Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series

Abstract

BackgroundWhile 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.ObjectiveTo report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.MethodsWe 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.ResultsFive 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.ConclusionBoth hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

“…Clinically, premutation carriers can manifest connective tissue-related features such as hyperextensible finger joints, large ears, and connective tissue dysplasia that are more subtle than those seen in FXS ( 57 ). Case report evidence including five females with premutation and Ehlers Danlos syndrome phenotype suggests there may be related commonalities in pathogenesis ( 58 ). Possible pathophysiologic mechanisms hypothesized include FMRP deficiency, mRNA toxicity, and sex effects ( 58 ).…”

“…Case report evidence including five females with premutation and Ehlers Danlos syndrome phenotype suggests there may be related commonalities in pathogenesis ( 58 ). Possible pathophysiologic mechanisms hypothesized include FMRP deficiency, mRNA toxicity, and sex effects ( 58 ). FMRP is known to regulate multiple connective tissue pathways including elastin, actin, and matrix metalloproteinase (MMP9), a class of enzymes involved in bone development, wound healing, and pathology such as arthritis and intracerebral hemorrhage ( 59 , 60 ).…”

The Relationship Between Generalised Joint Hypermobility and Autism Spectrum Disorder in Adults: A Large, Cross-Sectional, Case Control Comparison

“…Moreover, the current study did not include any known genetic forms of ASD. 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 ). The current sample was overall high functioning and, therefore, the group of individuals with early identified autism and intellectual disabilities, which tend to be associated with genetic syndromes, were missed.…”

Fragile X Premutation: Medications, Therapy and Lifestyle Advice

“…The major cause behind the clinical signs and symptoms seen in the premutation carriers is elevated mRNA and at the upper end of the premutation (>120 CGG repeats), the level of the FMR1 protein (FMRP) can be reduced significantly. 8 Though FMRP is present in all our cells, it is most abundant in the brain. On the molecular level, FMRP binds with transcripts and exerts its various effects by regulating RNA synthesis, mRNA transport, and mRNA translation for hundreds of genes and by binding with certain proteins such as ion channels to control their function.…”