Clinical spectrum of STX1B -related epileptic disorders

Abstract

Objective The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B , encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. Methods We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results We describe 17 new variants in STX1B , which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion These data expand the genetic and phenotypic spectrum of STX1B -related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A , the most important gene associated with fever-associated epilepsies.

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

“…We have described the first case of Koolen‐de Vries syndrome caused by a KANSL1 missense mutation (Case 1); all prior cases of Koolen‐de Vries have been caused by either heterozygous deletions or truncation variants . We have also corroborated some of the most recent findings about the multiple phenotypic presentation of STX1B‐related epilepsies . Case 8 is a 44‐year‐old woman with mild ID and cerebellar ataxia who has had focal impaired awareness seizures and temporal epileptiform abnormalities on electroencephalogram (EEG).…”

“…Typically, epilepsy syndromes related to STX1B are either genetic epilepsy with febrile seizures plus or developmental and epileptic encephalopathy. Whereas cerebellar ataxia (present in our patient) has been commonly reported, only two families harboring missense variants have had clinical and EEG findings suggesting temporal lobe onset …”

“…27 We have also corroborated some of the most recent findings about the multiple phenotypic presentation of STX1B-related epilepsies. 28 Case 8 is a 44-year-old woman with mild ID and cerebellar ataxia who has had focal impaired awareness seizures and temporal epileptiform abnormalities on electroencephalogram (EEG). She was found to have an STX1B deletion, and loss of function variants are known to be pathogenic.…”

“…Whereas cerebellar ataxia (present in our patient) has been commonly reported, only two families harboring missense variants have had clinical and EEG findings suggesting temporal lobe onset. 28 Although a genetic diagnosis can end the diagnostic odyssey and need for ongoing investigation, a change in diagnosis may bring about different psychological reactions. Some individuals and/or caregivers will feel relieved and reassured if they had doubts about the initial diagnosis; however, others may have difficulty adjusting if they have developed an identity around the initial diagnosis.…”

Mapping Functional Protein Neighborhoods in the Mouse Brain

“…We also found a network comprising proteins involved in synaptic vesicle release and the guanine nucleotide binding protein GNAO1 ( Figure 7 ), a highly abundant protein in the brain, mutations in which cause severe epilepsy (Nakamura et al, 2013) or movement disorders (Kulkarni et al, 2016) . The mechanistic basis of GNAO1 epilepsy is unknown, but our network suggests that it is caused by disruption of chemical signaling, an inference made stronger by the fact that the other interaction partners, the t-SNAREs syntaxin 1A and B, and Ras-related protein 3A are also implicated in epilepsy (Baghel et al, 2016;Feliciano et al, 2013;Wolking et al, 2019) . Pourhaghighi et al 2019 also found an association between GNAO1 and SNAREs (their Figures 2 and 3), though, interestingly, not the same SNARE proteins, and they do not flag GNAO1 as a disease-related protein (their Figure 3).…”