Understanding
Okur-Chung Neurodevelopmental Syndrome
Research Explained
Clinical Phenotyping and Case Reports (24)
Authors: Drenushe Zhuri, Fulya Dusenkalkan, Guzin Tunca Alparslan, Hakan Gurkan Written By: Tierney Baum, PhD, Strategic R&D Consultant Link to publication: https://pmc.ncbi.nlm.nih.gov/articles/PMC10862324/ Most OCNDS patients are reported to have either a missense or nonsense variant in their CSNK2A1 gene. In 2023 a research group from Trakya University reported a patient with a novel CSNK2A1 mutation. At the time of publication this was the first reported frameshift variant reported in an OCNDS patient.
Authors: Swetha Ramadesikan, Iftekhar A. Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A. Varga, Umamaheswaran Gurusamy, Matthew T. Pastore, Emily R. Sites, Murugu Manickam, Dennis W. Bartholomew, Jesse M. Hunter, Peter White, Richard K. Wilson, Rolf W. Stottmann, Daniel C. Koboldt Research Explained By: Tierney Baum, PhD, Strategic R&D Consultant Link to Publication: https://linkinghub.elsevier.com/retrieve/pii/S2666-2477(24)00119-2 Research Explained Summary: Microcephaly, or smaller head size, has been reported in patients with OCNDS, but at the time of writing this publication microcephaly was not currently listed in the overall clinical spectrum of symptoms for OCNDS in the Online Mendelian Inheritance in Man database (OMIM). OMIM is a comprehensive collection of human genes and their associated genetic phenotypes (traits). Researchers in this study describe four individuals with OCNDS as well as an analysis of symptoms that are present in patients presented in existing OCNDS publications. They found that individuals with OCNDS, on average, have a smaller head circumference. The study also concluded that ~1/3rd of OCNDS individuals have full microcephaly. Strikingly, study investigators also found that microcephaly was associated with specific patient variants in the CSNK2A1 gene that affect different parts of the protein made by CSNK2A1, called CK2. 36% of individuals with variants in the kinase domain of CK2 (amino acids 39-324 representing approximately 75% of the protein) presented with microcephaly compared to only 14% of individuals with variants in other domains of the protein. The kinase domain of the CK2 protein is essential for activating the protein; dysfunction of this domain often results in fewer functioning CK2 proteins in the cell. Furthermore, a section of the kinase domain, called the ATP/GTP loop (also known as the Gly-rich loop), is critical for this activation because it is where the molecule that stores and releases energy for cells binds. Researchers found that up to 62% of patients with variants in this segment of CK2 (amino acids 49-53) had microcephaly. The two main conclusions of this paper were: Microcephaly is relatively common in OCNDS patients and should be included in the clinical list of symptoms. Microcephaly significantly correlates with the location of the CSNK2A1 variant. Researchers suggest further studies are needed to investigate if there are other connections between patient symptom profiles and their specific variant. This study is a step forward in understanding how patient variants may affect symptom presentation in children with OCNDS.
Authors: Newell Belnap, Aiai Price-Smith, Keri Ramsey, Kamawela Leka, Anna Abraham, Emma Lieberman, Katie Hassett, Sai Potu, Natasha Rudy, Kirstin Smith, Fady M. Mikhail, Kirstin G. Monaghan, Andrea Hendershot, Jeroen Mourmans, Maria Descartes, Matthew J. Huentelman, Jennifer Sills, Sampath Rangasamy, Vinodh Narayanan Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to Paper: https://onlinelibrary.wiley.com/doi/10.1111/cge.14408 Research Explained Summary: In this study, researchers profiled and compared OCNDS symptoms present within and across three families. This report is the first study of families with OCNDS inherited by children from their parents, instead of the more common inheritance pattern where the OCNDS genetic variant is new and only is present in the child. This report also confirms that both men and women with OCNDS are fertile. When comparing each of these families, there was a striking difference in the symptoms experienced by each parent and child, even though the OCNDS genetic variant is the same. For example, two half-sisters (individuals that share only one parent) in a family with OCNDS experienced vastly different effects with one displaying behavioral issues, musculoskeletal problems, growth irregularities, and difficulty feeding among other symptoms that were present but much less severe in their half-sister. When comparing across families, symptoms were even more divergent, despite two families having the same disease-causing DNA variant. Although both families displayed the p.Lys198Arg (K198R) variant in the CSNK2A1 gene, the most common disease-causing variant found in OCNDS patients, one of the families had multiple cases of generalized muscle weakness (hypotonia), while the other instead experienced behavioral issues. Together, this report shows that OCNDS symptoms vary greatly even within individuals with the same genetic changes causing OCNDS. These symptoms also varied within families, indicating that it is unlikely that researchers will be able to correlate specific OCNDS-causing DNA variants with specific symptoms. More generally, these findings indicate that there may be many people with undiagnosed OCNDS throughout the world due to the varying severity of symptoms and therefore varying diagnosis/treatment needs.
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.
Authors: Davide Colavito, Elda Del Giudice, Chiara Ceccato, Maurizio Dalle-Carbonare, Alberta Leon, Agnese Suppiei Publication Date: March 22, 2018 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/s10038-018-0434-y Research Explained Summary: This article reports on a patient with OCNDS whose first presentation was isolated retinal dystrophy, or progressive dysfunction of the retina and therefore, vision. This is the first instance where vision problems were the primary symptom that brought the patient into the clinic and resulted in an OCNDS diagnosis. At birth, the patient showed no evidence of any disabilities that might have indicated OCNDS or other disorders. However, at four months of age, the patient was admitted to a hospital for suspected low vision and infantile nystagmus, a condition where the patient’s eyes rapidly and involuntarily shake in a horizontal or vertical direction. After doctors examined the individual, a diagnosis of isolated Leber’s congenital amaurosis was reached, which is a family of conditions that include varying degrees of severe vision loss at an early age. The doctors also initiated genetic testing to determine the cause, as this disease is primarily a genetic disorder. By 10 months of age, the patient was displaying symptoms more typical of OCNDS, including poor muscle tone (hypotonia), poor muscle control (ataxia), sleep disturbances, and general failure to reach psychological and motor milestones expected for normal development. Genetic results showed a c.1061-1G>C mutation in CSNK2A1, the gene whose mutation causes OCNDS. This was the first report of an OCNDS patient with retinal dystrophy. This case report highlights that ocular/retinal symptoms of OCNDs should be monitored and might be more common than previously thought.
Authors: H L Duan, J Peng, N Pang, S M Chen, J Xiong, S Q Guang, F Yin Publication Date: May 2019 Link to article: https://pubmed.ncbi.nlm.nih.gov/31060130/ Research Explained Summary: This publication is a case report of an individual with OCNDS that has the c.524A>G (p.D175G) variant in the CSNK2A1 gene and is the first report of OCNDS in the mainland of China. The patient was a 1 year and 8-month-old boy with symptoms that included microcephalus (small head), broad nasal bridge, micrognathia (small lower jaw), and hypotonia. The authors then summarized the clinical findings of OCNDS at the time of publication, which included mostly individuals with missense changes (a genetic alteration that occurs when a single base pair in DNA is substituted, resulting in a different amino acid being incorporated into a protein) in the CSNK2A1 gene, with the K198R change being the most common.
