|Ahead of print
|Association of apolipoprotein ε4 allele with intellectual disability in children with cerebral palsy
N Sreedevi1, N Swapna2, Santosh Maruthy1, Rajesh Kundapur3, Charles Sylvester3
1 Professor, Department of Speech-Language Sciences, All India Institute of Speech and Hearing, Mysore, Karnataka, India
2 Professor, Department of Speech-Language Pathology, All India Institute of Speech and Hearing, Mysore, Karnataka, India
3 Scientist, Unit for Human Genetics, All India Institute of Speech and Hearing, Mysore, Karnataka, India
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|Date of Submission||22-Aug-2022|
|Date of Acceptance||31-Oct-2022|
|Date of Web Publication||28-Feb-2023|
Background: The apolipoprotein E (ApoE) protein is the most essential lipid transporter in the brain which is vital in neurodevelopment. The production of ApoE is regulated by several genes and increases under certain conditions such as cerebral injury. This study was carried out to assess the association between APOE alleles on intellectual disability (ID) and assess their relationship with cerebral palsy (CP) in south Indian children.
Materials and Methods: The participants (n = 45) were children aged 1–15 years of age, who were diagnosed with CP and presenting with speech or hearing impairment. All patients were of South Indian descent. Family history, medical history, clinical investigations, and cognitive abilities of the patients were recorded. Exome sequencing of the APOE gene was performed.
Results: APOE ε4 allele was detected in 9/45 (P = 0.002) CP patients. Both carriers and noncarriers of the ε4 allele had mild-, moderate-, severe-, and profound intellectual disabilities.
Conclusion: The role of APOE ε4 as a possible biomarker in cognition decline in CP is still questionable, but the ε4 allele as a potential risk factor for developing Alzheimer's disease is strongly relevant. Further studies are warranted to study the association of the APOE ε4 allele in CP and ID.
Keywords: Apolipoprotein E, cerebral palsy, children, intellectual disability, ε4 allele
|How to cite this URL:|
Sreedevi N, Swapna N, Maruthy S, Kundapur R, Sylvester C. Association of apolipoprotein ε4 allele with intellectual disability in children with cerebral palsy. Arch Ment Health [Epub ahead of print] [cited 2023 May 28]. Available from: https://www.amhonline.org/preprintarticle.asp?id=370756
| Introduction|| |
Cerebral palsy (CP) is a spectrum of chronic heterogeneous medical conditions resulting from a nonprogressive injury to the developing brain. Along with motor disability, additional comorbidities such as below-average intellectual functioning, epilepsy, cognitive decline, behavioral issues, and sensory impairments are also associated with CP; adults with CP are at greater risk of late-onset Alzheimer's disease (AD) and related dementia.,, Apolipoprotein E (ApoE), a polymorphic protein is central in the metabolism of cerebral and peripheral cholesterol and fat-soluble compounds in the brain., ApoE is synthesized by astrocytes that are packed with cholesterol and phospholipids which are vital in neurodevelopment to form a lipid-protein complex, which binds to the ApoE receptors on the surfaces of nerve cells which maintains and repairs cell membrane, neurotransmission, and neuronal repair., The ApoE encoded by APOE gene (ApoE denotes protein; APOE denotes gene) is located on chromosome 19q13.32 (NC_000019.10) which is highly polymorphic with two common functional variants: c. 388T >C p.Cys130Arg (rs429358, legacy nomenclature p.Cys112Arg,) and c. 526C >T p.Arg176Cys (rs7412, legacy nomenclature p.Arg158Cys) defining the ε4 and ε2 alleles, respectively., The expression of the APOE gene differs by cell type and is strongly linked to the lipid loading of cells. The words cognitive decline or cognitive impairment is used interchangeably with intellectual disability (ID) in this article.
It is well established that the APOE ε4 allele is a strong risk factor to develop dementias and most commonly late-onset AD, and the APOE ε2 allele is protective.,, APOE ε4 allele is also a validated biomarker in the prognostication of psychiatric disorders such as traumatic brain injury, major depressive disorder, autistic disorders, schizophrenia, and cognitive decline., Even though a significant association between the occurrence of the APOE ɛ4 allele and CP was demonstrated, no clear evidence has been produced.,,, Moreover, the association between APOE ε4 allele and cognition is thought to be adapted by age. Moreover, most of the research on APOE is based on adults (65 years+) making it intricate to understand how APOE shapes cognitive function in the duration of life. Due to the significant association between APOE alleles and neurological outcomes, we conducted this cohort study to assess the association between APOE alleles on ID and assess their relationship with CP in South Indian children.
| Materials and Methods|| |
The participants were children between the age of 1 and 15 years with CP. Informed consent was obtained from the parents/guardians after explaining the purpose of the study. About 5 ml of venous blood was collected from 45 clinically confirmed CP patients (26 males and 19 females) of South Indian descent, who were referred to the All India Institute of Speech and Hearing (AIISH), Mysore, for speech and hearing impairment assessment. Family/medical history, clinical investigations, and cognitive abilities were recorded. The study was carried out at the Unit for Human Genetics, AIISH, Mysore, from February 2016 to April 2019. This study protocol was approved by the Institutional Ethics Committee of AIISH, Mysore, India.
