Hot water epilepsy and SYN1 variants

DOI: 10.1111/epi.14572 GRAY MATTERS Letter Hot water epilepsy and SYN1 variants To the Editors: We read with great interest the article “X‐Linked Focal Epilepsy With Reflex Bathing Seizures: Characterization of a Distinct Epileptic Syndrome” by Nguyen et al.1 The authors described several males from a large family with focal reflex seizures triggered by contact with water, learning disabilities and/or autism, and a nonsense pathogenic variant in SYN1 (Xp11.3‐p11.2). We had previously characterized the electroclinical manifestations of a family affected by childhood onset hot water epilepsy (HWE), subsequently followed by nonreflex seizures.2 The proband presented with focal seizures during contact with water at age 8 years. The episodes—occurring especially after hot water had been poured on his body— were characterized by a sensation of rising heat, dystonic posture of unilateral limbs, and cyanosis of the lips, followed by oral automatisms and inability to speak. Ictal electroencephalography (EEG) was characterized by bilateral rhythmic theta activity over the frontocentral and vertex regions. Three years after seizure onset, he exhibited nonreflex seizures consisting of a tingling ascending sensation starting from the lower limbs. His maternal uncle showed the same epileptic phenotype. Despite normal but below average intelligence quotient (80), the proband showed learning disability involving reading, writing, and calculation, and his maternal uncle exhibited mild intellectual disability (ID). We recently performed whole exome sequencing (WES) in this family and identified a splice‐site pathogenic variant in SYN1 (NM_133499.2: c.527+1G>T). This variant segregates with the disease (present in proband, mother, and maternal uncle, absent in father; Figure 1) and is absent from the ExAc browser, ClinVar, and 1000 Genomes. Analysis of the splice donor mutation (GCGgtgagt to GCGttgagt) using the Human Splice Finder tool (http://www.umd.be/HSF3/, PMID 1933 9519) revealed a significant decrease in donor site score from 92% to 66% (position weight matrix algorithm) and the potential preference of a cryptic donor site five nucleotides upstream (GTCgtgcgt), thus leading to a shift in the reading frame. Prior testing of SCN1A produced normal results,2 and WES did not identify other pathogenic or likely pathogenic variants affecting genes that have been previously associated with epilepsy/seizures in humans or mice. The pathogenesis of reflex seizures caused by contact with water is largely unknown, with proposed loci on chromosomes 4 and 101 and a family with a variant in SLC1A13 that was, however, present at a low frequency in the general population. 2162 | Wiley Periodicals, Inc. © 2018 International League Against Epilepsy The male:female ratio of 2.5:1 supports the findings by Nguyen et al1 and ours in favor of the hypothesis that HWE is caused by an X‐linked gene—such as SYN1—in a significant proportion of individuals. Although bathing seizures and HWE have been considered different entities by some authors in the past, the similar ictal semiology and EEG in individuals with the same genetic cause, despite the slight difference in the trigger (hot vs cold water), suggest that these conditions are part of the same spectrum. Clonic or generalized seizures may occur after a bath also in patients with Dravet syndrome at epilepsy onset, and one may think of SCN1A as a possible candidate gene, as we did when testing this gene first. However, the epileptic phenotype of patients with Dravet syndrome is usually characterized by more complex features such as prolonged uni‐ or bilateral convulsive febrile seizures, followed by afebrile seizures and slowing of psychomotor development.4 The update on our family demonstrates that additional pathogenic variants in SYN1 cause seizures triggered by contact with water, and we strongly agree with Nguyen et al1 that this is a distinctive epileptic syndrome. Based on the nine patients with extensive and reliable evaluation described thus far,1,5 the phenotype can thus be described as follows: 1. Focal onset reflex seizures triggered by contact with water with onset in the first 2 decades of life represent the core phenotype, with or without ID/learning disability and intrafamilial variability; 2. Nonreflex seizures follow the initial presentation in 16%-38% of individuals,1 with good response to antiepileptic treatment, and self-induced seizures are not uncommon; and 3. Ictal EEG is characterized by rhythmic theta activity over the frontocentral/temporal regions. By review of the literature, we also noticed that truncating mutations are associated with reflex seizures triggered by contact with water,1,5 whereas the majority of patients affected by only neurodevelopmental diseases (autism/behavioral problems/ID) have missense variants. Therefore, we infer that different types of mutations cause different phenotypes, with truncating variants having an effect on firing/ bursting activity, as suggested by functional studies.6,7 In conclusion, our update expands the phenotype of SYN1‐related disorders, which represent a unique and recognizable condition. Epilepsy triggered by contact with wileyonlinelibrary.com/journal/epi Epilepsia. 2018;59:2162–2165. | GRAY MATTERS 2163 F I G U R E 1 Pedigree of the family showing an X‐linked inheritance pattern. Black squares denote affected males; dotted circles indicate unaffected female carriers. wt, wild type. The pathogenic variant is reported in parentheses below the family members who were tested; males are hemizygous, and females are heterozygous for the variant. Individual I‐4 is an obligate carrier and presumed to harbor the heterozygous variant, although she was not directly tested (modified from Vignoli et al2) water is a new and exciting area of research, and we encourage colleagues to test patients with this distinctive phenotype for SYN1 mutations, to clarify the hypotheses raised by our commentary. ACKNOWLEDGMENTS The authors would like to thank the family for their kind collaboration. 2 Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, Utah 3 Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada Correspondence Angela Peron, Centro Epilessia, Ospedale San Paolo, Dipartimento di Scienze della Salute, Milano, Italy. Email: [email protected]. DISCLOSURE The authors have no conflicts of interest to report. 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. Keywords bathing seizures, hot water epilepsy, reflex seizures, SYN1, synapsins ORCID Angela Peron http://orcid.org/0000-0002-1769-6548 Angela Peron1,2 Nissan V. Baratang3 Maria Paola Canevini1 Philippe M. Campeau3 Aglaia Vignoli1 1 Child Neuropsychiatric Unit, Epilepsy Center, San Paolo Hospital, Department of Health Sciences, University of Milan, Milan, Italy REFERENCES 1. Nguyen DK, Rouleau I, Sénéchal G, et al. X‐linked focal epilepsy with reflex bathing seizures: characterization of a distinct epileptic syndrome. Epilepsia. 2015;56:1098–108. 2. Vignoli A, Savini MN, La Briola F, et al. Hot water epilepsy: a video case of European boy with positive family history and subsequent non‐reflex epilepsy. Epileptic Disord. 2014;16:96–100. 3. Karan KR, Satishchandra P, Sinha S, et al. Rare SLC1A1 variants in hot water epilepsy. Hum Genet. 2017;136:693–703. 4. Dravet C, Bureau M, Oguni H, et al. Dravet syndrome (severe myoclonic epilepsy in infancy). In: Bureau M, Genton P, Dravet C, et al, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5th ed. Montrouge, France: John Libbey Eurotext Ltd, 2012. 5. Garcia CC, Blair HJ, Seager M, et al. Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J Med Genet. 2004;41:183–6. 6. Lignani G, Raimondi A, Ferrea E, et al. Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short‐ term plasticity. Hum Mol Genet. 2013;22:2186–99. 7. Guarnieri FC, Pozzi D, Raimondi A, et al. A novel SYN1 missense mutation in non‐syndromic X‐linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility. Hum Mol Genet. 2017;26:4699–714.