Authors: Ruohao Wu, Wenting Tang, Liyang Liang, Xiaojuan Li, Nengtai Ouyang, Zhe Meng Publication Date: June 10, 2020 Link to article: https://rs.yiigle.com/cmaid/1202672 Research Explained Summary: This publication is a case study on an individual with OCNDS that has the c.149A>G (p. Tyr50Cys) variant in the CSNK2A1 gene. At the time of publication, this variant had not yet been reported. Research showed that this specific part of the gene has been highly conserved across species and that this DNA change was predicted change of the original spatial structure of CK2α protein and the loss of the original protein function.
Authors: Priya Ranganath, Prajnya Ranganath, V S Vineeth, Ashwin Dalal, Siddaramappa J Patil Publication Date: 2021 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Link to article: https://irp.cdn-website.com/5b9bc46f/files/uploaded/report_of_an_asian_indian_patient_with_okur_chung.12.pdf Research Explained Summary: This publication is a case report of a 6-year-old female with OCNDS that is of Asian-Indian origin. She presented with symptoms not previously reported for individuals with the p.Arg47Gln (R47Q) variant in the CSNK2A1 gene including a frontal upsweep with unusual patterning of scalp hairs, breath-holding spells, and talipes equinovarus (club foot). The authors noted that 3 other individuals with the same genetic variant also had facial dysmorphology including hypertelorism (abnormally increased distance between the eyes), arched eyebrows, low-set ears, and retrognathia (abnormal posterior positioning of the jaw). By publishing this report, the authors expanded knowledge about the symptom presentation across different ethnicities and helps define the presentation of individuals with the specific R47Q variant.
Authors: Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey Publication Date: December 14, 2023 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Link to Paper: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0292664 Research Explained Summary: The authors sequenced the DNA of individuals who had a rare disorder called Pituitary stalk interruption syndrome (PSIS), a condition that affects the pituitary gland, a crucial organ in the brain that regulates various hormones. They wanted to learn more about the potential genetic causes of PSIS. In individuals with PSIS, the pituitary stalk, a structure connecting the brain to the pituitary gland, is abnormally formed or absent. This disruption leads to hormonal deficiencies, including growth hormone (GH) deficiency, impacting growth, reproduction, and other bodily functions. Diagnosis often involves imaging studies, and management typically requires lifelong hormone replacement therapy to address the hormonal imbalances caused by the syndrome. The results of sequencing identified a single patient with Okur-Chung Neurodevelopmental Syndrome (OCNDS), harboring the most common CSNK2A1 missense variant, K198R. The child had the typical clinical phenotype of OCNDS including hypotonia, autism, and delay in the ability to walk. Major conclusions from this publication include the suggestion that obtaining a genetic diagnosis in cases of isolated PSIS will remain challenging and that PSIS is a disorder that should be considered when analyzing the full phenotypic spectrum of OCNDs in future studies.
Authors: Hossein Jafari Khamirani, Sina Zoghi, Ali Motealleh, Mehdi Dianatpour, Seyed Mohammad Bagher Tabei, Sanaz Mohammadi, Seyed Alireza Dastgheib Publication Date: March 31, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801326/ Research Explained Summary: This case report presents an OCNDS patient who displayed regular seizures, an atypical characteristic for those with OCNDS. The patient presented to the clinic at age 8 due to cognitive, motor, and language developmental delays. At this time, the parents reported severe sleep issues and several episodeclinics of two different forms of seizures, known as myotonic and atonic. These seizures manifest differently: myotonic seizures are characterized by twitching and jerking of the arms and legs, whereas atonic seizures are characterized by a loss of muscle control and/or tension. Other OCNDS symptoms included behavioral issues, autism spectrum disorder, short stature, and muscle weakness (hypotonia). She also displayed poor dental development, although this had not yet been associated with OCNDS. Previously, the patient had been diagnosed with a urea cycle disorder, which causes toxic substances normally excreted through urination to build up in the bloodstream. As a result of this, genetic testing was performed revealing a mutation in the CSNK2A1 gene causative of OCNDS. When later tested again to confirm the urea cycle disorder, the test came back normal. She was being treated for this disorder but discontinued the treatment upon this finding. The authors also reviewed all 33 previously reported OCNDS cases, ranking the relevance of specific symptoms. Developmental delay was reported in all cases, although with great variability in severity. Most patients displayed speech delays, intellectual disability, and dysmorphic facial features. Only 9/31 patients included in this portion of the review were determined to have had seizures, and this patient is the only to have been reported to have two different kinds of seizures. This report displays the great variability present between OCNDS patients.
Authors: Ruo-Hao Wu, Wen-ting Tang, Kun-yin Qiu, Xiao-juan Li, Dan-xia Tang, Zhe Meng, Zhan-wen He Publication Date: May 26, 2021 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161887/ Research Explained Summary: This case report profiles two new OCNDS patients, then expands to broadly review the literature of all reported OCNDS patients to identify potential correlations between each patient’s specific genetic mutations and any symptoms they experience. The first patient arrived at the clinic at age 3 with severe growth retardation and recurrent febrile seizures . Her development in terms of movement and speaking occurred at a normal pace, but she had her first febrile seizure at nine months of age, experiencing a total of five episodes. All the seizures went away on their own and didn’t require treatment. During her initial consultation, other reported abnormalities included a smaller than usual pituitary gland (a gland which regulates most hormones in the body), and mild immunodeficiency. The second patient arrived at the clinic at age 2, also with major growth delay. This patient’s developmental milestones were severely delayed – she could not yet sit, stand, or speak. However, unlike the first patient, she had a perfectly functioning immune system. Genetic testing was performed on both patients, finding mutations in the CSNK2A1 gene. Each patient had a different mutation, with the first patient having p.H160R, while the second had p.R80C. Both mutations were predicted to be the major cause of their symptoms. A full search of the OCNDS literature revealed 35 patients with detailed workups. The authors tried to link specific mutations found in CSNK2A1 to specific manifestations of OCNDS. The only connection they were able to find was mutations in a specific domain of the CSNK2A1 gene known as the “ATP/GTP binding-loop" were more likely to lead to multi-organ abnormalities, although these symptoms weren’t necessarily more severe. This study further illustrates the wide variety of manifestations of OCNDS and confirms the lack of a strong correlation between what mutation a patient has with their symptoms.
