Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series
Open accessAbstract
Background: While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 ( FMR1 ) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55–200 repeats) of the FMR1 gene may be overlooked. Objective: To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype. Methods: We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS. Results: Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity. Conclusion: Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.
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Genetic syndromes are rare in ASD (found in 5% of the total ASD population), but many syndromic forms of ASD share a hypermobile phenotype (e.g., Fragile X syndrome).
“Whilst genetic syndromes are rare in ASD (only found in 5% of the total ASD population (35), many syndromic forms of ASD share a hypermobile phenotype (e.g., Fragile X syndrome) (14, 36).”
From The Relationship Between Generalised Joint Hypermobility and Autism Spectrum Disorder in Adults: A Large, Cross-Sectional, Case Control Comparison (2022) · cites this paper as [36]
Tassanakijpanich et al. (unpublished) collected case studies identifying a fully presenting hEDS phenotype in adult female fragile X premutation carriers.
“Recently, Tassanakijpanich et al. [36] (unpublished data) have collected a series of case studies identifying a fully presenting hEDS phenotype in adult female fragile X premutation carriers, including a case with Marfanoid habitus, arachnodactyly, and right ventricular dilation.”
From The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders (2020) · cites this paper as [36]
The presence of an EDS-like phenotype associated with the FMR1 gene suggests upregulated protein translation may lead to collagen dysregulation.
“Although data are still preliminary, the presence of an EDS-like phenotype associated with the FMR1 gene, a negative regulator of protein translation, suggests upregulated protein translation may lead to collagen dysregulation.”
From The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders (2020) · cites this paper as [36]
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- Authors
- Tassanakijpanich, N., McKenzie, F. J., McLennan, Y. A., Makhoul, E., Tassone, F., Jasoliya, M. J., Romney, C., Petrasic, I. C., Napalinga, K., Buchanan, C. B., Hagerman, P., Hagerman, R., & Casanova, E. L.
- Affiliations
- Prince of Songkla University (TH)
- UC Davis Health (US)
- University of California, Davis (US)
- Greenwood Genetic Center (US)
- Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, South Carolina, USA
- Corresponding author
- Hagerman, Randi
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2021-06-30
- Volume
- 59
- Issue
- 7
- Pages
- 687-690
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC8717836
- OpenAlex
- W3175793096
- Cited by
- 9
- References
- 20
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 1
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- IDDRC MIND Institute, University of California, Davis (U54 HD079125)
- the Tides Foundation
- NICHD (HD036071)
- the National Center for Advancing Translational Sciences and National Institutes of Health (UL1 TR001860)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- hypermobile Ehlers-Danlos syndrome, fragile X premutation, FMR1 gene, CGG repeat expansion, joint hypermobility, connective tissue diseases, FMRP, RNA toxicity, MMP-9, elastin, extracellular matrix, fragile X premutation carriers
- MeSH terms
- Child, Preschool, Ehlers-Danlos Syndrome, Female, Fragile X Syndrome, Heterozygote, Humans, Male, Phenotype, Trinucleotide Repeat Expansion, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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