FULL LENGTH ORIGINAL RESEARCH

X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome *Dang Khoa Nguyen, *†Isabelle Rouleau, †Genevi
eve S en echal, ‡Ana In es Ansaldo, *Micheline Gravel, §¶Fabio Benfenati, and *#Patrick Cossette Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

SUMMARY

Dang Nguyen is an epileptologist at CHUM Notre-Dame and associate professor of neurology at University of Montreal.

Objective: We recently reported a Q555X mutation of synapsin 1 (SYN1) on chromosome Xp11-q21 in a family segregating partial epilepsy and autistic spectrum disorder. Herein, we provide a detailed description of the epileptic syndrome in the original family. Methods: A total of 34 members from a large French-Canadian family were evaluated. Family members with seizures or epilepsy underwent (when possible) clinical, neuropsychological, electrophysiologic, and neuroimaging assessments. Results: Epilepsy was diagnosed in 10 family members (4 deceased, 6 living). In addition to occasional spontaneous complex partial seizures, seven family members clearly had reflex seizures triggered by bathing or showering. Hippocampal atrophy was found in two of five epileptic family members family members who underwent magnetic resonance (MR) imaging. Video–electroencephalography (EEG) recordings of three triggered seizures in two affected members showed rhythmic theta activity over temporal head regions. Ictal single-photon emission computed tomography (SPECT) showed temporoinsular perfusion changes. Detailed neuropsychological assessments revealed that SYN1 Q555X male mutation carriers showed specific language impairment and mild autistic spectrum disorder. Female carriers also exhibited reading impairments and febrile seizures but no chronic epilepsy. Significance: Available evidence suggests that impaired SYN1 function is associated with hyperexcitability of the temporoinsular network and disturbance of high mental functions such as language and social interaction. The presence of reflex bathing seizures, a most peculiar clinical feature, could be helpful in identifying other patients with this syndrome. KEY WORDS: Bathing epilepsy, Reflex epilepsy, Hot-water epilepsy, Genetics of epilepsy, Focal epilepsy, Temporal, Insula(r).

Accepted April 23, 2015; Early View publication June 19, 2015. *Division of Neurology, CHUM Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada; †Department of Psychology, University of Quebec in Montreal, Montreal, Quebec, Canada; ‡Montreal University Geriatric Institute Research Center, Universite de Montreal, Montreal, Quebec, Canada; §Department of Experimental Medicine, National Institute of Neuroscience, University of Genova, Genova, Italy; ¶Department of Neuroscience and Neurotechnologies, The Italian Institute of Technology, Genova, Italy; and #Centre of Excellence in Neuromics, Universite de Montreal, Montreal, Quebec, Canada Address correspondence to Dang K. Nguyen, Neurology Division, CHUM H^ opital Notre-Dame, 1560 Sherbrooke East, Montreal, QC, Canada H2L 4M1. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy

Traditionally, partial (focal) epilepsies have been considered to be an acquired disorder secondary to lesions such as hippocampal sclerosis, tumors, trauma, vascular malformations, and malformations of cortical development. Over the past two decades, various syndromes of nonlesional focal epilepsies with simple (Mendelian, monogenic) inheritance have been described, such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in genes coding for subunits of the nicotine acetylcholine receptor (CHRNA4 or CHRNB2),1 autosomal dominant partial epilepsy with auditory features (ADPEAF) caused by mutations in the LGI1 gene,2 and autosomal dominant

1098

1099 Reflex Bathing Seizures

Key Points • • • •

SYN1 is a gene on chromosome X encoding a neuronspecific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. In this reported family, nonsense Q555X mutations of SYN1 in male carriers were associated with epilepsy and specific language impairment or mild autistic spectrum disorder. Seizures were of focal onset (most likely of temporoinsular origin), occurring spontaneously but more frequently triggered by bathing or showering. Female carriers also exhibited reading impairments and febrile seizures but no chronic epilepsy.