Authors: Shanshan Xu, Jinzhun Wu, Lingli Lu, and Jia Song. Publication Date: August 3, 2020 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-01096-w Research Explained Summary: This case report describes the co-occurrence of two genetic diseases in one patient, including both OCNDS and tricho-rhino-phalangeal syndrome (TRPS). It also follows the clinical analysis of both parents of the patient to determine the origins of these two rare diseases. The patient first presented to a pediatric endocrinology clinic at almost 7 years old with short stature and developmental delay. Upon presentation, he displayed sparse scalp hair, short stature, and severe intellectual disability, although many blood tests for various physiological variables were normal otherwise. Prior to this, he suffered from developmental delays including walking for the first time and speaking at 4 years of age. He started school at 6 years old but couldn’t communicate with the other children. Genetic testing revealed two mutations that could be disease causing, one in the CSNK2A1 gene (the K198R mutation, the most common in OCNDS), and the TRPS1 gene. The patient’s father has a mild intellectual disability and short stature. Upon genetic testing, the father was found to have the same CSNK2A1 gene mutation as the patient, indicating that the patient inherited it from his father. His mother has sparse scalp hair, short stature, and facial features characteristic of TRPS. Via genetic testing, the mother was found to have the same mutation as the patient in the TRPS1 gene, indicating that the patient inherited TRPS from his mother. Both TRPS and OCNDS present variably in individual patients, although both diseases are characterized by short stature – the patient described herein was extremely short, likely due to a combination of both diseases. This report is the first to describe OCNDS coinciding with another rare disease.
Authors: Moe Akahira-Azuma, Yoshinori Tsurusaki, Yumi Enomoto, Jun Mitsui, Kenji Kurosawa Publication Date: March 29, 2018 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/hgv201811 Research Explained Summary: This case report described a Japanese male OCNDS patient conceived through in vitro fertilization (IVF) with distinctive features separating them from previously described patients, including specific facial features, a friendly and interactive disposition, and macrocephaly (brain/head larger than is typical). This patient was referred to a clinic at 2 years and 10 months of age for a genetic evaluation. At this time, he was nonverbal and was not walking without support. However, he started walking without support at 3 years old, and said his first meaningful words at the age of 6 years. He started school at 7 years old, which rapidly improved his speech to the point where he could answer simple questions but not express complex thoughts. Genetic testing was performed, and a mutation (specifically c.593A>G or p.K198R) in the CSNK2A1 gene was found, causative of OCNDS. The authors compared their patient’s specific symptoms with those found in other neurodevelopmental disorders further indicating the variety of symptoms OCNDS patients might display also appear in other disorders. Pop-up definition: In vitro fertilization (IVF) is a medical procedure that helps some people have babies when they have difficulty doing so naturally. Instead of the baby forming inside the mother's body, like in a natural pregnancy, IVF happens outside the body. [BC1] Here's how it works: Eggs are taken from a woman's ovaries and sperm from a man, and they are combined in a lab dish. When the egg and sperm meet and create an embryo, the doctors put that embryo back into the woman's uterus. If everything goes well, the embryo can grow into a baby inside the mother, just like a regular pregnancy.
Authors: Ceris I. Owen, Ramsay Bowden, Michael J. Parker, Jo Patterson, Joan Patterson, Sue Price, Ajoy Sarkar, Bruce Castle, Charulatha Deshpande, Miranda Splitt, Neeti Ghali, John Dean, Andrew J. Green, Charlene Crosby, Deciphering Developmental Disorders Study, and Katrina Tatton-Brown. Publication Date: December 16th, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38610 Research Explained Summary: Patients with a developmental disorder identified by the Deciphering Developmental Disorders Study at the Wellcome Trust Sanger Institute were genetically sequenced, and 11 were identified to have mutations in the CSNK2A1 gene, causative of OCNDS. Eight distinct mutations were found in these 11 patients, which were not found in the general population, the rest of their developmental disorder cohort, or the parents of the individual children. This indicates that these mutations are de novo, meaning that these mutations weren’t inherited from the child’s parents, but instead occur only in the children. Clinical features were analyzed, with the most frequently reported being intellectual disability at varying levels. Overall, the average amount of time it took for patients to start sitting without help, walking, or speaking were 11.5 months, 30.5 months, and 44 months respectively, which is significantly delayed from typical development. Other commonly observed manifestations included muscle weakness (hypotonia), behavioral issues, swallowing difficulties, short stature, small head/brain size (microcephaly) and heart defects. Although previous studies have reported characteristic facial features, this study indicated that while there were some recurrent features, these were not significantly indicative of OCNDS. Together with previous work, this study increases both the number of known OCNDS cases and validates symptoms found in previous cohorts and individuals. Particularly, this study indicates that cardiac dysfunction should be evaluated in OCNDS patients, a trait which hadn’t been seen before, further highlighting the differences across individuals with OCNDS.
Authors: A. T. G Chiu, S. L. C. Pei, C. C. Y. Mak, G. K. C. Leung, M. H. C. Yu, S. L. Lee, M. Vreeburg, R. Pfundt, I. van der Burgt, T. Kleefstra, T. M. T. Frederic, S. Nambot, L. Faivre, A. L. Bruel, M. Rossi, B. Isidor, S. Küry, B. Cogne, T. Besnard, M. Willems, M. R. F. Reijnders, and B. H. Y. Chung Publication Date: December 10th, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://onlinelibrary.wiley.com/doi/10.1111/cge.13196 Research Explained Summary: In this case series, eight new patients with OCNDS were identified. The authors analyzed the symptoms present in these patients and combined their analysis with that of six previously characterized patients to create a better summary of what defines OCNDS. Specifically, 13/14 patients displayed intellectual disability. However, one patient entered school and their performance was assessed to be above average. Autism, sleep disorders, excessive temper tantrums, muscle weakness (hypotonia), and physical brain abnormalities were the most common neurodevelopmental symptoms found. Other common traits included failure to thrive , short stature, skin abnormalities, gastrointestinal issues, and immunological issues. In terms of characteristic facial features, microcephaly (small brain/head) was very common with 8/14 patients displaying this, while other features such as a round face, broad nose, and low-set ears were reported but were less common. The genetic mutations present in OCNDS were also evaluated, including a total of 22 subjects across 4 studies reported to the date of publication of this paper. All mutations causing OCNDS were found in the CSNK2A1 gene, with most of them in an area of the gene that translates to a region known as the “protein kinase domain” of the protein that CSNK2A1 encodes, CK2α. Only two mutations found in these 22 patients fall outside of this specific region, indicating its importance for both proper function of the gene and overall human development. The most common mutation found among this cohort is called p.K198R and it is within this region. Together, this study reported 8 new patients diagnosed with OCNDS and performed an analysis of all symptoms and genetic mutations found to date. The authors recommend that patients with OCNDS be seen by a clinical geneticist and receive comprehensive assessment from a multidisciplinary team including physiotherapists, occupational therapists, speech therapists, and clinical psychologists. Pop-up definition: Failure to thrive (FTT) is a term used in healthcare to describe a condition in which a child, typically an infant or young child, is not growing or developing as expected for their age. [BC1]
Authors: Neil R. Ming, Deanna Noble, Steven Chussid, Alban Ziegler, Wendy K. Chung Publication Date: July 4, 2023 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Research Explained Summary: This study surveyed a wide variety of patients with neurodevelopmental disorders through an online questionnaire through Simons Searchlight, a natural history study supported by the Simons Foundation. The study records data from medical records and captures caregiver responses about patients with neurodevelopmental disorders, including OCNDS. Oral health is an important area of study, as many individuals with neurodevelopmental disorders have poor oral hygiene and broader dental abnormalities. 620 caregiver responses to the survey were recorded across 39 genetic neurodevelopmental disorders, with most surveys completed on behalf of children. 145 siblings of these patients without neurodevelopmental disorders served as a group to compare any findings against. Overall, the patients with neurodevelopmental disorders were found to display increased drooling, difficulty receiving dental care, late arrival of baby teeth, and abnormal growth of both baby and permanent teeth. Among the 39 genetic disorders tested, only patients in four groups, including OCNDS, were found to be more likely to have any specific dental issues when compared to the sibling control group. Of note, OCNDS was found to be associated with an increase in anomalies found in baby teeth, including long incisors, cracked teeth, missing enamel, small teeth, and fused teeth. Importantly, this is the first time that OCNDS has been associated with abnormal tooth development, indicating a potentially unmet need for improved dental care and surveillance in OCNDS patients.
