Abstracts

Rationale: Cnksr2 encodes for the protein CNKSR2 (Connector enhancer of kinase suppressor of Ras 2), which belongs to the CNK family of scaffold proteins. Among this family, CNKSR2 has the most selective brain expression. CNKSR2 mutations cause X-linked intellectual disability and an epilepsy-aphasia syndrome, which affects males more severely but may also manifest in females. Although several retrospective case series and case reports have described findings in males and females, there are not yet prospective data or systematic studies of the neuropsychological, electrographic, or imaging phenotypes of this disorder in the literature.


Methods: We are prospectively recruiting boys and girls with pathogenic CNKSR2 mutations and neurodevelopmental disorder to perform neuropsychological testing, overnight electroencephalogram (EEG), brain magnetic resonance imaging (MRI) with spectroscopy and functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) over a two-year period.


Results: We report study design and interim findings in 7 patients with CNKSR2 neurodevelopmental disorders, including gene mutations, results of a battery of neuropsychological testing, sleep-associated epileptiform activity, functional MRI, and MEG. We demonstrate a broad spectrum of neurological phenotypes, which encompasses autism spectrum disorder and global developmental delays, with or without epilepsy. In addition, we show correlations between spike-wave index and disruption of language networks in a subset of patients.


Conclusions: This natural history study is the first prospective assessment of children with CNKSR2 neurodevelopmental disorder and epilepsy-aphasia syndrome. The study will provide more detailed phenotypic characterization of this ultra-rare syndrome and establish a foundation for future clinical trials.


Funding: Preston-Werner Ventures