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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39113374
AIAN-27-430
10.4103/aian.aian_118_24
Case Report
Severe Developmental Delay and Behavior Abnormalities in a Patient with De Novo CAMK2B Mutation: A Case Report and Literature Review
Zhang Katherynn K.
Rupar Charles A. 1
Prasad Chitra 2
Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
1 Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
2 Department of Pediatric Genetics and Metabolism, London Health Sciences Centre, London, ON, Canada
Address for correspondence: Dr. Chitra Prasad, Department of Pediatric Genetics and Metabolism, London Health Sciences Centre London Ontario N6C2V5, Canada. E-mail: Chitra.Prasad@lhsc.on.ca
Jul-Aug 2024
08 8 2024
27 4 430434
20 2 2024
13 4 2024
16 5 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
The calcium/calmodulin-dependent protein kinase II-beta (CAMK2B) gene is important for calcium signaling and glutamatergic synapses, which impacts neuroplasticity and learning. Mutations in the CAMK2B gene, which cause autosomal dominant mental retardation 54 (Online Mendelian Inheritance in Man # 617799), can have multisystemic clinical impact. Due to the rarity of CAMK2B mutations at present, case reports about patients with CAMK2B mutations are limited. The present case report describes a patient with CAMK2B-related disorder confirmed by whole exome sequencing and adds to the current information in the literature. We review three case reports in literature with detailed descriptions of patients presenting with mutations in the CAMK2B gene. While there is a broad spectrum of phenotypic presentations, there appears to be an emerging neurobehavioral phenotype. Optimal management of patients will require attention to behavioral issues as well as involvement of neuropsychiatric expertise along with other supports for development and vision abnormalities.

CAMK2B mutation
mental retardation 54
neurobehavioral phenotype
whole exome sequencing
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pmcINTRODUCTION

The CAMK2B gene is a calcium/calmodulin-dependent protein kinase II-beta gene which causes autosomal dominant mental retardation 54 (Online Mendelian Inheritance in Man [OMIM]# 617799).[1] It is important for calcium signaling and glutamatergic synapses, which significantly impacts neuroplasticity and learning.[23] Mutations in the CAMK2B gene can be inherited in an autosomal dominant fashion or can be found de novo. The clinical impact of CAMK2B mutation-related disorders can be broad and multisystemic, resulting in poor growth, microcephaly, facial dysmorphia, strabismus and visual impairment, poor feeding, gastric reflux, constipation, hypotonia, central nervous system irritability, global developmental delays, autistic features, and behavioral abnormalities.[34] The case report illustrates the progression and clinical features of a 4-year-old female patient with a de novo pathogenic c.416C>T p.P139L mutation in the CAMK2B gene.

The case report describes the characteristics of our patient and presents a review of existing case reports with details of other patients with CAMK2B mutations. Due to the rarity of CAMK2B mutation, there are limited case reports about patients afflicted with the condition. A total of three existing case reports were reviewed for patients with CAMK2B mutations for their initial presentation, relevant medical history, and neurodevelopmental history. One of the three case reports, Rizzi et al.,[5] previously tabulated the main features of 14 individuals with CAMK2B variants. We have summarized detailed characteristics of our patients and the three case reports, as well as updated prevalence of the previously tabulated features.

CASE HISTORY

The patient was a 4-year-old female (delivered at term) initially seen at 8 months with failure to thrive, hypotonia, global developmental delay, liver dysfunction, and cortical visual impairment. She was the fourth child of a nonconsanguineous Mennonite couple whose other children were healthy. Her initial growth parameters were below the fifth percentile for height, weight, and head circumference. She was small, but proportionate for her age with no significant facial dysmorphism. She had noticeable hypotonia in the trunk area and poor, fleeting eye contact, but initially had no seizures until reaching 22 months of age. Currently, every 4–6 months, the patient had short focal seizures. Brain atrophy appeared nonprogressive on magnetic resonance (MR) imaging. Impressions from initial multiplanar, multisequence MR of the head without contrast found bilaterally symmetric signal abnormality in the central tegmental tracts. MR spectroscopy concluded major metabolites were normal for patient age with no evidence of lipid/lactate. An extensive genetic and metabolic workup was unremarkable (including mitochondrial studies). The microarray showed absence of heterozygosity. She was noted to have uniparental isodisomy 22. Testing for some of the OMIM morbid genes in this region gave negative results for PEX26, SCLC25A, ACO2, and PLA2G6. Whole exome sequencing revealed that she had a pathogenic de novo heterozygous c.416C>T p.P139L mutation in the CAMK2B gene. She began to develop weeklong encephalopathic episodes at 4 years of age, is continuously inconsolable, and engages in frequent self-harm behavior of hitting her face with her fists. She continues to have severe global developmental delay and is functioning at around 6-months level. She has starting to eat orally and is not using the gastrostomy feeds as much as before. She remains visually impaired. Socially, she does not engage with her parents or siblings.