Authors: Joanne Trinh, Irina Hϋning, Nadja Budler, Volker Hingst, Katja Lohmann, Gabrielle Gillessen-Kaesbach. Publication Date: July 20, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/jhg201773 Research Explained Summary: This case report identifies and describes a 7-year-old German boy with OCNDS. At birth, doctors suspected a neurodevelopmental disorder, initially anticipating Down syndrome. Microcephaly (small head/brain) became an obvious sign as the child grew, and motor and speech development were delayed to 2 and 3 years of age respectively. At the last check-up reported, microcephaly and global developmental and intellectual delays were still apparent. Sleep disturbances and hyperactive behavior were reported by the parents, and diagnostic tests showed that the patient underperformed in terms of social responsiveness and sensorimotor function, among other categories. These symptoms elicited genetic testing of the patient and his unaffected parents. Two novel and potentially causative mutations were found, one in the CSNK2A1 gene and one in the STAT2 gene. Both mutations were de novo, or only present in the patient, indicating this might be what differentiated the parents from their atypically developing son. At the time, STAT2 was known to biologically be involved in neurologic processes, although these studies were not confirmed in human patients. However, the CSNK2A1 gene had just been discovered as the causative gene for OCNDS, leading to an OCNDS diagnosis. This case report continued to illustrate the vast number of manifestations OCNDS can cause in different patients.
Authors: Volkan Okur, Megan Cho, Lindsay Henderson, Kyle Retterer, Michael Schneider, Shannon Sattler, Dmitriy Niyazov, Meron Azage, Sharon Smith, Jonathan Picker, Sharyn Lincoln, Mark Tarnopolsky, Lauren Brady, Hans Bjornsson, Carolyn Applegate, Amy Dameron, Rebecca Willaert, Berivan Baskin, Jane Juusola, and Wendy Chung. Publication Date: March 23, 2016 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://link.springer.com/article/10.1007/s00439-016-1661-y Research Explained Summary: This study was the first to identify OCNDS as a distinct neurodevelopmental disorder (NDD) with causative mutations in the CSNK2A1 gene, setting it apart from other NDDs. Genetic sequencing of 4,102 pediatric patients with intellectual disability and/or developmental delay had already been performed, and within those patients, five were identified as having mutations in the CSNK2A1 gene with a unifying set of symptoms that have now come to define OCNDS. Mutations were found throughout the CSNK2A1 gene, with a different mutation in each individual reported. The mutations were defined as likely loss-of-function mutations, meaning that the mutation prevented normal function of this gene. The mutations were also heterozygous, meaning that among the two copies every individual has of each gene, only one copy was altered. All patients identified in this study were female, although later studies would come to find male patients with OCNDS. All patients had developmental delay, while 4/5 showed a variety of symptoms including intellectual disability, behavioral issues, muscle weakness (hypotonia), speech issues, gastrointestinal issues, and dysmorphic facial features. 3/5 patients displayed decreased brain/head size (microcephaly), as well as musculoskeletal and immune issues. All these symptoms and their severity were highly variable between patients, but together formed a constellation of symptoms specific to OCNDS. The CSNK2A1 gene encodes part of a protein known as CK2, which is involved in a variety of important biological processes including embryonic development and cell growth/survival. Specifically, it was already known that mice lacking both copies of this gene (which is not seen in humans, as OCNDS patients only have changes on one copy) do not survive long enough to be born. The authors go on to discuss the different ways each mutation might lead to dysfunction of the CK2 protein on a molecular level. Together, this paper defined for the first time that OCNDS is a neurodevelopmental disorder characterized by specific traits and is caused by mutations in the CSNK2A1 gene.
Authors: Hiroaki Murakami, Tomoko Uehara, Yumi Enomoto, Naoto Nishimura, Tatsuro Kumaki, Yukiko Kuroda, Mizuki Asano, Noriko Aida, Kenjiro Kosaki, Kenji Kurosawa. Publication Date: September 22, 2021 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832215/ Research Explained Summary: This case report profiled a 5-year-old OCNDS patient whose distinguishing feature was their ocular symptoms. The patient was initially referred to an eye clinic at one month of age, as he had never opened his eyes. While brain MRI showed no abnormalities, an examination of the eyes revealed a variety of malformations, including bilateral persistent hyperplastic primary vitreous (PHPV), which leaves the patient with extra blood vessels in their eyes, potentially causing vision impairment in the future. The patient also had abnormally small eyes (microphthalmia) and missing tissue in the eye (coloboma). By age 2, broader developmental delays were evident, including developing head control at 6 months of age, crawling at 16 months, walking at 17 months, and speaking at 24 months. He also displayed various behavioral issues including restlessness and hyperactivity. As a result of this constellation of symptoms, genetic testing was performed, identifying a mutation in the CSNK2A1 gene known as p.Arg107*, indicative of OCNDS. This is only the second report of abnormal eye development in OCNDS and was much more severe than the initial report of a patient who only had retinal abnormalities. The researchers concluded that the wide variability of manifestations of OCNDS and the sparse appearance of ocular symptoms make it difficult to add poor eye development to the list of OCNDS symptoms, although future cases may clarify this potential link.
Authors: Antonio F. Martinez-Monseny, Dídac Casas-Alba, César Arjona, Mercè Bolasell, Paula Casano, Jordi Muchart, Federico Ramos, Loreto Martorell, Francesc Palau, Alfredo García-Alix, Mercedes Serrano. Publication Date: November 15 th , 2019 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.61405 Research Explained Summary: In this case report, a 5-year-old female patient from Spain with OCNDS was described. As a newborn, there were no obvious symptoms of OCNDS, however, she did have some facial characteristics of a midline defect, an issue that occurs during fetal development where organs and structures along the center of the body sometimes split into two or duplicate. The patient was found to have a kidney with two ureters (two tubes that carry urine to the bladder) and two pituitary glands (a pea-sized gland at the base of the brain that controls hormone levels throughout the body) instead of the typical one. In addition, she lacked a sense of smell and had duplicated vertebrae in her neck. During follow-up examinations, this patient displayed failure to thrive ,short stature, poor bone development, and delays in the ability to sit or stand. By the age of 6 she was not able to speak well but was integrated into mainstream schooling. She also had feeding issues, with mild problems swallowing and an inability to chew food. Genetic testing was run to determine the cause of these various. A specific mutation in the CSNK2A1 gene known as “p.Y50C” was found in the test results, which was computationally predicted to disrupt the function of the protein and cause OCNDS. A similar mutation had previously been found in another patient, known as “p.Y50S,” indicating that this mutation was likely the reason for the patient’s condition. However, midline defects and many of the other symptoms associated with this patient have not classically been associated with OCNDS, including her duplicated pituitary gland and vertebrae as well as her absence of smell. In fact, no genetic cause of a duplicated pituitary gland had ever been described until this patient. The doctors concluded that this might be more common among OCNDS patients than expected as it is easy to miss on an MRI and suggested that midline abnormalities may be a potential sign of OCNDS to look for in the future.
