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Review
. 2020 May 2;12(1):13.
doi: 10.1186/s11689-020-09310-9.

Developmental studies in fragile X syndrome

Khaleel A Razak  1 , Kelli C Dominick  2   3 , Craig A Erickson  4   5
Affiliations
Review

Developmental studies in fragile X syndrome

Khaleel A Razak et al. J Neurodev Disord. .

Abstract

Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field.

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Conflict of interest statement

KAR has no conflicts to report. KCD has received research support from the National Institute of Neurological Disorders and Stroke (NINDS), American Academy of Child and Adolescent Psychiatry, and Cincinnati Children’s Hospital Medical Center. She is a clinical trial site investigator for F. Hoffman-La Roche Ltd. and Ovid Therapeutics. CAE has received current or past funding from Confluence Pharmaceuticals, Novartis, F. Hoffmann-La Roche Ltd., Seaside Therapeutics, Riovant Sciences, Inc., Fulcrum Therapeutics, Neuren Pharmaceuticals Ltd., Alcobra Pharmaceuticals, Neurotrope, Zynerba Pharmaceuticals, Inc., Lenire Bioscience, and Ovid Therapeutics Inc. to consult on trial design or development strategies and/or conduct clinical trials in FXS or other neurodevelopmental disorders. CAE is additionally the inventor or co-inventor on several patents held by the Cincinnati Children’s Hospital Medical Center or Indiana University School of Medicine describing methods of treatment in FXS or other neurodevelopmental disorders.

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