Research Explained: Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures

Authors: Mitsuko Nakashima, Jun Tohyama, Eiji Nakagawa, Yoshihiro Watanabe, Ch’ng Gaik Siew, Chieng Siik Kwong, Kaori Yamoto, Takuya Hiraide, Tokiko Fukuda, Tadashi Kaname, Kazuhiko Nakabayashi, Kenichiro Hata, Tsutomu Ogata, Hirotomo Saitsu, Naomichi Matsumoto.

Publication Date: January 17, 2019

Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern

Link to article: https://www.nature.com/articles/s10038-018-0559-z

Research Explained Summary:

This case report describes four patients with neurodevelopmental disorders, united by their recurrent seizures. Two of these patients were confirmed to have OCNDS, while the other two have Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS). These disorders are caused by mutations in the CSNK2A1 (OCNDS) and CSNK2B (POBINDS) genes, which encode the proteins CK2α and CK2β. Genes are the molecular blueprint for proteins, which perform functions required for life. These proteins bind to each other and create a larger complex of proteins known simply as CK2. CK2 is an enzyme, meaning that it facilitates chemical reactions in a cell, potentially affecting many other proteins – CK2α performs these chemical reactions, while CK2β helps regulate the function of CK2 overall. The authors describe these patients in depth and review previously published cases to draw conclusions about what unites and separates these two diseases. Here, we will focus on their description of the patients with OCNDS. 

The two patients with OCNDS had global developmental delay, muscle weakness (hypotonia), and seizures. However, their other symptoms were overall different. One patient had aberrant facial and brain structures, short stature, and progressive muscle weakness that eventually led to respiratory failure. Afterwards, this patient always required a ventilator and a wheelchair. The second patient had more frequent seizures that lead to brain death at 1 year and 7 months of age, even though they had no obvious facial or brain structural issues like the first patient. These patients were found to have two different mutations in the CSNK2A1 gene. The differences in symptoms between these patients may be in part due to these different mutations, although most symptoms of OCNDS do not correlate well with any specific mutation patients have displayed. The first patient had the most common OCNDS mutation currently known, termed “p.K198R”, whereas the second patient with severe seizures had a mutation known as “p.R191*.”

When comparing these patients with previously published reports of OCNDS, every OCNDS patient was found to have developmental delay (28/28), while many had intellectual disabilities (26/28) and hypotonia (muscle weakness – 20/28). These traits were often, but not always, accompanied by issues moving, autistic traits, sleep problems, short stature, gastrointestinal issues, cardiac abnormalities, and seizures, among other symptoms. To date, the condition of the second patient with recurrent seizures who passed away at the age of 1 year and 7 months is the most severe OCNDS case reported, although both patients experienced severe symptoms.