partial epilepsy with variable foci (FPEVF) related to DEPDC5 mutations.3 These findings indicate a significant genetic component in nonlesional acquired focal epilepsies.4 In an analysis of a single large French-Canadian family with focal epilepsy, we recently identified synapsin 1 (SYN1) loss-of-function mutations on chromosome Xp11-q21 causing impaired synaptic function.5,6 The current study depicts in detail the electroclinical syndrome and additional features of the phenotype of our linkage family bearing mutations associated with synaptic deficits. More detailed clinical characterization is important to provide further insight into the pathogenesis of this epileptic syndrome and facilitate the identification of new families sharing the same genetic condition.

Methods Data collection The proband, VI-1 (Fig. 1), was referred to our adult epilepsy clinic for the continuing care of a childhood epileptic syndrome. Ascertainment of his case history revealed peculiar reflex bathing seizures and identified additional affected family members. We then performed an extensive study of the genealogy and clinical epileptology of this family. Most of the affected family members were identified by a collaborating key family member, the proband’s unaffected father. To identify other possible relatives with seizures, members of each of the living nuclear families were contacted by telephone. When there was a history of seizures, family members were met in person for detailed clinical history and examination. Information on perinatal events, head trauma, age at seizure onset, duration and type of seizures, number of seizures, association with fever, antiepileptic drug therapy, and cognitive functioning was obtained. Information from previous medical records was collected, including results from routine electroencephalography (EEG) record-

ings and imaging studies. Epilepsy was defined as a lifetime history of two or more seizures. Information on the deceased affected members was obtained by interviewing close relatives and medical charts when still available. Electrophysiology and neuroimaging If living family members agreed, video-EEG monitoring (Stellate Harmonie Systems; Natus Medical Incorporated, U.S.A.), Tc-99m HMPAO ictal single-photon computed tomography (SPECT), interictal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and brain magnetic resonance imaging (MRI) studies were performed. MRI studies were acquired using a 1.5 Tesla scanner with multisequence, multiplanar imaging of the brain and additional coronal fluid-attenuated inversion recovery (FLAIR) and short T1 inversion recovery (STIR) imaging through the temporal lobes. In addition to these standard techniques, one family member underwent a continuous simultaneous EEG-functional near infrared spectroscopy (EEG-fNIRS) study. fNIRS is an emerging neuroimaging technique that uses near-infrared light to noninvasively monitor oxyhemoglobin (HbO), deoxyhemoglobin (HbR), and total hemoglobin (HbT), as a proxy for cerebral blood volume (CBV). Unlike ictal SPECT, which can provide only a single perfusion brain image of cerebral blood flow during a seizure, combined EEG-fNIRS offers a continuous method of studying regional hemodynamic and oxygenation changes that occur before, during, and after seizures. Our method of recording seizures using EEG-fNIRS was described in detail previously.7–9 Neuropsychological evaluation Neuropsychological profiles and assessment of oral and written language abilities were performed by a team of neuropsychologists and speech-language pathologists blinded to the genetic status. Standardized Assessment for diagnosis of Autism (ADI-R & AGOS-G module 3) was performed in individuals VII-1 and VII-2.

Results Genealogical data We evaluated 34 members from a large French-Canadian family. The family originated from Mont-Laurier, a city in the province of Quebec (Canada). The branch of the family with multiple affected individuals descended from II: 2. Epilepsy was diagnosed in 10 persons in this family (III:9, IV:10, IV:15, V:4; VI:1, VI:25; VI:23, VI:15, VII:1; VII:2), four of whom were deceased (III:9, IV:10, IV:15, VI:23). All epileptic members were male with a pattern of inheritance compatible with X-linked recessive inheritance with incomplete penetrance (Fig. 1). Two additional family members (female) experienced a single febrile seizure without subsequent epilepsy. Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1100 D. K. Nguyen et al.

