Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

Tian, Junbin; Gao, Xu; Yang, Li

doi:10.3389/fnins.2022.780407

Cited by 33 publications

(28 citation statements)

References 356 publications

(421 reference statements)

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“…This is an interesting finding because previous research has indicated that repetitive behaviors can be subdivided into restrictive/repetitive sensory motor behaviors and insistence on sameness behaviors ( Cuccaro et al, 2003 ; Bishop et al, 2013 ), which in other publications have been classified as low-order (restricted) and high-order (sameness) behaviors ( Turner, 1999 ). Restricted behaviors can include dyskinesia, convulsions, and repeated manipulation of objects, while sameness behavior refers to a general insistence on routine consistency ( Tian et al, 2022 ). The discriminant coefficients indicate these two subscales are representative of opposite group membership, where greater deficits in restricted behaviors are associated with ASD males and greater deficits in sameness behaviors are associated with ASD females.…”

Section: Discussionmentioning

confidence: 99%

Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex

Jacokes

Jack²,

Sullivan³

et al. 2022

Front. Neurosci.

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Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the ‘female protective effect,’ which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.

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Section: Discussionmentioning

confidence: 99%

Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex

Jacokes

Jack²,

Sullivan³

et al. 2022

Front. Neurosci.

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“…Based on the discussed motor and nonmotor functions of the STN, especially its role in action inhibition, we argue that it probably plays an important, yet underexplored role in NDDs. For example, ASD, ADHD, Tourette’s syndrome, and schizophrenia are all characterized by restricted and repetitive patterns of behavior (RRBs) like stereotypies, perseveration, and tics, which are basically disorders of behavioral control ( Lewis et al, 2018 ; Vicente et al, 2020 ; Tian et al, 2022 ). Additionally, RRBs could be just behavioral manifestations of a broader cognitive inflexibility and an inability to stop unwanted actions or thoughts ( Tian et al, 2022 ).…”

Section: Clinical Importance Of Stnmentioning

confidence: 99%

“…For example, ASD, ADHD, Tourette’s syndrome, and schizophrenia are all characterized by restricted and repetitive patterns of behavior (RRBs) like stereotypies, perseveration, and tics, which are basically disorders of behavioral control ( Lewis et al, 2018 ; Vicente et al, 2020 ; Tian et al, 2022 ). Additionally, RRBs could be just behavioral manifestations of a broader cognitive inflexibility and an inability to stop unwanted actions or thoughts ( Tian et al, 2022 ). However, clinical and preclinical neuroimaging studies have not studied intra-basal ganglia connectivity or possible abnormalities of small nuclei like STN in RRBs (for review, see Wilkes and Lewis, 2018 ), although animal models demonstrated clear involvement of STN in stereotyped behavior ( Chang et al, 2016 ; Lewis et al, 2018 ; Wilkes and Lewis, 2018 ).…”

Section: Clinical Importance Of Stnmentioning

confidence: 99%

Transcriptional Profile of the Developing Subthalamic Nucleus

Bokulić

Medenica²,

Sedmak³

2022

eNeuro

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The subthalamic nucleus (STN) is a small, excitatory nucleus that regulates the output of basal ganglia motor circuits. The functions of the STN and its role in the pathophysiology of Parkinson’s disease are now well established. However, some basic characteristics like the developmental origin and molecular phenotype of neuronal subpopulations are still being debated. The classical model of forebrain development attributed the origin of STN within the diencephalon. Recent studies of gene expression patterns exposed shortcomings of the classical model. To accommodate these findings, the prosomeric model was developed. In this concept, STN develops within the hypothalamic primordium, which is no longer a part of the diencephalic primordium. This concept is further supported by the expression patterns of many transcription factors. It is interesting to note that many transcription factors involved in the development of the STN are also involved in the pathogenesis of neurodevelopmental disorders. Thus, the study of neurodevelopmental disorders could provide us with valuable information on the roles of these transcription factors in the development and maintenance of STN phenotype. In this review, we summarize historical theories about the developmental origin of the STN and interpret the gene expression data within the prosomeric conceptual framework. Finally, we discuss the importance of neurodevelopmental disorders for the development of the STN and its potential role in the pathophysiology of neurodevelopmental disorders.

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“…The pathogenesis of ASD is not fully clarified. It seems that it is caused by genetic factors affecting neural connectivity, consequently impairing social communication development and leading to stereotypies and restricted interests [1,2]. It has been hypothesized that the heterogeneous clinical presentation of ASD results from the interaction between multiple genes or gene combinations as well as epigenetic factors and exposure to environmental modifiers [3].…”

Section: Introductionmentioning

confidence: 99%

Detection of a de novo heterozygous ANK2 variant in a child with autism spectrum disorder and epilepsy: a case report

Morais

Quental

Lourenço

et al. 2023

Egypt J Med Hum Genet

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Background The pathogenesis of autism spectrum disorder (ASD) is not fully clarified. Next-generation sequencing technologies have greatly enhanced the identification of new genes associated with ASD. Variants in ANK2 gene are known to correlate with a broad spectrum of clinical cardiac phenotypes, but, more recently, it has also been pointed out as a candidate gene for the etiology of ASD. Case presentation We report the case of a female patient with ASD and epilepsy in whom clinical exome sequencing was performed for etiological enlightenment. A heterozygous variant of uncertain significance was identified in the ANK2 gene: c.3412C > T p.(Arg1138Ter). The child was submitted to a formal cardiac evaluation, ruling out cardiovascular abnormalities. The genetic variant was searched in her parents and was negative in both, suggesting a de novo variant, which favors its pathogenicity. Conclusions We recognize the challenge of assessing variant pathogenicity in candidate genes for ASD, and ANK2 gene is currently not associated with neurodevelopmental disorders in the Online Mendelian Inheritance in Man database. Nonetheless, our case can be added to other published reports of de novo ANK2 variants in children with ASD and neurological phenotypes (including seizures), some without cardiac impairment. Hopefully, this study provides a more detailed phenotypical description that is often lacking, and it may contribute to a better understanding of the association between ANK2 and ASD.

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Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

Cited by 33 publications

References 356 publications

Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex

Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex

Transcriptional Profile of the Developing Subthalamic Nucleus

Detection of a de novo heterozygous ANK2 variant in a child with autism spectrum disorder and epilepsy: a case report

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