and Stephani (2000) Watson and Marcus (1962) Matthews and Wright (1967) Radhakrishnan et al. (1995) Forster and Daly (1973) Wolf (1992) Desnous et al. (2011) Dravet et al. (2005) Michelucci et al. (2007) Sanchez-Carpintero et al. (2013) Senanayake (1990) Martínez et al. (2011)

Likely autosomal dominant with reduced, age-dependent penetrance Independent from seizures disorder

6p21 7q32 13q31 16p13

Likely autosomal dominant with incomplete penetrance

None

Reported in patients with ADTLE and other rare genetic epilepsies (e.g. Dravet Syndrome)

LGI1/Epitempin SCN1A

Unknown Familial cluster in Sri Lanka Cases associated with Rett syndrome Likely autosomal dominant

MECP2

Reading-induced seizures

Musicogenic seizures

Eating seizures

Hot-water seizures

Satishchandra (2003) Nguyen et al. (2015) Santos-Silva et al. (2015)

Startle-induced seizures

Labate et al. (2004) Bakker et al. (2006) Ferlazzo et al. (2009)

Usually none or overlapping with the diseases

10q21.3–q22.3 4q24–q28 Synapsin 1 GPR56 Various, depending on underlying disease

Table 2 Main genetic findings in animal models of reflex seizures. Reflex seizure type Photosensitivity

Audiogenic seizures

References

Animal models

Inheritance

Identified loci or genes

Killam (1979) Killam et al. (1966a, 1966b, 1966c) Fischer-Williams et al. (1968) Naquet et al. (1995) Szabo et al. (2004) Szabo et al. (2007) Davidson and Watson (1956) Doose et al. (1969) Herrlin (1960) Jeavons and Harding (1975) Waltz and Stephani (2000) Batini et al. (2004) Douaud et al. (2011) Frings et al. (1951) Skradski et al. (1998) Skradski et al. (2001) Shin et al. (2013) Schreiber and Graham (1976) Neumann and Seyfried (1990) Banko et al. (1997) Skradski et al. (2001) De Sarro et al. (2015) Misawa et al. (2002) Charizopoulou et al. (2011) Chabrol et al. (2010) Boillot and Baulac (2015) Faingold (2002) De Sarro et al. (2015) Serikawa et al. (2015) Ribak (2015) Garcia-Cairasco (2002) Doretto et al. (2003) Castro et al. (2015) Krushinsky et al. (1970) Romanova et al. (1993) Prieto-Martin et al. (2015)

Papio papio baboons

Unknown

None

Fayoumi chickens

Autosomal recessive

Frings mice (spontaneous)

Autosomal dominant?

Synaptic vesicle glycoprotein 2A (SV2A) Monogenic audiogenic seizure-susceptible (MASS1)

DBA/2J mice (spontaneous)

Likely complex

Audiogenic seizure prone 1 and 2 (Asp-1 Asp-2) Linkage to chromosome 17

Black Swiss mice (spontaneous)

Unknown

Knockout Lgi1 mice

Autosomal dominant

GEP rats (GEPRs)

Likely polygenic

Juvenile audiogenic monogenic seizures (JAMS1) Leucine-rich, glioma inactivated 1 (Lgi1) None

Wistar Audiogenic Rats (WARs)

Likely polygenic

None

Krushinsky–Molodkina (KM) rats

Likely polygenic

None

Genetic Audiogenic Seizure Hamsters (GASH) Feline audiogenic reflex seizures

Unknown

None

Unknown

None

Lowrie et al. (2015)