DISCUSSION

Commonalities of the present patient with those from previously described case reports include low birth weight, seizures or epilepsy, hypotonia, poor oromotor coordination, language deficits, and poor behavioral regulation. The specific pathogenic variant, presentation, medical history, and neurodevelopmental history of other previously described patients are detailed in Table 1. Among the case reports presented in Table 1, Rizzi et al.[5] tabulated the main features across known individuals with CAMK2B mutations.[3456] We combined the tabulated features with those of our patient and two other case reports published after 2020 to reflect an updated, overall prevalence for the following: global developmental delay 100%, hypotonia 88%, seizures 37%, microcephaly 63%, abnormality of brain morphology 38%, behavioral abnormality 87%, irritability and aggression 47%, sleep disturbance 27%, and self-injurious behavior 40% [Table 2].

Table 1 Summary of published detailed case reports of patients with CAMK2B mutations, their presentation, medical history, and developmental history

Ref.	Mutation	Presentation	Medical history	Development	
Our patient	De novo mutation
CAMK2B c. 416C>T p.P139L
Confirmed via WES
Uniparental disomy 22	Four-year-old Caucasian female, initially presented at 8 months with the following:
Failure to thrive

Hypotonia

Global developmental delay

Liver dysfunction

Cortical visual impairment

	Prenatal/birth Normal pregnancy and uncomplicated full-term birth

Small but proportionate for age, no facial dysmorphism

Family Fourth child of nonconsanguineous Mennonite couple; siblings healthy

Others Short focal seizures with stabilized brain matter loss on MRI

Chronic otitis media

Resolved liver dysfunction, ongoing visual impairment

	Motor Hypotonia in the trunk

Speech Delayed, able to use two or three words for mom

Cognition Functions around 6-months level at age 4

Behavioral Encephalopathic episodes, inconsolable, self-harm behavior

Social Poor, fleeting eye contact; does not engage with parents or siblings

	
Dwyer et al. [7]	De novo mutation
CAMK2B c. 328G>A p.Glu110Lys
Confirmed via WES	15-year-old Caucasian female, initially presented at 7 years of age with the following: Global developmental delay

New acute neuropsychiatric episodes

No dysmorphia

	Prenatal/birth Normal pregnancy

Full-term, vaginal delivery

Family Parents healthy

Four siblings healthy

Medications: Verapamil, worsened neuropsychiatric episodes, stopped due to cardiac toxicity

Paroxetine, stopped due to QTc prolongation

Valproic acid, magnesium oxide

	Motor Low tone, poor coordination

Motor skills at 11 months were at the level of 6 months old

At 15 years of age, can run, abnormal gait

Speech Poor oral motor coordination

Speech therapy with prompt technique at age 2

Narrative abilities by age 6

Ongoing problems with articulation and repetition at age 15

Normal comprehension and hearing

Cognition Visual apraxia and attention deficits

At age 15, difficult with single-digit addition

Behavioral Difficulty with self-regulation and soothing

Frustration and emotional distress at age 15 escalates to aggression toward other or self-injury

Impulsiveness limiting the ability to attend

Recurrent neuropsychiatric episodes with inconsolability

Social Enjoys interacting with adults and peers

Displays empathy

Difficult with conversation and conflict resolution

	
Heiman et al.[8]	Maternally inherited c. 85C>T; p.Arg29Ter mutation from an apparently healthy mother
Confirmed via WES	Three-year-old female of European descent: Initially presented with afebrile seizures at 11 months