Authors: Himanshu Goel and Sheridan O’Donnell Publication Date: May 31, 2024 Research Explained By: Gabrielle Rushing , PhD, Science Program Director Research Simplified Summary: This publication describes a family where two members have the same genetic change in the CSNK2A1 gene, causing OCNDS. This case report is unique as it presents the oldest known individual known living with OCNDS; specifically, the mother is 68 years old, and her son is 42 years old. Both individuals have the c.904del (p. Asp302Thrfs*27) change in the CSNK2A1 gene, which is a deletion that shifts the CSNK2A1 sequence out of alignment, resulting in a jumbled sequence that creates a protein that doesn’t function as it should. The mother had a history of learning difficulties and likely mild intellectual disability. The son had a history of depression, chronic headache, aggression, vision problems, poor coordination, and facial abnormalities. The mother shared some of the facial abnormalities. A newly reported symptom in OCNDS in this publication was cryptorchidism - a condition in which one or both of the testes fail to descend from the abdomen into the scrotum. The foundation has heard of one other instance of this in an OCNDS patient, but this is the first publication recording this symptom. He had mild to moderate intellectual disability and was employed as a physical laborer by a vocational service. This publication is important as it highlights the oldest known OCNDS patient to date, presents an additional case of OCNDS being inherited, provides new insights into OCNDS symptoms, and provides examples of OCNDS patients in adulthood.
Authors: Albin Blanc, Céline Bonnet, Marion Wandzel, Virginie Roth, Yannis Duffourd, Hanna Safraou, Bruno Leheup, Florence Muller, Julie D Colne, François Feillet, Emmanuelle Schmitt, Matheus Castro, Jullian Savatt, Adriano Burcheri, Christophe Nemos, Christophe Philippe, Laëtitia Lambert Publication Date: May 6, 2024 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Research Simplified Summary: This publication describes a 7-year-old male in France with a CSNK2A1 Arg47Gln (R47Q) variant, known to cause Okur-Chung Neurodevelopmental Syndrome (OCNDS). The authors describe novel features that are potentially associated with OCNDS, including: Clubfeet (a common birth defect affecting muscles and bones in the feet causing the foot to point down and turn in) Exotropia (a type of strabismus, or eye misalignment where one eye deviates outward), and Peg lateral incisor teeth (a condition where the second tooth on either side of the front teeth does not develop correctly and is small, pointed, and looks like a cone The authors propose that this case report may extend the phenotypic spectrum (which symptoms present) in OCNDS. Strabismus (eye misalignment) has been mentioned as a rare symptom in a previous Gene Review publication by Dr. Okur and Dr. Chung. Other dental malformations have recently been described in OCNDS including long incisors, cracked teeth, missing enamel, small teeth, and fused teeth. One limitation of this case study is that the child inherited a duplication (a type of mutation that involves the production of one or more copies of a gene or region of a chromosome) of genetic material on a different chromosome than CSNK2A1, but this duplication is currently classified as a variant of uncertain significance, meaning that we don’t have enough evidence to tell if this DNA change contributes to the symptoms that present in the child. Further research is needed to determine if specific symptoms correlate with specific changes in the CSNK2A1 gene and if the symptoms reported in this case study are more prevalent in the OCNDS population.
The CSNK2A1 Foundation explores the implications of Okur-Chung neurodevelopmental syndrome (OCNDS) on phenotype and genotype expansion. Learn about a novel frameshift variant discovered in a Chinese family and its potential impact on the clinical presentation of OCNDS.
Authors : Mohamed Wafik, Heidi Kuoppamaa, Priyal Hirani, John Hignett, Suzanne Lillis, Karine Lascelles, Shweta Sardesai, Kumudini Gomez, Muriel Holder-Espinasse
Variant Characterization Reports (6)
Authors: Deciphering Developmental Disorders Study Group Publication Date: January 25, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/nature21062 Research Explained Summary: This study collected genetic data from 8,361 individuals with neurodevelopmental disorders and sought to determine potential genes where mutations might lead to specific diseases, some previously described and others unknown. Because most individuals in this cohort were the only individuals in their family that had a neurodevelopmental disorder, genetic analyses of this cohort were powered to identify genes whose de novo mutation, or mutations not inherited from either parent, led to disease. Through this analysis, 14 genes were identified as potentially disease causing through their de novo mutation. Among these genes was CSNK2A1, which we now know is causative of OCNDS. 7 individuals with mutations in this gene were identified within this cohort. At the time, OCNDS had only recently been discovered within a small 5 patient cohort – this study found OCNDS among a much larger cohort and further helped characterize the disease.
Authors: Prasida Unni, Jack Friend, Janice Weinberg, Bolkan Okur, Jennifer Hochscherf, Isabel Dominguez Publication Date: October 13, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.frontiersin.org/articles/10.3389/fmolb.2022.851547/full Research Explained Summary: This paper leverages computational modeling to investigate the functional consequences of mutations in the CSNK2A1 and CSNK2B genes on the molecular level. Mutations in these genes lead to OCNDS and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) respectively. They are analyzed together in this paper due to the relatively similar symptoms presented by patients with these diseases and the relatedness of the proteins that are encoded by their corresponding genes. Genes are the molecular blueprint for proteins, which perform molecular functions required for life. The CSNK2A1 and CSNK2B genes encode the proteins CK2α and CK2β respectively. These proteins bind to each other and create a larger complex of proteins known simply as CK2. CK2 is an enzyme, meaning that it causes chemical reactions in a cell, potentially affecting many other proteins – CK2α performs these chemical reactions, while CK2β helps regulate the function of CK2 overall. In this paper, all currently known OCNDS and POBINDS causing mutations were identified and tested. Overall, 68 mutations in the CSNK2A1 gene were examined as potentially causing OCNDS. 12 total locations in the CSNK2A1 gene were found to be recurrently mutated, indicating that these sites are important in development, although there were 45 total mutation sites found. Most of these mutations were clustered closely together on the gene, indicating that the regions they are found in are important to the CSNK2A1 gene and CK2α protein function. These regions are known as the Gly-rich-loop and P+1 loop, which are critical for the enzymatic function of CK2α. The authors tried to predict the specific molecular alterations that CSNK2A1 mutations would have on CK2 protein function using computational algorithms. First, they used computational programs to predict which mutations lead to changes in CK2 enzymatic activity. Afterwards, they compared programs which attempted to determine which mutations lead to greater changes in the overall shape and structure of the CK2 protein. The authors identified mutations in specific domains of the CK2 protein and how they might affect the protein’s function and structure based on the best algorithms identified. Broadly, this study surveys all CSNK2A1 mutations known to date in depth and computationally profiled them on the genetic and protein level to determine specifically how each mutation might impact CK2 function. More knowledge in this area may lead to patient specific treatment approaches and potentially link distinct mutations to specific symptoms.