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pattern of familial PPR indicates a complex mode of transmission, involving several genes (Doose and Waltz, 1993; Jeavons and Harding, 1975; Striano et al., 2009; Waltz and Stephani, 2000). Almost 100% concordance was found in monozygotic twins (Davidson and Watson, 1956; Herrlin, 1960). Moreover, siblings of patients with generalized PPRs are more likely to show PPR than siblings of control subjects (19.3% vs 3.4%) (Doose and Gerken, 1973). An autosomal dominant mode of inheritance with reduced penetrance was proven by several family studies (Davidson and Watson, 1956; Doose et al., 1969; Herrlin, 1960; Jeavons and Harding, 1975; Waltz and Stephani, 2000; Watson and Marcus, 1962). This pattern of inheritance could be explained by the agedependent expression of PPR and by the existence of environmental triggers. However, for traits caused by more than one gene, reduced penetrance can also be due to independent segregation of another gene required for phenotypic expression. Subsequent family systematic studies also supported age-dependent penetrance of the PPR (Kasteleijn-Nolst Trenité et al., 1994), in part explaining the lack of studies of formal segregation analysis. Harding and Jeavons (1994) found up to 2.5-fold higher prevalence of the PPR trait in girls; this may probably be caused by differences in hormonal levels, which may also be the cause of the age-related onset. Alternatively, the influence of gender could be related to the two X chromosomes by genetic or epigenetic mechanisms or due to direct or indirect protective effects of the male sex chromosome (Stephani et al., 2004; Taylor et al., 2007). It is possible that variations in more than one gene can cause different PPRs, each associated with a certain epilepsy phenotype and respective syndrome-specific or seizure type-specific genetic factor. On the other hand, a single PPR gene could be modulated by different underlying epilepsy phenotypes to give rise to different PPR types (Kasteleijn-Nolst Trenité et al., 2005). Thus far, molecular genetic studies on PPRs have identified putative loci on chromosomes 6, 7, 13, and 16 (Pinto et al., 2005; Tauer et al., 2005) but no major gene has been identified. Each locus seems to be correlated with a predominant seizure phenotype. Evidence for linkage at 7q32 and 16p13 was found in PPR families with prominent myoclonic epilepsies (Pinto et al., 2005). These genomic regions contain genes relevant for the neuromodulation of cortical dynamics in humans, such as the genes encoding the metabotropic glutamate receptor 8 (GRM8) and the cholinergic-muscarinic type 2 acetylcholine receptor M2 (CHRM2) (Parra et al., 2005). A genome wide screen on 60 PPR-IGE families showed evidence for linkage at 6p21.2 in 19 PPR families and suggestive evidence for linkage at 13q31.3 in 25 PPR-IGE families with predominant absences and focal epilepsies (Tauer et al., 2005). de Kovel et al. (2010) found that the locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE. A candidate linkage study in 37 PPR families failed to show a linkage to the dopamine receptors gene regions DRD1 to DRD5, EPM1 (21q22.3) and IGE loci (1p, 2q36, 3p14, 3q26, 4p, 6p11, 6p21.3, 8p11 and 15q14) (Neubauer et al., 2005). It is well known that photosensitivity is a prominent feature in a rare epileptic encephalopathy due to de novo CHD2 mutations (Suls et al., 2013). To determine whether CHD2 mutations were also associated to photosensitivity in common epilepsies, Galizia et al. (2015) sequenced CHD2 in 580 patients with photosensitive epilepsy and 55 subjects with PPR without history of seizures. Authors found that unique CHD2 variations were over-represented in eyelid myoclonia with absences (EMA), but not in PPR without seizures. CHD2 is the first gene associated with EMA, one of the most representative photosensitive epilepsy syndromes. Interestingly, CHD2 does not encode an ion channel, but the chromodomain helicase DNA-binding protein 2 involved in transcriptional regulation, thus opening up new avenues for research into cortical excitability. Kasteleijn-Nolst Trenité et al. (2015) described a large