Figure 1. Pedigree of our French-Canadian family with X-linked focal epilepsy due to a Q555X mutation on SYN1: ⊙, female carrier; ■, Male affected; ◔, Female febrile seizure; arrow, the proband; single diagonal bar, deceased; double diagonal bars, divorced; + presence of Q555X mutation; lack of Q555X mutation. Epilepsia ILAE

Phenotype study Table 1 summarizes the clinical and paraclinical features of affected family members. None of the patients had a condition that could explain the occurrence of seizures. Two female family members had a single febrile seizure in childhood (V:5, VI:5). MRI and EEG findings were normal in both cases and neither family member was ever treated with antiepileptic drugs. In the 10 male epileptic family members, age of seizure onset ranged from 20 months to 20 years, except for a less documented patient with onset at 50 years of age. One had a febrile seizure (V:4). All 10 epileptic members had rare or occasional nonreflex complex partial seizures. Seven clearly had reflex seizures triggered by the experience of bathing or showering. In addition to bathing or showering, which by far was the most common trigger, two family members mentioned that their seizures could also occasionally be precipitated by rubbing the face with a wet cloth (V:4) or testing water temperature prior to entering the shower/bathtub (VI:25). In both cases, these seizures occurred in the context of water-related hygiene habits. One patient (VII:1) also reported having seizures during nail clipping, but this occurred on only four occasions. Seizures were mostly complex partial seizures with a warm or chilling aura (limb or body) followed by Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

alteration of consciousness, pallor, cyanosis, and hypotonia prior to stiffening with or without secondary generalized tonic–clonic convulsions. Seizure severity varied among members. None of the patients had auditory symptoms. Standard EEG studies in all patients were normal. Four patients were studied with continuous audio-video EEG monitoring. Three seizures triggered by rubbing the face with a wet towel were recorded from V:4, all originating from the right temporal scalp electrodes (Fig. 2). One seizure triggered by the act of washing of face and hands was recorded from VI:4 at mid-occurrence with already diffuse rhythmic activity. From VII:1, one seizure was recorded on video upon stepping out of the shower but without electrophysiologic data. Unexpectedly, another seizure, this time triggered by nail clipping, was successfully recorded from the same patient, both on video and EEG. For the latter, rhythmic delta activity over the right temporal leads was observed, which quickly spread to parasagittal head regions and evolved into a rhythmic spike and slow wave pattern with a maximum over the right temporal head regions. Three ictal SPECT scans were performed in two patients, disclosing right temporoinsular activation following an early injection (V:4; VII:1) and right temporoinsular hypoactivation following a late injection (VII:1) (Fig. 2). PET

1101 Reflex Bathing Seizures was obtained for four family members, two of whom showed left temporal hypometabolism (V:4, VI:15). MRI was obtained for all living patients, except for one who had a cardiac pacemaker: one had mild right hippocampal atrophy without sclerosis (V:4), another had mild left hemispheric and hippocampal atrophy without sclerosis (VII:1), whereas three had no abnormalities (VI:1; VI:25; VII:2). The patient with a cardiac pacemaker had a normal brain computed tomography scan (VI:15). Simultaneous EEGfNIRS recording of a triggered seizure in patient VII:1 showed an increase in oxygenated hemoglobin and CBV over the right temporal and perisylvian regions that was quickly followed by a similar but milder response contralaterally (Fig. 3). Imaging studies were not available for deceased epileptic family members. All six living male epileptic members and the two female members with a history of febrile seizures had extensive neuropsychological and language evaluations (Table 1). Among male members tested, two (VII:1; VII:2) presented a pervasive developmental disorder, severe mixed (expressive and receptive) language deficits, and mild mental retardation. Another three had mixed dyslexia, predominantly affecting the phonologic route in two (V:4; VI:15) and the lexical route in the other (VI:1). Although IQs for the three with dyslexia were in the borderline range, the severity of their reading deficits and the types of writing errors that were produced could not be accounted for solely by the lower than average IQ. Of the two female members tested, only one presented mild mixed dyslexia. Contrary to the three males, the IQs of female members were in the normal range. Response to treatment among the six living epileptic members was generally good, as five have had no seizures over the last year. Withdrawal of anticonvulsive therapy was attempted in two patients without success. Illustrative cases M.M. – This 50-year-old man (V:4) with a normal perinatal history had two febrile seizures at age 2 years and a few nonfebrile ill-described spells until age 5. Recurrence of seizures occurred at age 17, with episodes characterized by an aura of body chill, alteration of consciousness, manual automatisms, and rare secondarily generalized tonic–clonic activity, occurring distinctly upon rubbing his face with a wet cloth/towel or while showering, irrespective of water temperature. Seizure control was good but not perfect with clobazam (30 mg/day). Avoidance of the trigger and a switch to lamotrigine monotherapy (200 mg/day) resulted in seizure freedom for the last 6 years. Numerous standard EEG studies were normal. Continuous video-EEG monitoring disclosed no interictal epileptic activity. Three stereotypical seizures were provoked by rubbing his face with a wet cloth, revealing an ictal right temporal rhythmic theta activity with subsequent propagation (Fig. 2A and Video S1). Rubbing his face or other body parts with a dry towel or hands as well as bathing in hot (>40°C) or cold water failed

