Published Studies and Papers
This ultra-rare disorder, caused by variations on the SZT2 gene, was first identified in mice by PhD. Wayne Frankel whose study was published in the paper "Szt2, a novel gene for seizure threshold in mice" in the "National Center for Biotechnology Information ", and "PMC" (2009).
In a chemical mutagenesis screen we identified Szt2 (seizure threshold 2) as a gene that confers low seizure threshold to mice and may also enhance epileptogenesis. The semidominant phenotype was mapped to Chromosome 4 and narrowed further to a critical interval of approximately 650 kb. A novel large (>10 kb) transcript in the critical interval was found to have four-fold increased steady-state expression at the RNA level in Szt2 homozygous mutant brain. The corresponding 72 exon gene encodes a 378 kD protein with no significant or suggestive sequence similarities to any other protein. The mutant allele of Szt2 contains a splice donor mutation after exon 32, predicting transcriptional read-through, translational frameshift and premature stop. A second Szt2 allele, containing a gene-trap mutation in exon 21, also conferred a low seizure threshold and increased RNA expression, but unlike the ENU allele, some gene-trap homozygotes died embryonically. Szt2 is transcribed in many tissues, with the highest expression in brain, and it is also expressed during embryonic development. Szt2 is highly conserved in evolution, with a clear, single orthologue found in all land vertebrates and in many invertebrates. Interestingly, in mammals the Szt2 gene resides in a highly conserved head-to-head configuration with Med8 (which encodes a Mediator complex subunit), separated by only 91 nt. While the biological function of Szt2 remains unknown, its high conservation, unique structure and effect on seizure threshold suggest that it serves an important role in the central nervous system.
Seizure threshold defines a theoretical “set-point” below which a stimulus may produce a seizure. Mouse mutants with spontaneous epilepsy also often have a low seizure threshold, for example, as assessed by sensitivity to pentylenetetrazole (PTZ), the non-competitive GABAA receptor antagonist – suggesting that seizure threshold is a natural component of genetic susceptibility to epilepsy. Still, until we learn more about the genetic variants that cause common epilepsies and study them in animal models, the distinction, if any, between seizure threshold and susceptibility per se is likely to remain blurry. There indeed may not be a unitary relationship between the two. For example, in a prior assessment of electroconvulsive threshold in various inbred mouse strains, it was determined that the threshold of the spontaneously epileptic SWXL4 strain is at the midpoint of the distribution, with a number of non-epileptic inbred strains having a lower seizure threshold than SWXL-4 (Frankel et al., 2001). In contrast, even single-gene mutants on a strain background with a high seizure threshold (e.g. C57BL/6J) can be spontaneously epileptic (Yang et al., 2007). Nevertheless, other epileptic strains such as PL/J do have very low seizure thresholds (Kitami et al., 2004). Together these results suggest that the relationship between threshold per se and epilepsy is not straightforward, and depends heavily upon the overall genetic context.
We previously examined the electroconvulsive thresholds of inbred strains as a framework for ENU mutagenesis forward genetics screens (Frankel et al., 2001). Three novel low seizure threshold mutations obtained from our screen occurred in the Kcnq2 gene (see Frankel, Kearney et al., 2006, Yang et al., 2003), whose human orthologue is mutated in Benign Neonatal Familial Convulsions, a form of human epilepsy (Singh et al., 1998). These mutations lowered the median electroconvulsive threshold by 1.5 mA, placing the Kcnq2 mutants approximately in the middle of the seizure threshold profile of inbred strains. Here we introduce Szt2 as a novel seizure threshold gene. The encoded protein is highly conserved in evolution – with clear orthologues in vertebrates and some invertebrates - but no structural similarities to known proteins. In addition to having a low acute seizure threshold, Szt2 mutant mice also kindle more readily than controls, making Szt2 a potentially interesting candidate gene for seizure susceptibility.
Frankel WN, Yang Y, Mahaffey CL, Beyer BJ, O'Brien TP. Szt2, a novel gene for seizure threshold in mice. Genes Brain Behav. 2009 [PMC free article]
The following publication cites one of our children, and was published in 2016 by PhD. Charu Venkatesan:
Illustration: MRI of the patient at different time points. (A) MRI performed at 2 months of age showing Rathke's cleft cyst (arrow) and asymmetric hemisphere size (left cerebrum smaller than right). (B) MRI performed at 11 months of age showing linear, radially-oriented T2 hyperintensities within the white matter with unclear significance (arrows). (C, D) MRI performed at 2 years of age shows right periventricular heterotopia (arrow in C) and abnormal perisylvian gyral configuration (C and arrow in D).