The Science of CAMK2
By Bonnie Dwyer, M.D. a parent board member of CAMK2.org. Read
iPSC neuron cells, back-engineered from a patient’s blood, are being studied in vitro in a Petri dish to better understand CAMK2 mutations and to help find medications that might help for the disorder.
CAMK2 Case Report and Review of the Literature:
This is a professional medical report to be shared with your doctors. The importance of this report is that it provides evidence to doctors across the globe that CAMK2 disease can actually be treated. Not only that, the report lists medications that may be helpful. Download
The CAMK2 Care Pathway
Developed by a team of physicians specializing in this disorder, the Care Pathway is based on the most recent available scientific research by the CAMK2 Expertise Centre, part of ENCORE. It was designed to support parents and practitioners in delivering the highest-quality medical treatment. Download the Care Pathway here.
Scientific Resources for Professionals
Pan M, Liu PW, Ozawa Y, Arima-Yoshida F, Dong G, Sawahata M, Mori D, Nagase M, Fujii H, Ueda S, Yabuuchi Y, Liu X, Narita H, Konno A, Hirai H, Ozaki N, Yamada K, Kidokoro H, Bito H, Mizoguchi H, Watabe M, Horigane SI, Takemoto-Kimura S. A hyper-activatable CAMK2A variant associated with intellectual disability causes exaggerated long-term potentiation and learning impairments. Transl Psychiatry. 2025 Mar 26;15(1):95. doi: 10.1038/s41398-025-03316-4. PMID: 40140673; PMCID: PMC11947108.
Rigter PMF, de Konink C, Dunn MJ, Proietti Onori M, Humberson JB, Thomas M, Barnes C, Prada CE, Weaver KN, Ryan TD, Caluseriu O, Conway J, Calamaro E, Fong CT, Wuyts W, Meuwissen M, Hordijk E, Jonkers CN, Anderson L, Yuseinova B, Polonia S, Beysen D, Stark Z, Savva E, Poulton C, McKenzie F, Bhoj E, Bupp CP, Bézieau S, Mercier S, Blevins A, Wentzensen IM, Xia F, Rosenfeld JA, Hsieh TC, Krawitz PM, Elbracht M, Veenma DCM, Schulman H, Stratton MM, Küry S, van Woerden GM. Role of CAMK2D in neurodevelopment and associated conditions. Am J Hum Genet. 2025 Sep 4;112(9):2247. doi: 10.1016/j.ajhg.2025.08.001. Epub 2025 Aug 11. Erratum for: Am J Hum Genet. 2024 Feb 1;111(2):364-382. doi: 10.1016/j.ajhg.2023.12.016. PMID: 40795868; PMCID: PMC12460999.
Cheung JS, van Woerden GM, Veenma DCM. CAMK2; four genes, one syndrome? Delineation of genotype-phenotype correlations. Curr Opin Neurobiol. 2025 Feb;90:102935. doi: 10.1016/j.conb.2024.102935. Epub 2024 Dec 3. PMID: 39631163.
Borghi R, Trivisano M, Specchio N, Tartaglia M, Compagnucci C. Understanding the pathogenetic mechanisms underlying altered neuronal function associated with CAMK2B mutations. Neurosci Biobehav Rev. 2023 Sep;152:105299. doi: 10.1016/j.neubiorev.2023.105299. Epub 2023 Jun 28. PMID: 37391113.
Horii Y, Kuroda Y, Saito Y, Enomoto Y, Naruto T, Kurosawa K. A CAMK2B variant associated with tetralogy of Fallot, developmental delay, and growth retardation. Eur J Med Genet. 2023 Oct;66(10):104845. doi: 10.1016/j.ejmg.2023.104845. Epub 2023 Sep 19. PMID: 37734707.
Tolmacheva ER, Shubina J, Kochetkova TO, Ushakova LV, Bokerija EL, Vasiliev GS, Mikhaylovskaya GV, Atapina EE, Zaretskaya NV, Sukhikh GT, Rebrikov DV, Trofimov DY. CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report. Genes (Basel). 2023 May 28;14(6):1177. doi: 10.3390/genes14061177. PMID: 37372357; PMCID: PMC10298453.
