EDS and Its Mutations Unusually Evident in People With Gastroparesis

Trials into digestive system disorder find high number of Ehlers-Danlos patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A higher incidence of Ehlers-Danlos syndrome (EDS) is evident in people with gastroparesis — a condition in which the stomach doesn’t properly empty itself of food — than would be expected among the general public, researchers reported.

Genetic analysis revealed that mutations in genes associated with EDS, in particular COL5A1 and TNXB, occurred significantly more often in people with gastroparesis than in people without it.

The findings may explain the link between the two conditions, particularly for people with idiopathic gastroparesis in which the cause of the disease isn’t known.

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The work, “Enrichment of Patients with Ehlers Danlos Syndrome in Idiopathic Gastroparesis — A Gene Set Enrichment Analysis,” was published as a brief report in the journal Clinical and Translational Gastroenterology.

EDS encompasses a group of heritable connective tissue disorders mainly characterized by overly mobile joints, delayed wound healing, and fragile connective tissues. Different EDS types are caused by mutations in various genes, with least 20 different genes identified.

Digestive symptoms, including constipation, diarrhea, and acid reflux, have also been described in EDS patients. In particular, some patients have problems with gastric emptying, or clearing the stomach of food.

While conducting Phase 2 and 3 clinical trials (NCT02970968 and NCT04028492) in people with gastroparesis, researchers with Vanda Pharmaceuticals found that a particularly high number of gastroparesis patients had EDS.

The two trials involved 686 patients with either gastroparesis associated with diabetes — a condition caused by diabetes — or idiopathic gastroparesis, meaning no underlying cause had been identified. Symptoms of gastroparesis include nausea, vomiting, bloating, and abdominal pain.

Fourteen of these 686 patients had confirmed EDS in their medical records, a significantly higher EDS incidence than the 1 in every 5,000 people that serves as a “conservative” estimate for the general population.

Of these 14 patients, 94% were females with idiopathic gastroparesis, and an average age of 28.

Given the apparent association between the two conditions, the researchers explored the presence of EDS-associated gene mutations in gastroparesis patients. A genetic screening was performed for mutations in a core set of genes known to be involved in EDS: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, COL5A3, ADAMTS2, FKBP14, PLOD1, and TNXB.

All but one patient had a mutation in the core set of genes. Among these 13 people, 19 mutations were found, nine of which had been previously associated with EDS, the researchers reported.

Two mutations were found in more than one patient. Specifically, the p.G530S mutation in the COL5A1 gene and the p.K3015R mutation in TNXB were each found in two EDS patients.

Notably, the COL5A1 variant has been previously associated with classical EDS. In a larger group of gastroparesis patients, p.G530S was reported in five of 128 diabetic patients and 27 of 238 idiopathic patients, with the mutation being more significantly associated with idiopathic gastroparesis.

Further analysis compared mutations in the core genes of 238 idiopathic gastroparesis patients with 902 sex-, age-, and ancestry-matched people without gastroparesis, serving as controls.

A significantly higher frequency of mutations in COL5A1 and TNXB were observed in the idiopathic gastroparesis group than healthy controls.

“The results of this analysis imply that there may be more cases with underlying EDS and EDS variants than expected by chance in the gastroparesis set, perhaps explaining proportion of the idiopathic etiology,” the researchers wrote.

“There may be variants of consequence predisposing to risk for EDS outside the core genes tested,” they added, noting that a larger genetic study is warranted to “help discern any other genetic underpinnings of EDS in gastroparesis set of patients.”

Ultimately, study findings may help in better treating these “comorbid disorders,” the team concluded.