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Last updated: 8/8/2023
Years published: 2023
NORD gratefully acknowledges Gabrielle Rushing, PhD, Science Program Director, CSNK2A1 Foundation and Wendy Chung, MD, PhD, Chief, Department of Pediatrics, Boston Childrenโs Hospital, for the preparation of this report.
Summary
Okur-Chung neurodevelopmental syndrome (OCNDS) is an ultra-rare genetic neurodevelopmental syndrome caused by changes (variants or mutations) in the CSNK2A1 gene. These gene variants cause symptoms that affect individuals differently. Common symptoms include speech and motor delays, intellectual disabilities, behavioral challenges, sleep issues and other neurological problems. There are no known treatments or cures for OCNDS, so treatment is focused on symptom management. Most often, this gene change happens spontaneously and is not inherited, however, patients have been reported who have inherited a CSNK2A1 gene variant from a parent. OCNDS follows an autosomal dominant inheritance pattern, meaning that an individual with OCNDS has a 50% risk of passing the CSNK2A1 variant to each child.
Generally, individuals with OCNDS have developmental delays that vary in severity. OCNDS should be considered in individuals with the following clinical findings:
โข Mild-to-moderate developmental delay (DD) or intellectual disability (ID)
โข Generalized hypotonia in infancy and/or childhood
โข Speech delay
AND
โข Any of the following features presenting in infancy or childhood:
o Infant feeding difficulties
o Seizures, ranging from a single seizure event to intractable epilepsy
o Behavioral findings including repetitive (stereotypic) movements, autism spectrum disorder, aggressiveness and tantrums and attention-deficit/hyperactivity disorder
o Slow growth, failure to thrive or difficulty gaining weight
o Nonspecific facial differences (e.g., round face, short broad nasal tip)
The frequency, age of onset and age of resolution of symptoms is not well established, but the most observed symptoms of OCNDS are:
โข Speech delay/inability to speak
โข Motor delay (i.e., walking)
โข Intellectual disabilities, learning disabilities, features of autism spectrum disorder
โข Behavioral challenges such as tantrums, hand flapping other stereotypic movements
โข Sleep problems due to a disrupted sleep-wake cycle (circadian rhythm)
โข Neurologic characteristics (e.g., low muscle tone (hypotonia), clumsy movements, small head (microcephaly), epilepsy (seizures) gait abnormalities)
โข Nonspecific structural abnormalities in the brain
โข Short stature; often without growth hormone deficiency
โข Feeding difficulties starting from birth, reflux (heartburn), constipation
โข Minor infections of the ears and lungs
โข Crooked (misaligned) teeth and cavities
โข Hypermobility, hernias, hip dysplasia
โข Vision issues such as strabismus, near/far sightedness, astigmatism
โข Minor skeletal deformations in vertebrae
Information about disease progression and life expectancy are not known at this time.
OCNDS is caused by changes (variants or mutations) in the CSNK2A1 gene. OCNDS follows autosomal dominant inheritance. This means that an individual only needs a single pathogenic variant (referred to as heterozygous) in the CSNK2A1 gene to cause medical problems. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual (known as de novo). The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Heterozygous mutations are like having two different versions of a gene in the bodyโs instructions. Genes can be considered as small pieces of code that tell the body how to grow, develop and work properly. Usually, we inherit one set of genes from our mother and another set from our father. When a variant happens, it means thereโs a small change in one of those gene sets. Heterozygous means the genetic code is different in each of the two genes (i.e., one gene with the regular code, and the other gene has a slightly altered code). Sometimes variants lead to unique traits or health conditions, such as OCNDS.
The CSNK2A1 gene provides instructions to produce (encode) the alpha subunit of a protein called casein kinase 2 (CK2). CK2 is an important kinase (enzyme) that is abundant in the brain and is important for the development of neurons and synaptic transmission. Synaptic transmission is how neurons communicate with each other โ they send messages across small gaps called synapses. This process helps our brain process information and is important for learning and memory. Research is still ongoing to determine how variants in CSNK2A1 affect normal functioning.