family featuring a combination of reflex epilepsies, including PPR, limb jerks evoked by flickering sunlight and speaking-induced jawjerks. Genetic analysis showed evidence for linkage in four regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. The authors hypothesized that SCNM1 mutation could lead to increased susceptibility to PPR and epilepsy, but they were not able to replicate these findings in a general cohort of 134 unrelated photosensitive subjects. 3.2. Animal models of photosensitivity The Papio papio baboon represents a good model of generalized epilepsy with photosensitivity derived by natural selection in the wild (Naquet et al., 1995). The high prevalence of photosensitivity in the African Papio papio baboons compared to other primates living in the same areas, supports the hypothesis of a genetic determinant for this trait. However, specific genetic studies have not yet been undertaken (Szabo et al., 2004, 2007). Killam et al. (1966a, 1966b, 1966c) originally described the susceptibility to light-induced and related spontaneous seizures of baboon Papio papio. In particular, IPS (20–30 Hz) for up to 5 min at hourly intervals were able to induce myoclonic seizures preceded by paroxysmal discharges in the fronto-rolandic cortex and secondarily generalized tonic–clonic seizures. Of note, humans express maximal photosensitivity at IPS at 12–18 Hz and the related photoparoxysmal responses arise commonly in the occipital lobes (Szabo et al., 2007). Furthermore, the Papio papio baboons, either photosensitive or not, show spontaneous non-epileptic myoclonus, in analogy with some human epilepsies such as PMEs (FischerWilliams et al., 1968; Killam, 1979; Naquet et al., 1995). Another non-mammalian model of photosensitivity is represented by the epileptic strain of Fayoumi chickens (Fepi) that carry a spontaneous gene mutation in the acceptor site of the second intron of synaptic vesicle glycoprotein 2A (Douaud et al., 2011). This mutation determines photogenic and audiogenic reflex epilepsy with autosomal recessive transmission, but was never reported in humans. The seizure phenotype consists of stimulus-locked motor symptoms (myoclonus) usually followed by generalized, selfsustaining convulsions (Batini et al., 2004; Crichlow and Crawford, 1974; Fadlallah et al., 1995). Finally, genetics of animal models of photosensitivity is far from being unraveled and further research is warranted. 4. Primary reading epilepsy Primary reading epilepsy (PRE) is an idiopathic condition and several familial cases have been reported. However, apart from some early reports, the inheritance of PRE has been scantily investigated. Reading-induced jaw jerking has been described in paired cases of parent and child (Matthews and Wright, 1967; Radhakrishnan et al., 1995) as well as in monozygotic twin pairs (Forster and Daly, 1973). Furthermore, a clear-cut inheritance of spike-and-wave reflex activation during reading has been well documented in asymptomatic family members of patients with PRE (Daly and Forster, 1975). Rowan et al. (1970) reported a phenotype analysis of a patient with PRE, whose daughter exhibited seizures unrelated to reading but clearly related to television viewing. Nevertheless, EEG discharges were found in these siblings during reading, along with evidence of photosensitivity and pattern sensitivity in the daughter, thus suggesting a continuum between PRE and photosensitive epilepsy. In a review on 111 PRE patients by Wolf (1992), among 69 index subjects, 28 (41%) had a family history of seizures, and, of 20 first degree family members with sufficient information, 11 had PRE and 3 had IGE.

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Valenti et al. (2006) performed a clinical and neurophysiological analysis of a multigeneration family with IGE, language-induced jaw jerking and ictal stuttering (Yacubian and Wolf, 2015), suggesting a single inherited mutation with modifying genetic and environmental factors influencing phenotype variability. Furthermore, the EEG pattern of generalized epilepsies shared by affected members appeared to be transmitted as a Mendelian trait. Reflex seizures triggered by writing tasks were also reported in two siblings with JME (Chifari et al., 2004). Hence, the existence of an electro-clinical continuum with common genetic background between IGE and language-induced reflex epilepsies can be hypothesized.

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de Palma et al. (2012) reported a case of a boy with seizures triggered by the smell and taste of food, carrying a maternallyinherited MECP2 duplication. Duplication of MECP2 is known to cause an X-linked mental retardation syndrome, of which typical features are infantile hypotonia, poor speech development, recurrent respiratory infections, epilepsy, and progressive spasticity. Most affected males inherit the MECP2 duplication from a carrier mother; however, spontaneous de novo duplications have been reported (Ramocki et al., 2010). Martínez et al. (2011) described three epileptic Rett patients with seizures triggered by food intake or proprioception; interestingly, only one out of three reported had a molecular diagnosis (MECP2 mutation c.880C>T/p.Arg294Stop and X-chromosome inactivation pattern).

