Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls

Abstract

BackgroundA growing body of literature suggests etiological overlap between Ehlers-Danlos syndrome (EDS)/hypermobility spectrum disorders (HSD) and some cases of autism, although this relationship is poorly delineated. In addition, immune, autonomic, and endocrine dysregulation are reported in both conditions and may be relevant to their respective etiologies.AimsTo study symptom overlap in these two comorbid spectrum conditions.Methods and ProceduresWe surveyed 702 adults aged 25+ years on a variety of EDS/HSD-related health topics, comparing individuals with EDS/HSD, autism, and unaffected controls.Outcomes and ResultsThe autism group reported similar though less severe symptomology as the EDS/HSD group, especially in areas of immune/autonomic/endocrine dysregulation, connective tissue abnormalities (i.e., skin, bruising/bleeding), and chronic pain. EDS/HSD mothers with autistic children reported more immune symptoms than EDS/HSD mothers without, suggesting the maternal immune system could play a heritable role in these conditions (p = 0.0119).Conclusions and ImplicationsThese data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, which is typically more severe in the former. This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD).

The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders

“…This form of EDS often presents with periventricular heterotopias, a structural anomaly that has also been noted in autism [ 69 , 70 ]. Raw data from our own previous study [ 16 ] likewise indicate that, compared to sex-matched controls, women with EDS/HSD report higher rates of epilepsy (5% vs. 1%), a figure that is similar to those with autism without intellectually disability (Mann–Whitney U, one-tailed, W = 17284.5, p = 0.042, EDS/HSD N = 367, control N = 98). (See Supplementary File S1, Table S6 for abbreviated raw data).…”

“…Preliminary work from Casanova et al [ 16 ] also suggests that autism and EDS/HSD co-occur within the same families. The researchers found that more than 20% of mothers with EDS/HSD reported having autistic children—a rate not significantly different from those reported by mothers who themselves are on the autism spectrum.…”

“…(See Supplementary File S1, Table S6 for abbreviated raw data). It should be noted, however, that some individuals within our study—though not all—reported seizure disorders following some form of head trauma [ 16 ]. Higher rates of head trauma in this clinical population have been reported in our study and others [ 71 ], possibly related to events of syncope or even coordination issues and increased numbers of accidents.…”

“…Both the immune system and connective tissue engage in significant crosstalk and it is therefore possible that impairment may arise anywhere along this reversible feedback loop, leading to a common phenotype [ 16 , 134 , 135 ]. For instance, in utilizing raw data reported originally in Casanova et al [ 16 ], we show statistically similar profiles of immune-mediated symptoms as reported by female patients across hEDS, cEDS, and vascular EDS (vEDS) subgroups, suggesting that—at least in the case of cEDS and vED—primary collagen impairment also leads to immune dysregulation (Mann–Whitney U, 2-tailed, W = 239–4960.5, p = 0.080–0.232) ( Figure 2 ). (See Supplementary_File_S1 “Tab7_EDS_Immune” for abbreviated dataset; see [ 16 ], Supplementary Materials for full raw datasets).…”

“…Meanwhile, although there are currently no accurate prevalence rates or known genetic associations for the remaining subtype, hypermobile EDS (hEDS), clinical opinion and the fact that it makes up 80–90% of EDS cases strongly suggests it is a common condition. It is therefore probable the majority of hEDS cases are associated with small effect polygenic risk factors and environmental exigencies [ 15 , 16 ]. A whole genome/exome sequencing investigation, the Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) study, is currently underway that will hopefully help to address some of these questions [ 17 ].…”