No visual or gastrointestinal abnormalities

Muscle tone normal

Hearing evaluation unremarkable

	Prenatal/birth Birth weight 15th percentile, length sixth percentile

Family: Second child of nonconsanguineous, healthy parents

6-year-old sister has speech delay and learning difficulties, no seizures

	Motor (not described) Speech Prominent delay in expressive speech

Cognition (not described) Behavioral Poor impulse control

Behavioral outbursts with difficulty regulating emotions

Social (not described)	
Rizzi et al.[5]	c. 416C>T, p.(P139L)
Confirmed via WES	22-year-old female of South Asian origin: Oldest known patient so far

Severe intellectual disability

Absence of language

Optic atrophy

Cerebellar atrophy via MRI

	Prenatal/birth Birth weight <3rd percentile, length 10th percentile

Facial dysmorphism

Family: Postterm c-section, nonconsanguineous parents

Medications: Carbamazepine, for epilepsy at age 6

	Motor Psychomotor delay, hypotonia, absent tendon reflex

Short period of sitting, has not acquired the ability to walk

Speech Poor oromotor skills, feeding difficulties

Language is absent, vocalizes without communication purpose

Cognition (not described in detail)
Behavioral (not described)
Social Absent eye contact

	
MRI=Magnetic resonance imaging, WES=Whole exome sequencing

Table 2 Tabulation of CAMK2B features among our patient and other reported patients from our literature review

Features	Our patient	Dwyer et al. 2022[7]	Heiman et al. 2021[8]	Patients with features from Rizzi et al.[5]*	Total patients from Rizzi et al.[3456]*	Total patients overall[345678] and our patient**	Percentage	
Global developmental delay	1	1	1	14	14	17	100%	
Hypotonia	1	1	0	13	14	17	88%	
Seizures	1	0	1	3.5	12	15	37%	
Microcephaly	1	0	0	9	13	16	63%	
Abnormality of the brain morphology	1	0	0	5	13	16	38%	
Behavioural abnormality	1	1	1	10	12	15	87%	
Irritability/aggression	1	1	1	4	12	15	47%	
Sleep disturbance	0	0	0	4	12	15	27%	
Autism spectrum disorder	0	0	0	3	12	15	20%	
Self-injurious behaviour	1	1	0	4	12	15	40%	
*Rizzi et al. 2020, Table 1., includes Kury et al. 2017[3], Akita et al. 2018[4], and Iwama et al. 2019.[6] **Total overall includes the denominator of total patients accounted for from Rizzi et al. plus three additional patients from our case report

Overall, this case report contributes to the existing but limited literature of patients with CAMK2B mutations confirmed by whole exome sequencing. While there is a broad spectrum of phenotypic presentations, there appears to be an emerging neurobehavioral phenotype. The episodes manifest as recurrent encephalopathy with behavioral changes, headache, loss of language, and loss of complex motor coordination. Verapamil, lithium, lamotrigine, valproic acid, magnesium oxide, and riboflavin effectively controlled a patient’s symptoms in a report by Dwyer et al.[7] In the case reported by Dwyer et al.,[7] the medications effective for mitigating the neuropsychiatric symptoms may have done so by decreasing CAMK2B activity and associated calcium signaling, whereas medications that appeared to worsen the symptoms may have done so by increasing CAMK2B activity and associated calcium signaling. By classifying CAMK2B mutations as “gain of function’’ or “loss of function’’ based on CAMK2B catalytic activity, it may be possible to guide personalized empiric treatment regimens tailored to specific CAMK2B mutations. The exact pathogenesis of these recurrent periods of encephalopathy is not clear; however, periodic fluctuations in calcium levels in a critical brain region have been thought to trigger the occurrence of these symptoms.

Thus, optimal management of patients will require attention to behavioral issues as well as neuropsychiatric expertise, along with other supports for development and vision abnormalities. Due to the multiple active medical issues present, multidisciplinary care involving medical professionals, allied health professionals, and support groups is essential for the well-being of a child and family living with CAMK2B-related disorders [Figure 1].

Figure 1 Schematic overview of multidisciplinary care involved for a child living with CAMK2B-related disorders

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient and her family have given their consent for her images and other clinical information to be reported in the journal. They understand that her names and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

The case report was prepared with the permission and support of the patient’s family.
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REFERENCES

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