The WNT/β-catenin Pathway and Matrix Metalloproteinase-9 in hypermobile Ehlers-Danlos Syndrome and Autism Spectrum Disorder: A Possible Connection.

Hypermobile Ehlers-Danlos Syndrome (hEDS), a connective tissue disorder also known as Ehlers-Danlos Syndrome Type III or Ehlers-Danlos Syndrome Hypermobility Type, and Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, present notable symptom overlap and higher than expected level of comorbidity. A recent systematic review and meta-analysis found that the overall prevalence of joint hypermobility in autistic individuals was 22.3%, rising to 31% when clinically assessed. The overall prevalence of Ehlers-Danlos Syndrome or Hypermobility Spectrum Disorder was 27.9%, rising to 39% when clinically assessed rather than self-reported. This comorbidity is likely underrepresented due to factors including gender-related underdiagnosis, limited awareness, and fragmented care. Despite this, research at the disorders' intersection remains limited. In this narrative review, we aim to (i) examine hEDS and ASD from a clinical and molecular perspective; (ii) review literature regarding the WNT/β-catenin pathway and matrix metalloproteinases' involvement in fibroblast phenotypes, extracellular matrix regulation, and synaptogenesis; and (iii) evaluate how pathway dysregulation may connect each disorder's tissue and neurodevelopmental traits. Although both disorders remain pathophysiologically elusive, we hope to shed light on their co-occurrence and promote future research by exploring how these disorders are possibly linked, specifically via WNT/β-catenin and matrix metalloproteinase activity.