to trigger a seizure. A first ictal SPECT revealed right temporoinsular activation, whereas the second showed bilateral temporoinsular activation that was more pronounced on the right than the left (Fig. 2B). Brain MRI disclosed a mild atrophy of the right hippocampus without sclerosis. Neuropsychological evaluation showed borderline intellectual function without any dissociation between the verbal and performance scales. Some retrieval difficulties (impaired free recall with correct recognition) were observed in memory tests, independent of the type of material. Verbal working memory was impaired, whereas spatial working memory was spared. Significant reading and writing deficits were observed. Difficulties were noted in the application of phoneme-grapheme conversion rules. The pattern observed was consistent with a dysfunction of the phonologic processing route. A.B. – This 17-year-old boy (VII:1) is the product of a normal pregnancy and vacuum-assisted delivery without complications (Apgar score 9/10/10). However, he showed delays in development, sitting only at 9 months, walking at 21 months, forming sentences only at age 6 years, and still enuretic and encoporetic until age 7 years. Neuropsychological evaluation revealed an IQ significantly inferior to normal, more so for verbal than for nonverbal scales. Severe mixed (receptive and expressive) language deficits were observed. Pervasive developmental disorder was diagnosed by a specialized team. Onset of seizures occurred at the age of 4 years, with spells characterized by an aura of body chill followed by fixed gaze, impairment of consciousness, cyanotic lips, hypersalivation, and hypotonia lasting a minute. Postictally, the child would present worsened language difficulties and sleepiness. Initially recurring once a month, spells gradually increased in frequency to biweekly after 6 months, and daily after a year, convincing parents to seek medical attention. Of interest, three fourths of spells occurred as he stepped out of the shower/bath, the remaining one fourth befalling mainly when the child was tired. The patient had a moderate but only transient response to valproic acid, with only a dozen spells over the following year. When seizures worsened again to weekly spells, clobazam was added without further benefit and with significant hyperactivity. Investigations included an MRI that disclosed a mild left hemispheric atrophy (including the hippocampus). EEG, electrocardiography (ECG), and heart ultrasound were normal. During a first monitoring session in March 2005, an ictal SPECT was obtained during a typical seizure that occurred as the boy was stepping out of a shower (no EEG data available) (Video S2). The late injection revealed mild right temporoinsular hypoactivity (Fig. 3B). Apart from post shower seizures, the patient also had a stereotypical spell a minute after vaccination as well as four identical spells in the context of nail clipping, one of which was recorded during video-EEG monitoring. EEG disclosed rhythmic delta activity over the right temporal head regions that quickly spread to parasagittal head regions Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1102 D. K. Nguyen et al. Table 1. Summary of clinical and paraclinical findings Pedigree

Sex

Age

Age at onset

FS

L.C.