OCNDS has been reported in an equal number of males and females. As of July 2023, over 180 individuals are registered with the CSNK2A1 Foundation, a non-profit patient advocacy group dedicated to finding a cure for Okur-Chung neurodevelopmental syndrome and ensuring affected individuals have the opportunities and supports necessary for happy and full lives. A map of global cases is available here.
OCNDS can only be diagnosed through genetic testing (e.g., whole exome or whole genome sequencing). There are likely many individuals with OCNDS who do not have a formal diagnosis due to lack of access to testing. OCNDS shares symptoms with many other neurodevelopmental disorders, and there is not a specific symptom that prompts a clinician to order genetic testing, which can lead to delayed diagnosis or misdiagnosis. Diagnostic challenges for families are lack of access to testing and genetic counselors.
As of July 2023, no clinical practice or consensus guidelines have been published.
Recommended evaluations include the following:
โข Neurologic (EEG, MRI, gait/coordination)
โข Development (motor, cognitive, speech/language)
โข Neuropsychiatric (behavioral concerns, sleep issues, anxiety, ADHD, ASD-like behaviors)
โข Gastrointestinal (nutritional status, oromotor function)
โข Ophthalmologic
โข Cardiovascular
โข Genitourinary
โข Respiratory/sleep
โข Genetic counseling
A detailed list of recommendations is available in this GeneReview.
Therapies that may be used include:
โข Feeding therapy (including gastrostomy tube)
โข Growth hormone therapy (to treat short stature in individuals with evidence of growth hormone deficiency)
โข Standardized anti-seizure medications (ASM) for individuals with epilepsy. No single ASM has been shown to be effective specifically for OCNDS.
โข Orthopedics, physical therapy, occupational therapy (for motor coordination issues)
โข Early intervention programs for developmental delay/intellectual disability
โข Applied behavioral analysis (ABA) therapy for autism spectrum disorder
โข Other therapies may be appropriate. Consultations with developmental pediatricians and/or pediatric psychiatrists may be helpful depending on the individual.
Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight https://classic.clinicaltrials.gov/ct2/show/NCT01238250
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Belnap N, Price-Smith A, Ramsey K, et al. Inherited CSNK2A1 variants in families with Okur-Chung neurodevelopmental syndrome. Clin Genet. 2023;10.1111/cge.14408.doi:10.1111/cge.14408
Ballardin D, Cruz-Gamero JM, Bienvenu T, Rebholz H. Comparing two neurodevelopmental disorders linked to CK2: Okur-Chung neurodevelopmental syndrome and Poirier-Bienvenu neurodevelopmental syndromeโtwo sides of the same coin? Front Mol Biosci. 2022;9:850559. Published 2022 May 26. doi:10.3389/fmolb.2022.850559
Caefer DM, Phan NQ, Liddle JC, et al. The Okur-Chung neurodevelopmental syndrome mutation CK2K198R leads to a rewiring of kinase specificity. Front Mol Biosci. 2022;9:850661. doi:10.3389/fmolb.2022.850661
Dominguez I, Cruz-Gamero JM, Corasolla V, et al. Okur-Chung neurodevelopmental syndrome-linked CK2ฮฑ variants have reduced kinase activity. Hum Genet. 2021;140(7):1077-1096. doi:10.1007/s00439-021-02280-5
Blanquet PR. Casein kinase 2 as a potentially important enzyme in the nervous system. Prog Neurobiol. 2000;60(3):211-246. doi:10.1016/S0301-0082(99)00026-X
Yang CP, Li X, Wu Y, et al. Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes. Nat Commun. 2018;9(1):838. doi:10.1038/s41467-018-03247-3
Okur V, Cho MT, Henderson L, et al. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features. Hum Genet. 2016;135(7):699-705. doi:10.1007/s00439-016-1661-y
INTERNET
Chung W, Okur V. Okur-Chung Neurodevelopmental Syndrome. 2022 Jun 9. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK581083/ Accessed July 31, 2023.
Okur-Chung Neurodevelopmental Syndrome OCNDS/ Facebook group. https://www.facebook.com/groups/524315764434784/ Accessed July 31, 2023.
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