5. Musicogenic seizures 7. Hot water seizures Musicogenic seizures usually occur in patients with focal symptomatic or cryptogenic temporal lobe epilepsy, but they have also been reported in rare genetic epilepsy syndromes. In Dravet Syndrome, despite the most common precipitant of reflex seizures is fever, music as well as intermittent lights and visual patterns have also been reported as precipitant stimuli (Desnous et al., 2011; Dravet et al., 2005). Sanchez-Carpintero et al. (2013) reported a case of a 7-year-old boy with Dravet syndrome, who experienced myoclonic seizures triggered by certain melodies, mainly from electronic devices and occasionally simple melodies played on a piano. In this patient, a new mutation in SCN1A gene was detected; in particular, a small deletion was found, c.4021delC, which resulted in the generation of a stop at codon 1348 (Leu1341fsX1348). It has been speculated that the cortical hyperexcitability in Dravet syndrome may be due to a genetic predisposition (Striano et al., 2013). In particular, alterations in SCN1A could reduce sodium currents in inhibitory GABAergic interneurons, which are crucial in the control of cortical excitability (Yu et al., 2006). Telephone-induced seizures have been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone (Brodtkorb et al., 2002; Gu et al., 2002; Michelucci et al., 2004). Michelucci et al. (2007) reported a 36-year-old woman with a 11-year history of recurrent complex focal and secondarily generalized seizures evoked by answering the telephone, including mobile phone. Other auditory stimuli, such as hearing the answering machine and the noise of a helicopter, could elicit the seizures. Mutation analysis identified a de novo heterozygous c.406C-T mutation in exon 4 of the LGI1/Epitempin gene, resulting in an arginine to tryptophan substitution at position 136 (Arg136Trp). Replacement of this charged amino acid with the hydrophobic tryptophan likely hampers the function of the mutated protein, ultimately resulting in the epilepsy phenotype. The function of the LGI1/Epitempin gene is still unclear, but its mutations were found in about half of the families with autosomal dominant lateral temporal epilepsy (ADLTE) (Nobile et al., 2009). 6. Eating seizures Eating-induced seizures are usually focal and occur in the setting of symptomatic epilepsies (Aguglia and Tinuper, 1983; Italiano et al., 2014; Loreto et al., 2000; Labate et al., 2006). Evidences for genetic susceptibility were firstly provided by Senanayake (1990) who described eating-triggered seizures in 20 subjects among 59 siblings in nine families from Sri Lanka. External factors such as food and eating habits have been hypothesized to contribute to sibling clustering. Yacubian et al. (2004) reported a family with three women presenting temporal lobe seizures provoked by eating, and normal MRI. Authors hypothesized an idiopathic form of temporal lobe epilepsy in this family (Yacubian et al., 2004).

In hot water epilepsy (HWE) (bath epilepsy, water-immersion epilepsy) seizures are triggered by contact or immersion in hot water. These seizures are very rare in Western literature, with anecdotal cases described in symptomatic epilepsies; by contrast, this type of epilepsy is singularly frequent in southern of India, probably in relation to the peculiar habits of pouring hot water (40–50◦ ) over the head. A self-limiting, infantile form (onset before age 1 year) of HWE has also been described (Ioos et al., 2000). In the “adult” type of HWE, age at onset is variable although children are more frequently affected (Satishchandra, 2003); outcome is also variable and seizure-freedom may be reached by most patients. Familial clustering is observed and positive family histories have been reported in about 18% of patients (Satishchandra, 2003). The same author postulated that an aberrant, genetically determined, thermoregulatory system sensitive to a rapid rise in temperature, could account for HWE (Satishchandra, 2003). Although HWE is observed predominantly in South India, there does not appear to be a major founder effect for the disorder. HWE seems to be genetically heterogeneous. Seven families with autosomal dominant inherited HWE were examined by linkage analysis and two loci for HWE at chromosome 10q21.3–q22.3 (Ratnapriya et al., 2009a) and 4q24–q28 (Ratnapriya et al., 2009b) were identified. Kaplan et al. (2009) reported a six generations Turkish family of 75 individuals, of which seven suffered from HWE. This pedigree suggested an autosomal dominant inheritance. In a large French-Canadian family with developmental dyslexia/autism spectrum disorder and focal seizures occurring both spontaneously or in the context of bathing/showering epilepsy, Nguyen et al. (2015) found a mutation in the synapsin 1 gene, encoding a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. In this genetically susceptible family, reflex seizures were probably sustained by a hyperexcitability of the temporo-insular network. Finally, Santos-Silva et al. (2015) described a 5-year-old boy with bilateral frontoparietal polymicrogyria (BFPP) and HWE. Interestingly, this patient exhibited a novel mutation (R271X) in the GPR56 gene on chromosome 16q21. Different mutations in this gene are commonly associated to BFPP, but this is the first reported case of BFPP with HWE. Further analyses are warranted to assess the role of this mutation in HWE. 8. Startle-induced seizures in humans They consist of an intense startle response followed by clear clinical or electrographic manifestations of epileptic seizures, following unexpected sensory stimuli (Aguglia et al., 1984; Andermann and Andermann, 1986). They usually occur in patients with focal epilepsy secondary to large brain lesions (such as perinatal hypoxic injury with congenital hemiparesis, cortical dysplasias,

