Sex differences in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders - Ehlers-Danlos syndromes (EDS) comprise a heterogeneous group of heritable genetic connective tissue/ collagen disorders characterized by fragile soft connective tissue and widespread distribution that manifests in the skin, ligaments, joints, blood vessels and internal organs. Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are the most common form of EDS comprising 80-90% of cases and are believed to affect an estimated 3% or 255 million people worldwide. Although the mutations responsible for most types of EDS have been identified, the genes responsible for hEDS and HSD are unknown. Comorbidities associated with hEDS/HSD include subluxations/dislocations, pain, fatigue, anxiety, fibromyalgia, migraine/headaches, inflammatory bowel disease, mast cell activation syndrome, and many other conditions leading to reduced quality of life. As an autosomal dominant genetic condition hEDS/HSD would be expected to display a 1:1 sex ratio, but several studies have revealed a sex ratio of 9:1 women to men. Although sex differences are known to be important factors in the natural history of HSD and hEDS, no studies have systematically examined serum biomarkers, immune phenotype and/or comorbidities in hEDS/HSD according to sex. Because of the current gaps in knowledge, the average time from onset of symptoms to diagnosis is 14 years. Thus, there is a critical need to research sex differences in hEDS/HSD to better understand the pathogenic mechanisms and to provide a more comprehensive multi-disciplinary treatment approach to relieve the suffering of this large population of understudied patients. The overall goal of this proposal is to examine biological sex differences in immune defects that lead to higher hEDS in females compared to males and mitochondrial defects that lead to higher HSD in females compared to males.