DNA extraction and targeted exome sequencing
Genomic DNA was extracted from peripheral blood by using PureLink™ Genomic DNA Mini Kit (Thermo Fisher Scientific) according to the manufacturer's instructions. Targeted exome sequencing was performed on the Ion Proton™ next-generation sequencing system (Life Technologies) according to the manufacturer's protocols. All sequencing data passed specific minimal quality control requirements, and the sequence read alignment and variant calling were performed with the reference genome (hg19) using TMAP Alignment (Thermo Fisher Scientific). Variants were detected using the Ion Reporter (Thermo Fisher Scientific).
Data collected were analyzed using Statistical Package for the Social Sciences (SPSS v21 IBM Corp., New York, USA). Descriptive (i.e., mean, standard deviation, and 95% confidence intervals (CI) were used. The level of significance was set as P < 0.05.
| Results|| |
The participants were evaluated based on sex, age, CP subtypes, topography, birth complications, and intellectual abilities [Table 1]. We investigated the distribution of APOE alleles in CP in South India; among the 45 cases, 9 (20%, P = 0.002, CI = 0.0785–0.3215) were positive for ε4 allele c. 388T >C p.Cys130Arg (rs429358, legacy nomenclature p.Cys112Arg,) and 1 (2%, P = 0.323 CI = −0.0226–0.0670) carried the ε2 allele c. 526C >T p.Arg176Cys (rs7412, legacy nomenclature p.Arg158Cys) [Table 1]. The ε4 and ε2 alleles were heterozygous in this study. No family history of AD was endorsed or recorded. The ε4 carrier CP patients with different degrees of ID were considered in this study, and the ε4 allele was found in decreased frequency, and over 78% of the CP cases did not show the presence of the ε4 allele.
|Table 1: Apolipoprotein E alleles, prenatal morbidities, and intellectual disability in children with cerebral palsy|
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| Discussion|| |
We investigated the distribution of APOE alleles in children with CP from South India. The influence of the APOE ε4 allele as a risk factor for cognition decline and AD has been discussed. The ε4 allele is a major element of the genetic predisposition for late-onset AD due to an increased amount of amyloid plaques in the brain tissue,, and carriers of the ε4 allele may impact cognition in children with CP.,, In this study, 9/45 (20%) children carried the ε4 allele, and 1/45 (2%) carried the ε2 allele. Previous studies have examined the role of APOE alleles as a risk factor for the development of CP in children.,, On contrary, several meta-analyses' and population-based case–control studies found no association between the ε4 allele and CP risk.,,
In this investigation, the ε4 carriers [Table 1] and ε4 noncarriers 35/45 (78% P = 0.000, CI = 0.6515–0.9041) had below-average intellectual ability and were diagnosed with mild-, moderate-, severe-, and profound intellectual disabilities (data of noncarriers is not shown), which eventually rules out the association of the ε4 allele in cognitive impairment in children with CP. Previous studies have demonstrated no association of the APOE ε4 allele in cognitive decline in the general population and cases with multiple sclerosis, but not in CP.,, ID or cognitive decline is a condition characterized by below-average intellectual functioning (intelligence quotient <70); children with CP have intellectual disabilities which occur often in conjunction with each other, and additional comorbidities and other developmental disabilities are also associated with CP., In India, the prevalence of ID is not well known and has been reported from around 1/1000 to 32/1000, depending on varied criteria and the prevalence of CP in India is higher than global estimates. However, the association between CP and ID has not been well-studied.
Several studies have shown a risk of cognitive impairment in CP patients which is not linked to the APOE ε4 allele and is thought to be adapted by age.,, Cognition may be adversely impacted in childhood in the presence of risk factors for AD and carriers of the APOE ε4 allele have an increased risk of developing AD., Considering the results from this investigation and in contrast with the previous studies, it is unlikely that the APOE ε4 allele is associated with ID in children with CP, but other risk factors are still relevant. An earlier study revealed decreased cognition in children with APOE ε4 allele as one of the risk factors for AD, and another study revealed a link between the ε4 allele and ischemic stroke which may also lead to vascular dementia, which commonly coexists with AD. Since the APOE ε4 allele is a strong candidate in the cause of AD, the carriers of the ε4 allele in this study may have a potential risk of developing AD. Nevertheless, patients with homozygous APOE ε4 allele presented worse in the cognitive tests because of the ε4-mediated increased risk of developing mild cognitive impairment or AD. However, not all patients with AD carry an APOE ε4 allele, and not all carriers of the APOE ε4 allele develop AD.
| Conclusion|| |
In conclusion, our data demonstrated no association of the variant rs429358 (c. 388T >C p.Cys130Arg) or the APOE ε4 allele with ID in children with CP. Both carriers and noncarriers of the ε4 allele had mild – moderate – severe – profound intellectual disabilities. However, the risk factor for AD is still relevant.
The sample size was relatively small and the patients were selected from a single center, which may limit the generalizability. Therefore, further studies confirming the current findings are necessary to contribute to our understanding of the role of APOE variants in ID to assess cognitive domains in a larger cohort would be valuable.
The authors thank the Director of All India Institute of Speech and Hearing, Mysore, and also acknowledge the patients and their families for the participation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Unit for Human Genetics, All India Institute of Speech and Hearing, Mysuru, Karnataka
Source of Support: None, Conflict of Interest: None
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