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schizencephaly) but they have also been reported in the setting of autoimmune encephalitis, symptomatic generalized epilepsy as well as chromosomal disorders or genetically inherited lysosomal storage disorders (Bakker et al., 2006; Italiano et al., 2014; Zuliani et al., 2014). In particular, Ferlazzo et al. (2009) described 13 patients with trisomy 21 presenting a peculiar form of Lennox–Gastaut Syndrome (LGS), characterized by late onset and frequent occurrence of reflex seizures provoked by sudden unexpected sensory stimuli. Authors postulated that dendritic rarefaction and decreased interneurons, as well as functional abnormalities leading to decreased brain inhibition, could explain this particular presentation of LGS in trisomy 21. Finally, excessive startle response and generalized myoclonic seizures were reported in genetically inherited lysosomal storage disorders including as partylglucosaminuria, GM1 and GM2 gangliosidosis and infantile Krabbe disease, probably related to alterations of cortical neuronal circuits secondary to lysosomal storages in glial and neuronal cells (Labate et al., 2004). 8.1. Animal models of audiogenic seizures Both sudden or gradual onset auditory stimuli may induce seizures in several animal models. Differently from humans, these animal models usually have a strong genetic determinant in the absence of evident cerebral lesions. Animals susceptible to audiogenic seizures (AGS) are considered as genetic experimental model for “apparently generalized” reflex epilepsies (Seyfried et al., 1999). Frings mice and Dilute Brown Agouti coat color mice (DBA/2J) are two well-established spontaneous models of generalized AGS. The Frings mice carry a spontaneous mutation of MASS1 (monogenic audiogenic seizure-susceptible) gene, located on mouse chromosome 13 (Frings et al., 1951; Skradski et al., 1998, 2001). Shin et al. (2013) have reported that MASS1 protein, also called VLGR1 (very large G protein-coupled receptor 1), is widely expressed in the superior and inferior colliculi, which play an essential role in the generation and in the spreading of AGS. DBA/2J mice show a spontaneous susceptibility to AGS due to multiple genetic factors. To date, three loci, localized on chromosomes 4, 12 and 17 have been identified. In particular, Asp-1 and Asp-2 genes, respectively located on chromosome 4 and 12, have been hypothesized as candidate genes due to their implications in Ca2+ -ATPase activity change (Banko et al., 1997; Neumann and Seyfried, 1990). In DBA/2J mice, seizure susceptibility is lost by the 24–27th postnatal day (Schreiber and Graham, 1976; Skradski et al., 2001); seizures arise after a loud mixed-frequency sound (12–16 kHz; 90–120 dB) and are characterized by a wild running phase followed by clonic convulsions and a tonic extension, ending in often fatal respiratory arrest (Buchhalter, 1993; De Sarro et al., 2015). Black Swiss mice have also high susceptibility to acoustic stimuli. In particular, this susceptibility is highest at 2–3 weeks of age gradually disappearing by adulthood. JAMS1 (juvenile audiogenic monogenic seizures) gene, located on chromosome 10, was identified as the gene linked to the AGS in this strain (Charizopoulou et al., 2011; Misawa et al., 2002). The knockout (KO) Lgi1 (Leucine-rich, glioma inactivated 1) mouse model as well as Lgi1 mutant rat model (missense L385R mutation) lead to an autosomal dominant form of focal epilepsy associated with auditory features. Homozygous and heterozygous Lgi1 mice show relevant differences, in particular, homozygous KO (Lgi1−/− ) mice present spontaneous seizure, whereas heterozygous KO (Lgi1+/− ) mice only show a higher susceptibility to soundtriggered seizures than control mice. Therefore, Lgi1+/− should be considered a model for human autosomal dominant lateral temporal epilepsy with auditory features (Boillot and Baulac, 2015; Chabrol et al., 2010).

