Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series
Nattaporn Tassanakijpanich1,2, Forrest J McKenzie2,3, Yingratana A McLennan2,4
1Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand.
Insights
Fragile X premutation carriers may have overlooked connective tissue issues like hypermobile Ehlers-Danlos syndrome (hEDS). This study reports five such cases, highlighting shared molecular pathways.
Area of Science:
- Genetics
- Molecular Biology
- Connective Tissue Disorders
Background:
- Full mutation Fragile X Mental Retardation 1 (FMR1) gene expansions are linked to connective tissue problems.
- Connective tissue issues in fragile X premutation carriers (fXPCs) may be underdiagnosed.
Purpose of the Study:
- To report five cases of FMR1 fXPCs presenting with a hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.
- To explore potential shared pathogenesis between fXPCs and hEDS.
Main Methods:
- Collected medical histories and FMR1 molecular data from five patients meeting hEDS criteria.
- Assessed patients for joint hypermobility and loose connective tissue.
Main Results:
- Five female cases aged 16-49 with FMR1 CGG-repeat sizes from 66 to 150 were identified.
- All cases exhibited hEDS symptoms since childhood.
- Identified shared molecular pathogenesis involving reduced FMR1 protein, extracellular matrix disruption, and RNA toxicity.
Conclusions:
- The hEDS phenotype and FMR1 premutation may co-occur due to overlapping molecular pathways.
- Recognizing this association is crucial for accurate diagnosis and management.
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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