III:9

M

83 yr †

NA

No

P.E.C. P.C. M.M.

IV:10 IV:15 V:4

M M M

42 yr † 82 yr † 50 yr

20 yr 50 yr 1 yr 8 mo

No No Yes (2 FS 17 yr after facerubbing with wet towel or showering (chilling aura, alteration of consciousness); rare 2ary GTC CPS after bath/shower (chilling aura, alteration of consciousness, oral and manual automatisms, with or without 2ary GTC)

CPS during shower or while testing temperature of shower/ faucet water (heat sensation rising in left arm, fixed gaze, alteration of consciousness, rare 2ary GTC) CPS after bath/swimming (semiology?) rare 2ary GTC CPS after shower/bath (chilling aura, alteration of consciousness, hypotonic), rare 2ary GTC) CPS during bath (chilling aura, alteration of consciousness, respiratory arrest, cyanotic, hypotonic) and nail clipping CPS after shower/bath (warmth sensation, facial flushing, moist skin, fixed gaze, chewing automatisms and altered consciousness) No No

Spontaneous seizures

Prior AED trial

Treatment

CPS (aura, ocular revulsion, alteration of consciousness, jerks of upper extremities, and cyanotic) CPS (semiology?) CPS (semiology?) Rare CPS in infancy (fixed gazed, alteration of consciousness, fall to floor)

N.A.

PHT + CBZ + Pb

N.A. N.A. PHT, CLB

None N.A. LTG

Occasional CPS

LTG

Rare CPS and 1 GTC

Pb (hyperactivity); CBZ (partial efficacy); CLB (not effective; aggressivity); PHT (partial efficacy); VPA (not effective; fatigue) None

LTG

Occasional CPS

N.A.

N.A.

Occasional CPS

VPA (allergy); CBZ (allergy), CLB

LTG, LEV

Occasional CPS (25% of seizures)

VPA (partial efficacy); CLB (hyperactivity)

LTG + CBZ

4 CPS (warmth sensation, altered consciousness)

None

CBZ

No No

None None

None None

EEG, electroencephalography; MRI, magnetic resonance imaging; CT, computed tomography; SPECT, single-photon emission computed tomography; PET, positron emission tomography; M, male; F, female; yr, years; mo, months; wk, weeks; nl, normal; N.A., not available; RS, reflex seizures; CPS, complex partial seizures; 2ary GTC, secondary generalized tonic–clonic activity; FS, febrile seizure; sz-free, seizure-free; LTG, lamotrigine; CBZ, carbamazepine; CLB, clobazam; Pb, phenobarbital, PH, phenytoin; LEV, levetiracetam; †, deceased; ↓, reduction; neuropsych, neuropsychological; PDD, pervasive developmental disorder; IQ, global intellectual quotient; VIQ, verbal IQ; PIQ, performance IQ. Clinical characteristics of affected members of our French-Canadian family with X-linked focal epilepsy due to a Q555X mutation on SYN1.

Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1103 Reflex Bathing Seizures

Seizure status

interictalEEG

~2/mo

nl

N.A

N.A

N.A

N.A

N.A

N.A

N.A. N.A. sz-free

N.A. N.A. N.A.

N.A. N.A. R temporal rhythmic theta

N.A N.A. Mild R hippocampal atrophy

N.A. N.A. R temporoinsular

N.A. N.A. ↓ L temporal

N.A. N.A. Dyslexia

N.A. N.A. 78/79/80

sz-free

nl

N.A.

nl

N.A.

nl

Dyslexia

78/83/76

sz-free

nl

Late diffuse rhythmic theta

nl

N.A.

nl

nl

104/122/84

N.A.

N.A.

N.A.

N.A.

N.A.

N.A.

N.A.

N.A.