The genetically epilepsy-prone rats (GEPRs) are made up of two substrains, the moderately epileptic GEPR-3 and the more severely epileptic GEPR-9, show generalized tonic–clonic seizures in response to standardized sound stimuli. Genetic analysis of QTL for seizures has not been reported yet (De Sarro et al., 2015); although inheritance seems to be multigenic rather than monogenic in this model. According to Faingold (2002), the vulnerability to the AGS is related to a genetic predisposition along with environmental insult to the brain. In GEPR-9s the first genetic insult could be linked to an abnormal GABA neurotransmission, whereas the environmental insult could be a loud sound stimulus, which initiates AGS (Serikawa et al., 2015); GEPRs are also susceptible to other stimuli such as hyperthermia (De Sarro et al., 2015). Neuroanatomical studies report an abnormal GABAergic system in the inferior colliculus of GEPR rats as responsible for the beginning and propagation of audiogenic seizures. In particular, in the central nucleus of the inferior colliculus an increased number of GABAergic neurons in the GEPRs as compared to control rats has been observed. However, further studies are needed to better clarify whether this increased number of GABAergic neurons is an epileptogenic mechanism causing seizures or is a compensatory mechanism in response to seizures or even an epiphenomenon (Ribak, 2015). The Wistar Audiogenic Rats (WARs) model was developed by Wistar rats. WARs exhibit vulnerability to acoustic stimulation. In particular, seizures phenotype is characterized by wild running, jumping, falling and tonic–clonic seizures. The polygenic defect underlying the disorder has never been investigated. The Krushinsky–Molodkina (KM) rat strain, the first selected for susceptibility to AGS, was characterized by Krushinsky and Molodkina in Moscow in the 1940s. In particular, sound stimulation in KM rats lead to wild running episode and tonic–clonic convulsions. Also in this strain genetic determinants may play a major role but they have never been investigated (Krushinsky et al., 1970; Romanova et al., 1993). Genetic Audiogenic Seizure Hamsters developed in Salamanca (GASH-Sal), manifest AGS in response to acoustic stimuli. The genetic background underlying this disorder has not been yet investigated whereas an impairment of GABA neurotransmission has been reported (Prieto-Martin et al., 2015). In particular, GASH-Sal rats have shown a lower expression of K+ /Cl− cotransporter KCC2 protein in several brain regions including cortex, cerebellum, hippocampus and hypothalamus when compared to control animals. This decreased expression of KCC2, which maintain a low [Cl− ]i , seems to modulate GABAergic system leading to seizure susceptibility. Likewise, studies have also reported mutations in the KCC2 gene in patients with epilepsy (Kahle et al., 2014; Puskarjov et al., 2014). Finally, Lowrie et al. (2015) have described the phenotype of feline audiogenic reflex seizures. Actually, studies have been undertaken to identify the genetic basis in this strain. Overall, acoustically induced seizures have been encountered in several different strains and species and in most cases polygenic causes have been suggested; the most consistent data regard the involvement of Lgi1 gene.

9. Conclusions Reflex seizures represent an intriguing chapter that has always aroused curiosity in epileptologists. The possibility to reproduce seizures in laboratory, to analyze the characteristics of effective stimuli, and to study the progression of clinical signs and EEG discharges, has greatly contributed to the understanding of some basic pathophysiological mechanisms (Wolf, 2015). The genetic background of reflex seizures and epilepsies is heterogeneous and mostly unknown with no major gene identified in