Authors: Danielle Caefer, Nhat Phan, Jennifer Liddle, Jeremy Balsbaugh, Joseph O’Shea, Anastasios Tzingounis, Daniel Schwartz Publication Date: April 19, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.frontiersin.org/articles/10.3389/fmolb.2022.850661/full Research Explained Summary: In this article, the researchers deeply characterized the effects of a mutation in the CSNK2A1 gene known as p.K198R. This mutation is the most prevalent mutation found in OCNDS to date. The CSNK2A1 gene encodes a component of the protein known as CK2, an enzyme that causes chemical reactions, generally acting on other proteins in what is known as a “signaling cascade” to modify their ability to perform subsequent functions such as cell growth. To act on its target proteins, CK2 must recognize these proteins. Proteins are comprised of subunits known as amino acids, and a specific string of amino acids in a row can be recognized by other proteins as sites for binding – this is how CK2 knows which proteins to modify. However, the authors of this paper found that the K198R mutation in CSNK2A1 changes the ability of CK2 to bind to sites on specific proteins that it normally acts on, instead biasing CK2 towards new binding sites on different proteins. The researchers then looked for proteins that the K198R mutant CK2 would act on but that the normal CK2 protein wouldn’t act on, indicating potential differences that could be leading to the symptoms seen in OCNDS. Previously, it was thought that this mutation generally decreased CK2 activity instead of changing what downstream proteins it targeted. Together, these results help inform the growing body of research regarding what the molecular function of common OCNDS mutations are so that eventually these differences can be targeted therapeutically.
Research Explained: Improvement of variant reclassification in genetic neurodevelopmental conditions
Authors: Michelle Kowanda, Rebecca Sheedy Smith, Jamie Lundy, Catherine Kentros, Elisheva Kleinman, Lauren Kasparson Walsh, Gerhard Schratt, Cora M. Taylor, Wendy K. Chung Publication Date: April 8, 2024 Research Explained By: Gabrielle Rushing , PhD, Science Program Director Research Simplified Summary: This research paper focuses on the reclassification of genetic variants in neurodevelopmental conditions. Variants are changes in the letters of our DNA that can affect our health – you can think of a variant like a misspelled work in the ‘DNA instruction book’. In some cases, the classification of these variants as either harmful (e.g., pathogenic/likely pathogenic) or benign can change over time as new evidence emerges. Sometimes variants are classified as ‘variants of uncertain significance’ or ‘VUS’ meaning that scientists need more information to decide how to classify them. This study looked at the reclassification of VUS in a large group of rare diseases that affect brain development enrolled in Simons Searchlight, including OCNDS. The researchers found that about 20% of the variants were reclassified, with some being upgraded to a more harmful classification and others being downgraded to a less harmful classification. They interpreted classification using existing published research, analyzing DNA from family members, and used the variant reinterpretation guidelines tool from the American College of Medical Genetics and Genomics. The study found that certain genes, such as SCN2A, SLC6A1, and STXBP1, were more likely to have their variants reclassified. For the CSNK2A1 gene, the authors found 13 individuals with a VUS in Simons Searchlight. Out of these 13, 6 were reclassified as pathogenic or likely pathogenic. Regular reevaluation of genetic variants is important because it can affect clinical care and help researchers better understand these conditions. The study also highlighted the need for more diverse representation in genetic databases to ensure equitable healthcare for all populations.
Link to Paper: https://doi.org/10.3389/fmolb.2022.831693 Authors: Werner C, Gast A, Lindenblatt D, Nickelsen A, Niefind K, Jose J, and Hochscherf J Research Explained By: Dr. Jennifer Hochscherf Research Explained Summary: Patients with OCNDS have a change or mutation in the gene that contains the blueprint for the protein “protein kinase CK2alpha”. There are always two copies of this gene in the cell and the mutation only occurs in one of them. The blueprint determines the sequence in which different building blocks, so-called amino acids, are linked together in a long chain. However, this long chain should not be thought of as a straight thread, but rather it takes on a spatial three-dimensional structure that is determined by the sequence of the building blocks. This three-dimensional structure is crucial for the function of proteins. The protein CK2alpha is an enzyme, a protein kinase to be more specific. Enzymes are tools of the cell to assist and catalyze chemical reactions. The CK2alpha reaction is the chemical modification of a second protein (the so-called “substrate protein”) by attachment of a phosphate group. This “phosphorylation” event is a metabolic signal with several possible consequences for the substrate protein: for example, it can be switched on or off, it can be marked for degradation or for transport to a specific location within the cell. In summary: correct and carefully out-balanced cellular phosphorylation reactions by CK2alpha and other protein kinases are crucial events to keep cells healthy and beneficial for the whole organism. CK2alpha can phosphorylate different substrate proteins, and it recognizes them by a specific amino acid sequence on their surface. It is most important that this recognition works well and that the substrate proteins of CK2alpha are not mixed up with those of other protein kinases. To assist this job, CK2alpha has a binding partner called CK2beta. Together, they form a stable complex, the so-called CK2 holoenzyme, which in total consists of two CK2alpha and two CK2beta proteins and which is the predominant form in the cell. In our research, funded by the CSNK2A1 foundation, we aimed to elucidate the consequences of the most common mutation reported for OCNDS patients, which leads to the exchange of the amino acid lysine at position 198 to arginine in CK2alpha (CK2α Lys198Arg ). We therefore examined several aspects of the CK2α Lys198Arg variant, such as the subunit interaction, stability, three-dimensional structure and activity and compared them with the non-mutated form, the “wild type”. We found that the mutation does not affect the interaction with CK2beta, and that the thermal stability of the protein is even slightly increased. We applied a technique called X-ray crystallography that enables to determine and visualize the three-dimensional structure of a protein with near to atomic resolution to investigate the molecular details of the CK2α Lys198Arg structure. The mutated position 198 is located in the substrate recognition site of CK2alpha that exposes a positively charged surface area and preferentially binds negatively charged residues of its substrate proteins. In a CK2alpha X-ray structure solved in the absence of a substrate protein, the positively charged region is often occupied by two negatively charged sulfate ions. These sulfate ions thus mark the binding sites for negatively charged amino acid building blocks in the substrate protein that belong to the sequence recognized by CK2alpha. The most striking feature of the CK2α Lys198Arg structure is that the position of one of the characteristic sulfate ions is shifted compared to the wild-type. Although this shift of the anion binding site seems subtle at first sight, this structural finding supports the conclusion drawn by Caefer et al. (2022) that the CK2alpha mutant Lys198Arg does not primarily lead to a loss of function, but to a change in substrate specificity. To detect possible selectivity changes due to the Lys198Arg mutation, comprehensive enzymatic activity assays have been performed in Prof. Joachim Jose’s research group at the University of Münster, Germany. The outcome of these assays support the conclusion by Caefer et al. (2022) that the substrate spectra of CK2α Lys198Arg and wild-type CK2alpha differ from each other, meaning that CK2α Lys198Arg has some substrate proteins not phosphorylated by wild-type CK2alpha and vice versa. In particular proteins of the nervous system might be differentially phosphorylated by the variant CK2α Lys198Arg and the wild-type form. Understanding the molecular basis of OCDNS is important to identify the direction in which research should continue and ultimately to develop strategies for the development of therapies.
