Hot water epilepsy and SYN1 variants

Abstract

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 bodywere 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 10 1 and a family with a variant in SLC1A1 3 that was, however, present at a low frequency in the general population.

Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

“…Synapsin I is a phosphoprotein that coats the cytoplasmic side of SVs and plays multiple roles in the regulation of SV trafficking between the RP and the readily releasable pool (RRP) and in the facilitation of the post-docking steps of release 8 . Nonsense and missense mutations in the gene encoding SynI have been associated with epilepsy, autism spectrum disorder (ASD) and intellectual disability in humans [9][10][11][12] . SynI autoantibodies have been identified in serum and CSF from patients suffering of various neurological disorders, including limbic encephalitis, multiple sclerosis, epilepsy, anxiety, depressive and bipolar disorders, but not in healthy controls 13,14 .…”

Familial SYN1 Pathogenic Mutations Related Neurodevelopmental Disorders in Asian Pediatric Patients

“…Since Garcia CC et al rstly connected SYN1 mutation with neurodevelopmental disorder in 2004, 16 causative variants including ten missense mutations, ve nonsense mutations, and one splicing site mutation in the gene have been identi ed (containing this study) (Fig. 2) [1,2,[7][8][9][10][11][12][13][14][15][16]. These variants are clustered in B linker domain (A51G, S79W), actin-binding and synaptic-vesicle binding C-domain (W126X, W126R, c.527+1G>A, S212I, G240R, V266M, W356X, T359K, R420G) and proline-rich D-domain (R422X, Q482X, A550T, Q555X, T567A) of the encoded protein as indicated (Fig.…”

Assessment of Autism Zebrafish Mutant Models Using a High-Throughput Larval Phenotyping Platform

“…For both slc7a5 and syngap1b, we did not observe any strong mutational effects in non-PTZ treated larvae. For future studies, we will consider incorporating additional perturbations during motion tracking with known associations to enhanced behaviors and seizure phenotypes, such as heat (Warner et al, 2017;Peron et al, 2018) and startle (Tegelenbosch et al, 2012).…”