Rett Syndrome: Exploring the Autism Link
Open accessAbstract
The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down syndrome, suggests the possibility of common neurobiologic mechanisms whose elucidation could fundamentally advance our understanding. This review explores the commonalities and differences between autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in the methyl-CpG-binding protein 2 gene (MECP2), which is responsible for RTT in 95% of individuals with the disorder. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important test beds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances.
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Both mutations and duplications of the MeCP2 gene have been associated with Rett syndrome and ASDs.
“Dysfunction of MeCP2 has been implicated in significant cognitive impairment, and both mutations and duplications of the gene have been associated with Rett syndrome and ASDs (LaSalle and Yasui, 2009;Percy, 2011;Cukier et al., 2012).”
From The Environmental Neurotoxicant PCB 95 Promotes Synaptogenesis via Ryanodine Receptor-Dependent miR132 Upregulation (2014) · cites this paper as Percy, 2011
The ‘Role of MECP2’ section reports that MECP2 mutations are common in classic Rett syndrome. The ‘Continuum of MECP2 Associated Phenotypes’ section describes a MECP2 duplication disorder but says its phenotype is distinct from Rett syndrome. The ‘Autism and RETT Syndrome: Molecular Convergence’ section links altered MECP2 expression to autism; it does not establish that both MECP2 mutations and duplications are associated with ASDs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPerturbations in lipid homeostasis may influence both neurological and non-neurological RTT symptoms, including abnormal responses to stress, high anxiety levels, and bone anomalies.
“Sterols are the precursors of steroid hormones, bile acids and vitamin D; thus, perturbations in lipid homeostasis may influence both neurological and non-neurological RTT symptoms, including abnormal responses to stress, high anxiety levels, and bone anomalies52.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [52]
The Animal Models section reports enhanced anxiety, fear, and elevated corticosterone in an RTT mouse model; Medical Issues in Rett syndrome identifies anxiety and scoliosis among clinical concerns (page numbers unavailable). The paper does not link these symptoms to perturbations in lipid homeostasis or discuss sterols as their possible cause. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDysfunction of MeCP2 has been implicated in significant cognitive impairment.
“Dysfunction of MeCP2 has been implicated in significant cognitive impairment, and both mutations and duplications of the gene have been associated with Rett syndrome and ASDs (LaSalle and Yasui, 2009;Percy, 2011;Cukier et al., 2012).”
From The Environmental Neurotoxicant PCB 95 Promotes Synaptogenesis via Ryanodine Receptor-Dependent miR132 Upregulation (2014) · cites this paper as Percy, 2011
MeCP2 mutations result in a number of pathologies including microencephaly, general growth retardation, motor clumsiness, ataxia, and autistic features, including social withdrawal, loss of language, and stereotypy.
“MeCP2 mutations result in a number of pathologies including microencephaly, general growth retardation, motor clumsiness, ataxia, and autistic features, including social withdrawal, loss of language, and stereotypy [699].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [699]
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- Authors
- Percy, A. K.
- Affiliations
- Civitan International (US)
- Corresponding author
- Percy, Alan K.
- ORCID
- Percy, Alan K.
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2011-08-01
- Volume
- 68
- Issue
- 8
- Pages
- 985
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC3674963
- OpenAlex
- W1966717823
- Cited by
- 144
- References
- 22
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 11 · 2023: 2 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 9 · 2016: 12 · 2015: 10 · 2014: 11 · 2013: 20 · 2012: 18
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD038985, U54HD061222)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- Rett syndrome, autism spectrum disorder, MeCP2, neurodevelopmental disorders, fragile X syndrome, Down syndrome, natural history (disease), animal models, phenotypes, genetic mechanisms
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Humans, Phenotype, Transcription, Genetic, Rett Syndrome, Comorbidity, Methyl-CpG-Binding Protein 2
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