CAMK4‐related Case of Hyperkinetic Movement Disorder

Ca2+/calmodulin-dependent protein kinase (CAMK) is a class of enzymes that constitute a family of 81 proteins.1 CAMKs family includes, but is not restricted to five types in the mammalian brain.2 They are considered cornerstone regulators of calcium signaling in different diseases and health states. The importance of CAMKs is evident in regulating the cell life cycle and rearrangement of the cell's cytoskeletal network.3 Moreover, they are involved in various stages of neural development, including proliferation, migration, differentiation, and survival.4 To the best of our knowledge, there have been only three patients reported.5-7 Here, we report the 4th individual with CaMK4-related neurodevelopmental disorder. We described a proband presenting with a phenotype of intellectual disability, hyperkinetic movement, and epilepsy, who was found to have a de novo p.Q318P (c.953 A > C) heterozygous mutation in CAMK4. We also conducted a literature review comparing our patient with the three patients reported by Zech et al.5-7 Our proband is a 16-year-old male patient followed for intellectual disability, autism spectrum disorder (ASD), generalized epilepsy, and hyperkinetic movements. Written informed consent was obtained from the family to participate in this study. The patient had a normal pregnancy and was born full-term with vacuum assistant delivery. His parents are non-consanguineous and the family history was unremarkable. The initial concern arose at the age of 3 months because of axial hypotonia and delay in acquiring milestones with an initial diagnosis of cerebral palsy. Over the next few years, he developed generalized epilepsy (age, 6 years old) with tonic–clonic and absence seizures and hyperkinetic movement disorder (age, 5 years old). His hyperkinetic movements exhibit a mixed phenotype with generalized chorea, mostly involving the upper body, tonic dystonic posturing in the lower extremities, and bulbar area with a dystonic tremor in the upper extremities as well as stereotypies. The movements demonstrated nocturnal exacerbation as well as worsening with activity, stress, and anxiety (Video 1). An extensive workup was conducted to investigate the underlying diagnosis. The patient underwent prolonged electroencephalogram (EEG) monitoring that demonstrated multifocal interictal epileptiform discharges. The hyperkinetic movements were captured without ictal EEG correlates confirming that those were not epileptiform in origin. He underwent repeated brain magnetic resonance imagings that showed nonspecific T2 hyperintensities in the peritrigonal white matter and slightly bulky corpus callosum. His most recent brain image (15 years) demonstrated an interval cerebellar volume loss. The metabolic workup was unremarkable. Karyotype and microarray were normal. MECP2, Prader Willi, and Angelman syndrome genetic testing were negative. X-linked mental retardation genetic panel in 2012 showed Variant of unknown significance (VUS) in ACSL4 (maternally inherited and does not explain his clinical phenotype). Trio-WES found a de novo heterozygous likely pathogenic variant in the CAMK4 NM_001744.5:c.953A > C; p.(Gln318Pro). From a management perspective, the patient's hyperkinetic movements showed a good response to low-dose tetrabenazine. Moreover, he continued to experience refractory seizures despite the treatment with levetiracetam, valproic acid, and lacosamide. CAMK4 gene mutations have been of interest in disease causing among researchers. To date, only three cases with de novo heterozygous CAMK4 gene variants were reported. All reported cases exhibit a clinical spectrum of neurodevelopmental abnormalities and movement disorders.5-7 We report the fourth case with a de novo heterozygous mutation that fits the clinical entity of the variants described above. Common features of CAMK4-related disorder include tremors, dystonia, chorea, athetoid movements, global developmental and intellectual disability, and ASD or autistic-like behaviors. All three reported cases described dystonia and chorea, whereas two of the three had myoclonus and ataxia. Our patient showed dystonia, chorea, athetosis, and tremor. Dystonia and chorea in the reported cases tended to appear 3 to 20 years after initial symptoms. Similarly, our patient developed hyperkinetic movements at the age of 5 years. The previous case reported by Zech et al,5 showed poor response to levodopa, anticholinergics, and botulinum toxin injections. However, our patient displayed an overall favorable response to low-dose tetrabenazine. Levodopa, anticholinergics, or botulinum toxin were not required given the good response on tetrabenazine. One of the three patients experienced seizures in infancy that spontaneously resolved. Conversely, our patient has developed drug-refractory epilepsy (Table 1). The previously reported patients showed de novo truncating and splice site variants in exon 10 or the exon 10-intron 10 junction, which overall has deleterious effects on the protein's regulatory domain. Correspondingly, our patient's variant affects exon 10. However, our patient has a missense variant that was classified as likely pathogenic according to The American College of Medical Genetics and Genomics classification hence, labeling him as the first likely pathogenic missense variant affecting CAMK4 gene. The pathogenic molecular mechanism of this variant is currently unknown, but we speculate it might act via a gain-of-function process. The variant falls into the autoinhibitory domain and it has been previously shown in in vitro cellular experiments that certain point mutations in this domain may be activating.8 Little is known about the phenotype of the CAMK4-related disorders. We expanded the spectrum of CAMK4-related disorders by reporting the fourth case. Indeed, further studies should be conducted to understand the full phenotype of this condition and identify any phenotype–genotype correlations. We thank the parents for their tireless support and care for the patient. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. I.A.: 1A, 1B, 1C, 3A, 3B K.A.: 1C, 3B H.G.: 1C, 3B C.G.: 1C, 1B, 3B. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required. Patient informed written consent was obtained and documented. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for Previous 12 Months: CG recieved honoraria from Medtronic.

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