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Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications

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Abstract

There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD) with multiple forms of ASD having been identified over the decades. Among these, a genetic etiology can be identified in 20–40% of cases when a full genetic work-up is completed. The Fragile X premutation state (characterized by the presence of 55–200 CGG repeats in the FMR1 gene) is a relatively newly identified disease state that has since been associated with several disorders including fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI) and most recently, fragile X-associated neurodevelopmental disorders (FXAND) which commonly includes anxiety and depression. In addition to these associated disorders, extant literature and clinical observations have suggested an association between the premutation state and ASD. In this paper, we review the literature pertinent to this and discuss possible molecular mechanisms that may explain this association. This includes lowered levels of the FMR1 Protein (FMRP), GABA deficits, mitochondrial dysfunction and secondary genetic abnormalities that is seen in premutation carriers as well as their increased vulnerability to environmental stressors. Understanding these mechanisms can facilitate development of targeted treatment for specific sub-groups of ASD and premutation disorders in future.

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  • 20 October 2022

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Abbreviations

ASD:

Autism spectrum disorder

FXS:

Fragile X syndrome

FMRP:

FMR1 Protein

PM:

Premutation

FMR1 :

Fragile X messenger ribonucleoprotein 1 gene

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Acknowledgements

We thank the families who have participated in our studies and also the fragile X team including students at the MIND Institute for their excellent collaboration.

Funding

This research was supported by grants from NICHD including HD036071 and the MIND Institute Intellectual and Developmental Disabilities Research Center P50 HD103526. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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  1. Ramkumar Aishworiya and Dragana Protic are Joint authors.

Authors and Affiliations

  1. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA

    Ramkumar Aishworiya & Randi Hagerman

  2. Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore

    Ramkumar Aishworiya

  3. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore, 117597, Singapore

    Ramkumar Aishworiya

  4. Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Dragana Protic

  5. Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA, 95817, USA

    Randi Hagerman

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RA conceptualized the article, wrote the first draft and subsequent versions of the manuscript. DP was a major contributor to the manuscript and revised versions of the manuscript. RA and DP contributed equally to this paper. RH conceptualized the article and critically reviewed and revised versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ramkumar Aishworiya.

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RA and DP have no competing interests pertinent to this publication. RH has received funding from Azrieli Foundation for treatment studies in fragile X syndrome and she has consulted with Zynerba about treatment in fragile X syndrome.

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Aishworiya, R., Protic, D. & Hagerman, R. Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications. J Neurol 269, 4676–4683 (2022). https://doi.org/10.1007/s00415-022-11209-5

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