Rare szs

nl

N.A

N.A (CT nl)

N.A

↓ L temporal

Dyslexia

78/82/78

sz-free

nl

N.A.

Mild left hemispheric atrophy (including hippocampus)

1st: ¯ R temporoinsular; 2nd: right superior temporal

N.A

PDD+mixed language deficits

51/45/72

sz-free

nl

N.A.

nl

N.A.

N.A.

PDD+mixed language deficits

65/71/70

sz-free sz-free

N.A

N.A N.A

nl nl

N.A N.A

N.A N.A

Mild dyslexia nl

100/98/104 96/99/93

Ictal EEG

MRI

Ictal SPECT

Neuropsych assessment

PET

IQ/VIQ/PIQ

Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1104 D. K. Nguyen et al. A

B

Figure 2. Paraclinical findings for M.M. (V:4). (A) Ictal rhythmic theta activity over the right centrotemporal region spreading to the right hemisphere with incremental amplitude and decremental frequency during a seizure triggered by rubbing the face with a wet towel (filters used: high-frequency filter, 15 Hz, low-frequency filter, 1 Hz); (B) Right temporoinsular activation on ictal SPECT. Epilepsia ILAE

Discussion

the living epileptic members with reliable data and/or extensive investigations, this proportion rises to 100% (6/6). Two additional female members had single febrile seizures. This syndrome is phenotypically different from the three forms of idiopathic partial epilepsy with an identified mutation or locus. ADNFLE is characterized by clusters of brief tonic and hyperkinetic motor seizures occurring mostly during sleep.1,10 ADPEAF (aka ADLTE) is characterized by simple partial seizures with auditory symptoms and secondary generalization.2,11 FPEVF is relatively heterogeneous with nocturnal or diurnal simple or complex partial seizures originating from temporal, frontal, occipital, or centroparietal areas.3,12 All three forms have an autosomal dominant inheritance.

Reflex bathing seizures: a distinctive feature associated with SYN1 Q555X mutations We describe a five-generation French-Canadian family with recessive X-linked inherited partial epilepsy with or without secondary generalization of variable penetrance. The clinical characteristics of the epileptic syndrome include a male gender, an onset usually in childhood, and seizures often persisting through adult life, with intrafamilial variation in severity. A most peculiar clinical feature is the occurrence of reflex complex partial seizures triggered by the experience of bathing or showering, as seen in 70% of epileptic family members (7/10). When considering only

Pathogenesis Reflex seizures are epileptic events triggered by specific motor, sensory, or cognitive stimulation (see Italiano et al.13 for review). Reflex seizures have traditionally been classified into “generalized” and “focal,” although this dichotomy is the subject of controversy. Several “focal” reflex seizure types have been described, such as seizures precipitated by somatosensory/proprioceptive stimuli, praxis or thinking, music, eating, reading, and hot water or bathing. It is generally assumed that such patients have regions of cortical hyperexcitability overlapping with areas physiologically activated during these specific sensory stimulations and

and evolved into a rhythmic spike and slow wave pattern with a maximum over the right temporal head regions. An early ictal SPECT disclosed right superior temporal hyperperfusion. Simultaneous EEG-fNIRS recording of a triggered seizure showed an increase in oxygenated hemoglobin and cerebral blood volume over the right temporal and perisylvian regions quickly followed by a similar but milder response contralaterally (Fig. 3). A significant decrease in seizure frequency was noted with lamotrigine. Because both spontaneous and triggered seizures continued three to five times per year, carbamazepine was later added. The patient has been seizure free for the last 3 years.

Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1105 Reflex Bathing Seizures A

B

Figure 3. Simultaneous EEG-fNIRS recording (VII: 1). (A) Topographic uncorrected T-stats of hemodynamic oxygenated hemoglobin variations during the time course of the triggered seizure. (B) Rhythmic epileptic theta activity over the right temporal region at seizure onset. Epilepsia ILAE

cognitive or motor activities.13 Although reflex seizures may be secondary to a structural lesion (such as a focal cortical dysplasia), most cases are considered primary or idiopathic with a likely genetic basis. In all six living epileptic male family members and the two female members with only febrile seizures, we identified a Q555X mutation in SYN1, an X-linked gene encoding a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis.5 In hippocampal neurons of SYN1 knockout mice, this mutation dramatically altered trafficking and release of synaptic vesicles and pool sizes.5 Imbalances in release dynamics of synaptic vesicles resulted in higher network excitability and firing/bursting activity.6 SYN1 knockout mice develop seizures from around 2 months of age that are typically elicited when animals are directly or indirectly handled during cage-changing procedures, suggesting that environmental factors at least play a role in the provocation of the seizures. The handling situation that induces seizures in these mice is complex and

involves several potential key factors, including sensory stimuli (e.g., sudden sounds, vestibular activation, and somatosensory stimuli), motor program activation, and emotional stress.14 In the family described herein, we propose that the experience of bathing/showering activates a genetically based hyperexcitable temporoinsular network which, when sufficiently activated, culminates in a focal seizure. Implication of the temporal lobe is suggested by ictal semiology, scalp EEG ictal recordings, and occasional hippocampal atrophy reported herein as well as experimental data from hippocampal neurons of SYN1 knockout mice.5,6 Insular cortex involvement in this syndrome is suggested by (1) ictal SPECT findings; (2) its capacity to generate a wide variety of ictal manifestations including somatosensory, viscerosensory, autonomic and motor symptoms as encountered in our patients15; (3) cumulative evidence suggesting that the insula is involved in the processing of viscerosensory, somatosensory, auditory, and vestibular stimuli as well as Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

1106 D. K. Nguyen et al. being part of the limbic and autonomic networks.16 Notably, water is known to activate the human anterior insula,17 and the discriminative thermosensory cortex appears to lie in the dorsal margin of the middle/posterior insula.18 Recent reports of seizures triggered by tactile, audiogenic, and gustatory stimuli19,20 raise the possibility that the insula is particularly prone to generate reflex seizures as it is a key integrative multisensory region. Temporal and insular areas, known to be structurally and functionally connected,16,21 could be entrained/recruited into seizure activity in handled mice or humans bathing (showering, of washing hands or face) when a sufficient threshold is reached due to imbalances in excitatory over inhibitory influences. Analogous to or distinct from hot-water epilepsy (HWE)? Since the first report by Allen in 1945, there have been >600 patients with HWE reported in the literature, the majority of whom live in Southern India.22,23 In this part of the world, the usual practice is to pour mugfuls of hot water directly over the body or head in quick succession from a bucket of water at a temperature of 40–50°C. Seizures that occur in this context may occur either at the beginning, in the middle, or even at the end of the bath.23 Children are more frequently affected than adults and male more than female subjects (2-2.5:1).20 Accumulated evidence suggests that seizures originate from the temporal lobe: (1) auras reported by patients often have a temporal flavor (epigastric sensation, dej
a vu, sense of fear, remembering the past, and feeling of living in the future); (2) EEG findings are usually normal, but interictal lateralized or localized spike discharges in the anterior temporal regions and “diffuse” abnormalities are found in 15–20% of patients; (3) scarce published reports of ictal EEG data mention temporal or hemispheric rhythmic activity; (4) ictal SPECT data obtained from five cases reveal hyperperfusion in medial temporal structures and the hypothalamus. Spontaneous seizures may develop a few years later in 16–38% of patients.24 A positive history of epilepsy among family members has been reported in 7–22.6% of cases, and familial HWE cases with more than one affected member have been noted in 7– 15% of Indian patients.25,26 Genome-wide linkage analysis of two large families provided evidence of linkage to chromosome 10q2127 and 4q24-q28,28 but the specific genes remain to be identified. Based on studies in an experimental animal model, it was proposed that HWE patients have a genetically determined aberrant thermoregulatory system rendering them extremely sensitive to rapid rises in temperature during hot water baths, which could precipitate a seizure.26,27,29,30 Although the phenotype of our affected members contains some similarities to HWE patients, such as ictal semiology, electrophysiologic, and SPECT data, there are some distinctive features. The most obvious one is the mode of inheritance, with clear evidence of recessive X-linked transEpilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