Link to Paper : https://rdcu.be/cjYNS Authors : Dominguez I, Cruz-Gamero JM, Corasolla V, Dacher N, Rangasamy S, Urbani A, Narayanan V, and Rebholz H Research Explained By : Dr. Heike Rebholz Research Explained Summary : All patients diagnosed with OCNDS share one thing in common: they have one change in the gene that encodes for a protein called CK2. There are two genes that encode the genetic blueprint for CK2 in every cell, and in OCNDS one of them has such a change, also called mutation. We know that approximately 30 patients are reported in scientific journals, but that there are many more patients all over the world. Thus far, 16 different genetic changes, all in the same gene, have been described in the literature. However, to date, nobody knew how this change actually affected CK2 itself, how and if it altered its ability to perform its function in every cell of our body. We wanted to answer this question and, to achieve this, produced the unmutated and 16 different “mutated genes” which we then expressed in bacteria and also in cultured mammalian cells. We found a reduction of activity for all of the 16 CK2 mutations. CK2 is a kinase, that is a protein whose job is to alter other proteins in the cell by adding a phosphate group to them. Thus, our findings indicate that, in OCNDS, the mutation renders CK2 less able to perform such phosphorylation events. It is encouraging, however, that this loss of activity does not have a large overall impact on the general health of cells used in our studies and that important proteins that are known to be modified by CK2 are not necessarily affected. What that means is that at least in some cases, the remaining healthy and “unmutated” version of CK2 can compensate for the one, “mutated” copy of CK2. We further found that very few of the mutations also lead to changes in the localization of CK in the cells. While our findings are very basic and not directly applicable to the clinic, the question of CK2 activity had to first be addressed and will allow for further studies. The search now focuses on identifying the actual proteins that are affected by the mutation and are responsible for the disease-characteristic symptoms. This will bring us a big step closer to better understanding what happens in the condition and ultimately will identify proteins, which can be therapeutically targeted and lead to new treatments. If you have any further questions, please contact Jennifer Sills at jennifer@csnk2a1foundation.org
Relevant Literature Reviews (3)
Authors: Christian Borgo, Claudio D’Amore, Stefania Sarno, Mauro Salvi, Maria Ruzzene Publication Date: May 17, 2021 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/s41392-021-00567-7 Research Explained Summary: In this review article, the authors summarize all research conducted to date on the protein CK2 (Casein Kinase 2), an aggregate of multiple proteins that form a complex including two copies each of CK2α and CK2β, and how it relates to various human diseases. CK2 is an enzyme, meaning that it causes chemical reactions. Its two sub-components perform different functions – CK2α is the catalytic domain that performs the reaction, while CK2β is a regulatory domain that controls when the reaction happens. Unlike many enzymes that perform chemical reactions within a cell, CK2 does not need to be activated by another protein to perform its function. Generally, CK2 acts on other enzymes that are performing functions such as cell survival, growth, and migration among other functions, further increasing their ability to stimulate cells to perform these actions. CK2 was first implicated in human disease in 1995 as a pro-cancer molecule due to its higher-than-expected presence in various cancers. Generally, cancers use their high levels of CK2 to promote cell survival and growth, granting them the ability to continue growing in the face things that usually kill cancers, such as the immune system and therapeutics. Other research groups have implicated roles for CK2 in infections, diabetes, cardiovascular diseases, retinal diseases, and inflammatory diseases. In addition, CK2 has been implicated in various neurodegenerative diseases associated with aging, including Parkinson’s, Alzheimer’s, Huntington’s, and Amyotrophic lateral sclerosis (ALS). Furthermore, CK2 has been implicated in a variety of behavioral neurologic disorders including Autism, ADHD, Schizophrenia, Major Depressive Disorder, and most relevant to the CSNK2A1 Foundation, OCNDS. Mutations in the CSNK2A1 gene, which encodes the CK2α subunit of CK2, cause OCNDS. OCNDS is a disease that manifests differently across individuals, but generally leads to symptoms including but not limited to developmental delays, muscular weakness, slow growth, and epilepsy. A similar disorder known as POBINDS caused by mutations in the CSNK2B gene that encodes CK2β has also recently been discovered, with patients displaying similar symptoms to OCNDS but with greater risk of seizure. In terms of treatment for these various CK2-related diseases, there are multiple CK2 inhibitors currently in clinical trials as anti-cancer drugs. The mechanism of action for CK2 in OCNDS is still unclear, meaning that we don’t know if a CK2 inhibitor would be a promising candidate treatment or if CK2 needs to be targeted in a different way.
Authors: Volkan Okur and Wendy Chung Publication Date: June 9, 2022 Research Explained By: Gabrielle Rushing, PhD, CSNK2A1 Foundation Science Program Director and Jennifer Sills, CSNK2A1 Foundation Founder and President Link to article: https://www.ncbi.nlm.nih.gov/books/NBK581083/ Research Explained Summary: Please visit our simplified version of the GeneReview on our Care Recommendations page here.
Link to Paper: Comparing Two Neurodevelopmental Disorders Linked to CK2: Okur-Chung Neurodevelopmental Syndrome and Poirier-Bienvenu Neurodevelopmental Syndrome-Two Sides of the Same Coin? (2022) Authors : Demetra Ballardin, Jose M. Cruz-Gamero, Thierry Bienvenu and Heike Rebholz Publication Review Explained By : Demetra Ballardin, Barbara Lecis Cocco, Jose Cruz-Gamero and Heike Rebholz Publication Review Explained Summary : OCNDS and POBINDS are two neurodevelopmental disorders that are caused by alterations in two genes that encode the blueprint of two different components of a protein called CK2. CK2 consists of two parts, a regulatory subunit that is termed CK2beta and the catalytic one that performs a biochemical reaction in our bodies, termed CK2alpha. OCNDS is caused by an alteration in the gene for CK2alpha, and POBINDS by alterations in the gene CK2beta. The two conditions are similar in many aspects, but also have differences, and in the literature thus far were never directly compared. With our review, we wanted to bring together patients’ data from both disorders in order to compare their symptoms and, via a literature survey, try to reason how known cellular function of CK2 could explain common and specific symptoms of both syndromes. It is not surprising that we observed that OCNDS and POBINDS patients share many symptoms, including growth deficits, neurological and behavioral problems. However, the syndromes also present important differences: OCNDS patients achieve their developmental milestones (onset of speech and walking) much later and have a higher prevalence of intellectual disabilities and stereotyped movements than POBINDS patients. However, POBINDS patients suffer more often from epilepsy, and this includes a high prevalence of generalized tonic clonic seizures that are often difficult to manage pharmacologically. OCNDS patients do not suffer from generalized tonic clonic seizures, but other, milder forms of seizures. Moreover, OCNDS patients present sleep disturbances and gastrointestinal issues that were not reported by POBINDS patients. We also tried to link certain symptoms such the loss of muscle tone and behavioral symptoms to known roles that CK2 plays in our brain, highlighting interesting processes that will be further studied to better understand OCNDS and POBINDS, and that could be the focus of therapeutic approaches. Studies using patients’ cells, mouse models and other models systems of the conditions will help to understand, on a molecular level, the similarities and the important differences between OCNDS and POBINDS.