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humans. Indeed, reflex seizures and epilepsies have most of the features that make genetic research difficult such as clinical, etiological and genetic heterogeneity, often-complex mode of inheritance and possible gene-environment interactions. In the next years, the widespread application of next-generation sequencing technologies will significantly increase the throughput, making whole-genome sequencing a possible way for obtaining global genomic information on patients. However, the benefits offered by these technologies should be merged with increasing information on animal models that represent an useful tool to study the mechanism underlying epileptogenesis and seizures, despite the challenging issue of transferring results from preclinical to clinical practice. In addition, some types of epilepsy cannot be represented in animal models (e.g. primary reading epilepsy) while some others (e.g. audiogenic seizures) were easily observed in several rodent strains as an innate feature, which permitted to select and develop specific animal models. Peculiarity of these models is the often polygenic nature of the disease, which is in agreement with what is observed in humans. Nevertheless, it is expected that such studies will lead to a better understanding of the multiple factors involved in the pathophysiology of reflex seizures, and eventually to develop preventive strategies focused on seizure control and therapy optimization. Conflict of interest None declared. References Aguglia, U., Tinuper, P., 1983. Eating seizures. Eur. Neurol. 22, 227–231. Aguglia, U., Tinuper, P., Gastaut, H., 1984. Startle-induced epileptic seizures. Epilepsia 25, 712–720. Andermann, F., Andermann, E., 1986. Excessive startle syndromes: startle disease, jumping, and startle epilepsy. Adv. Neurol. 43, 321–338. Bakker, M.J., van Dijk, J.G., van den Maagdenberg, A.M., Tijssen, M.A., 2006. Startle syndromes. Lancet Neurol. 5, 513–524. Banko, M.L., Allen, K.M., Dolina, S., Neumann, P.E., Seyfried, T.N., 1997. Genomic imprinting and audiogenic seizures in mice. Behav. Genet. 27, 465–475. Batini, C., Teillet, M.A., Naquet, R., 2004. An avian model of genetic reflex epilepsy. Arch. Ital. Biol. 142, 297–312. Boillot, M., Baulac, S., 2015. Genetic models of focal epilepsies. J. Neurosci. Methods, http://dx.doi.org/10.1016/j.jneumeth.2015.06.003. Brodtkorb, E., Gu, W., Nakken, K.O., Fischer, C., Steinlein, O.K., 2002. Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22-q24. Epilepsia 43, 228–235. Buchhalter, J.R., 1993. Animal models of inherited epilepsy. Epilepsia 34, S31–S41. Castro, G.P., de Castro Medeiros, D., de Oliveira Guarnieri, L., Mourão, F.A.G., Pinto, H.P.P., Pereira, G.S., Moraes, M.F.D., 2015. Wistar audiogenic rats display abnormal behavioral traits associated with artificial selection for seizure susceptibility. Epilepsy Behav., 2015, http://dx.doi.org/10.1016/j.yebeh.2015. 08.039, pii:S1525-5050(15)00514-4 (Epub ahead of print). Chabrol, E., Navarro, V., Provenzano, G., et al., 2010. Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice. Brain 133, 2749–2762. Charizopoulou, N., Lelli, A., Schraders, M., et al., 2011. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat. Commun. 2, 201. Chifari, R., Piazzini, A., Turner, K., Canger, R., Canevini, M.P., Wolf, P., 2004. Reflex writing seizures in two siblings with juvenile myoclonic epilepsy. Acta Neurol. Scand. 109, 232–235. Crichlow, E.C., Crawford, R.D., 1974. Epileptiform seizures in domestic fowl. II. Intermittent light stimulation and the electroencephalogram. Can. J. Physiol. Pharmacol. 52, 424–429. Daly, R.F., Forster, F.M., 1975. Inheritance of reading epilepsy. Neurology 25, 51–54. Davidson, S., Watson, C.W., 1956. Hereditary light sensitive epilepsy. Neurology 16, 235–261. de Kovel, C.G., Pinto, D., Tauer, U., et al., 2010. Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis. Epilepsy Res. 89, 286–294. de Palma, L., Boniver, C., Cassina, M., et al., 2012. Eating-induced epileptic spasms in a boy with MECP2 duplication syndrome: insights into pathogenesis of genetic epilepsies. Epileptic Disord. 14, 414–417. De Sarro, G., Russo, E., Citraro, R., Meldrum, B.S., 2015. Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs. Epilepsy Behav., http://dx.doi.org/ 10.1016/j.yebeh.2015.06.030, pii:S1525-5050(15)00361-3 (Epub ahead of print).

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