mission, as only male members developed epilepsy. Second, reflex bathing seizures usually occur in extremely young children and disappear in adolescence/adulthood unlike our affected family members. Third, the precipitant stimulus appears slightly different than in HWE. Indeed, although the contact of water is common to all subjects, the importance of water temperature varied from patient to patient. In some individuals, seizures could be triggered simply by wiping the face with a cold wet cloth or washing the hands with tepid water, whereas for others a large difference between room and water temperature seemed important in this probably complex seizure triggering system. Furthermore, the occurrence of four seizures induced by nail clipping in one of our patients also suggests that the somatosensory component of the stimulus may be more important than the thermosensory component. Fourth, unlike typical HWE patients, who have normal psychomotor development, our patients present a spectrum of neuropsychological abnormalities from dyslexia to pervasive developmental disorder. These differences may suggest that our patients have a syndrome distinct from typical HWE. The phenotype of our patients also differs from other previously reported cases of seizures triggered by water such as the case of HWE and McCune-Albright syndrome,31 the monozygotic twins with neonatal onset of hot water reflex seizures subsequently manifesting episodes of alternating hemiplegia,32 and finally the young girl with SCN1A mutation and severe myoclonic epilepsy, hemiconvulsion-hemiplegia syndrome, and also HWE.33 For the new syndrome described herein, we propose the label “X-focal epilepsy with reflex bathing seizures,” emphasizing the X-linked inheritance, the focal network activated, and the presence of reflex seizures occurring in the context of bathing. One reason that reflex seizures are useful in defining a characteristic phenotype is the infrequency with which it is reported. Developmental dyslexia and autism spectrum disorders All epileptic male family members exhibited neurodevelopmental disorders ranging from dyslexia or specific language impairments to pervasive developmental disorders. Female carriers with febrile seizures were less affected, as only one of the two had dyslexia. These findings are in line with previous work showing that mice lacking SYN1 show increased seizure propensity, learning deficits, and abnormal social behavior.34–37 Among synapsins, SYN1 is the most abundant and is highly expressed in the limbic system and neocortex. We speculate that abnormal development of temporoinsular cortices may be the common biologic mechanism underlying, at least in part, epilepsy and these neurodevelopmental disorders.

Conclusion In summary, we describe herein a large French-Canadian family presenting partial epilepsy and developmental

1107 Reflex Bathing Seizures dyslexia/autism spectrum disorder due to a Q555X mutation in the SYN1 gene on chromosome X. In these genetically susceptible patients, seizures can occur spontaneously but more frequently in the context of bathing/showering most likely by the activation of insular and temporal structures. Further investigations of the identified gene and its product will help elucidate how a genetic defect can produce abnormalities that differentially affect these structures, how an external stimulus can precipitate a brain from the interictal to the ictal state, and how it can impair high mental function such as language and social interaction.

Acknowledgments The authors wish to thank the patients and their families for their contribution to this study. Furthermore, the authors are grateful to H. Cossette, N. Levesque, J. Forand, S. Lebrun, and G. Imbeault for their help in the electroclinical recording of provoked seizures.

Funding The study is not industry sponsored.

Disclosure All authors report no disclosures. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Supporting Information Additional Supporting Information may be found in the online version of this article: Video S1. Video of a seizure triggered by rubbing the face with a wet towel (IV:4).

Epilepsia, 56(7):1098–1108, 2015 doi: 10.1111/epi.13042

Video S2. Video of A.B. (VII:1) having a seizure after stepping out of a shower.