Studies Analyzing Neurodevelopmental Syndromes, Including OCNDS (3)
Explore the phenotypic effects of genetic variants associated with autism. Learn how specific genetic factors influence traits, behaviors, and neurological development.
Authors: Alexandra Santana Almansa, LeeAnne Green Snyder, Wendy K. Chung, Jennifer M. Bain, and Siddharth Srivastava Written By: Tierney Baum, PhD, Strategic R&D Consultant Edited by: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation Link to Publication This recent publication focuses on characterizing motor disturbances in patients with neurodevelopmental disorders (NDDs) by analyzing available data in the Simons Searchlight database. Researchers in this study were interested in determining if certain genetic disorders were associated with a more severely affected motor presentation in patients. Both CSNK2A1 and the sister gene, CSNK2B, were included in the study.
Authors: Thomas W. Frazier, Robyn M. Busch, Patricia Klaas, Katherine Lachlan, Eva Loth, Constance Smith-Hicks, Mustafa Sahin, Antonio Y. Hardan, Mirko Uljarevic, NET Development Project Team Written By: Tierney Baum, PhD, Strategic R&D Consultant Edited by: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation Link to Paper Research Explained Summary: In this 2024 publication, researchers have developed an assessment tool called the Neurobehavioral Evaluation Tool (NET), which includes 11 different surveys that aim to help add to a growing understanding of neurobehavioral features and developmental strengths and weaknesses associated with specific neurodevelopmental genetic syndromes (NDGS).
OCNDS Models (1)
Authors: Jose M. Cruz-Gamero, Demetra Ballardin, Barbara Lecis, Chun-Lei Zhang, Laetitia Cobret, Alexander Gast, Severine Morisset-Lopez, Rebecca Piskorowski, Dominique Langui, Joachim Jose, Guillaume Chevreux and Heike Rebholz Publication Date: October 4, 2024 Research Explained By: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation Link to article: Cruz Gamero Author MS Research Explained Summary: This publication characterizes the first mouse model of OCNDS. Researchers generated a mouse that has the K198R mutation in the alpha subunit of CK2, representing approximately 1/3rd of OCNDS patients. Results indicate that the mice have behavioral symptoms that resemble what is observed in humans, including an increase in repetitive movements, autism-like behaviors, memory deficits, and altered circadian activity that potentially represents sleep issues observed in humans. Notably, the K198R mice are smaller and weigh less than typical mice, potentially mirroring the postnatal short stature often seen in humans with OCNDS. Further experiments demonstrated that the K198R mice have reduced CK2 activity and synapse formation in the hippocampus, a brain region important for learning and memory. Synapses are critical junctions where neurons communicate with one another and send messages. The authors found that K198R mice exhibit reduced synaptic plasticity, meaning the ability to respond to incoming messages to adjust the flow of information. This reduction suggests a possible mechanism for the behavioral and cognitive symptoms observed in OCNDS. There were no differences found in assays of motor abilities or social behavior. K198R mice did not exhibit spontaneous seizures but did show a reduced threshold (susceptibility) for seizures in assays where seizures where experimentally induced. This mouse model represents a significant advancement in developing therapies for OCNDS. Its resemblance to the human condition allows researchers to use it as a valuable tool for preclinical therapeutic testing.
Other (2)
Authors: Abdelhalim Loukil, Chloe Barrington, and Sarah C. Goetz Research Explained By: Sarah C. Goetz. PhD, Abdelhalim Loukil. PhD Link to Paper: A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability | PNAS Research Explained Summary: Primary cilia are tiny projections present the surface of our cells that act like an antenna: They help cells receive signals from their surroundings and respond by activating certain cellular programs. These programs are important to control the development of embryos and the functioning of tissues in the human body. Because of this, genetic changes that cause defects in the structure of cilia lead to many different human genetic disorders. The cilium assembles from an organelle called the centrosome, which forms the base of the cilium. Surprisingly, we found that CSNK2A1 is enriched at the base of the cilium, implicating it in the regulation or functioning of cilia. We found that the deletion of the CSNK2A1 gene from cells causes structural defects in the cilia: they become abnormally long and break more easily at the tip, which makes them less stable. Altogether, we found that CSNK2A1 is critical to maintaining normal movement of cellular materials inside the cilium, and for preserving the stable structure of cilia. We also tested whether the changes to CSNK2A1 that are linked with Okur-Chung neurodevelopmental disorder (OCNDS) might affect cilia. When we introduced known CSNK2A1 mutations into cells, this led to abnormal cilia shape, suggesting the OCNDS changes might interfere with the functioning of cilia. These findings highlight a potential linkage between CSNK2A1 function in regulating cilia and OCNDS. Our ongoing work will further describe this link and uncover its molecular basis.
Authors: Gabrielle V. Rushing and Jennifer Sills Publication Date: July 25, 2024 Research Explained By: Gabrielle Rushing, PhD, CSNK2A1 Foundation Science Program Director Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11273705/ Research Explained Summary: Patient organization perspective: a research roadmap for Okur-Chung Neurodevelopmental Syndrome Plain Language Summary Okur-Chung Neurodevelopmental Syndrome (OCNDS) is an ultra-rare disorder caused by variants in the CSNK2A1 gene. CSNK2A1 creates a subunit of CK2, a critical protein in brain development among other biological processes. There are no approved treatments for OCNDS, and current suggested treatments focus on symptom management. Individuals with OCNDS exhibit many symptoms at varying severity levels, including developmental delay/intellectual disabilities, autism, disrupted sleep, speech delays/inability to speak, short stature, and in approximately 25% of cases, epilepsy. We think that seizure prevalence may be underreported due to lack of extended EEG recordings for OCNDS patients and that seizures may preferentially occur at night as has been observed in other autism spectrum disorders. The CSNK2A1 Foundation was established in 2018 and aims to find a cure for OCNDS and provide support to affected individuals. The CSNK2A1 Foundation’s research tools and efforts have provided valuable insights into the biology of OCNDS and the natural history of the disorder. However, additional efforts are needed to fully understand how OCNDS affects the body and investigate potential treatment approaches. To accelerate OCNDS research, the foundation has developed a research roadmap that is presented in this perspective article. We describe OCNDS and the CSNK2A1 gene, highlight gaps in OCNDS research, discuss the research roadmap, and offer the founder’s perspective on our growth and future opportunities.