Horii Y, Kuroda Y, Saito Y, Enomoto Y, Naruto T, Kurosawa K. A CAMK2B variant associated with tetralogy of Fallot, developmental delay, and growth retardation. Eur J Med Genet. 2023 Oct;66(10):104845. doi: 10.1016/j.ejmg.2023.104845. Epub 2023 Sep 19. PMID: 37734707.
Dwyer BK, Veenma DCM, Chang K, Schulman H, Van Woerden GM. Case Report: Developmental Delay and Acute Neuropsychiatric Episodes Associated With a de novo Mutation in the CAMK2B Gene (c.328G>A p.Glu110Lys). Front Pharmacol. 2022 May 10;13:794008. doi: 10.3389/fphar.2022.794008. PMID: 35620293; PMCID: PMC9127182.
Fujii H, Kidokoro H, Kondo Y, Kawaguchi M, Horigane SI, Natsume J, Takemoto-Kimura S, Bito H. Förster resonance energy transfer-based kinase mutation phenotyping reveals an aberrant facilitation of Ca2+/calmodulin-dependent CaMKIIα activity in de novo mutations related to intellectual disability. Front Mol Neurosci. 2022 Sep 1;15:970031. doi: 10.3389/fnmol.2022.970031. PMID: 36117912; PMCID: PMC9474683.
Proietti Onori M, van Woerden GM. Role of calcium/calmodulin-dependent kinase 2 in neurodevelopmental disorders. Brain Res Bull. 2021 Jun;171:209-220. doi: 10.1016/j.brainresbull.2021.03.014. Epub 2021 Mar 24. PMID: 33774142.
Rizzi S, Spagnoli C, Salerno GG, Frattini D, Caraffi SG, Trimarchi G, Moratti C, Pascarella R, Garavelli L, Fusco C. Severe intellectual disability, absence of language, epilepsy, microcephaly and progressive cerebellar atrophy related to the recurrent de novo variant p.(P139L) of the CAMK2B gene: a case report and brief review. Am J Med Genet A. 2020 Sep;[online]. doi:10.1002/ajmg.a.61803
Kool MJ, Proietti Onori M, Borgesius NZ, van de Bree JE, Elgersma-Hooisma M, Nio E, Bezstarosti K, Buitendijk GHS, Aghadavoud Jolfaei M, Demmers JAA, Elgersma Y, van Woerden GM. CAMK2-Dependent Signaling in Neurons Is Essential for Survival. J Neurosci. 2019 Jul 10;39(28):5424-5439. doi: 10.1523/JNEUROSCI.1341-18.2019. Epub 2019 May 7. PMID: 31064859; PMCID: PMC6616294.
Proietti Onori M, Koopal B, Everman DB, Worthington JD, Jones JR, Ploeg MA, Mientjes E, van Bon BW, Kleefstra T, Schulman H, Kushner SA, Küry S, Elgersma Y, van Woerden GM. The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function. Hum Mutat. 2018 Dec;39(12):2008-2024. doi: 10.1002/humu.23647. Epub 2018 Sep 19. PMID: 30184290; PMCID: PMC6240363.
Chia PH, Zhong FL, Niwa S, Bonnard C, Utami KH, Zeng R, Lee H, Eskin A, Nelson SF, Xie WH, Al-Tawalbeh S, El-Khateeb M, Shboul M, Pouladi MA, Al-Raqad M, Reversade B. A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability. Elife. 2018 May 22;7:e32451. doi: 10.7554/eLife.32451. PMID: 29784083; PMCID: PMC5963920.
Akita T, Aoto K, Kato M, Shiina M, Mutoh H, Nakashima M, Kuki I, Okazaki S, Magara S, Shiihara T, Yokochi K, Aiba K, Tohyama J, Ohba C, Miyatake S, Miyake N, Ogata K, Fukuda A, Matsumoto N, Saitsu H. De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders. Ann Clin Transl Neurol. 2018 Jan 29;5(3):280-296. doi: 10.1002/acn3.528. PMID: 29560374; PMCID: PMC5846454.
Küry S, van Woerden GM, Besnard T, et al. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. Am J Hum Genet. 2017;101(5):768-788. doi:10.1016/j.ajhg.2017.10.003