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. 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. 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, 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 10 and a family with a variant in SLC1A1 that was, however, present at a low frequency in the general population. The male:female ratio of 2.5:1 supports the findings by Nguyen et al 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. 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 al that this is a distinctive epileptic syndrome. Based on the nine patients with extensive and reliable evaluation described thus far, the phenotype can thus be described as follows: