Prolonged Gastrointestinal Transit Times and Dysmotility in m.3243A>G Mitochondrial Disease

Gastrointestinal (GI) symptoms are frequently reported from carriers of the pathogenic mitochondrial DNA variant m.3243A>G, causing decreased mitochondrial adenosine triphosphate (ATP) production. ATP deficiency may adversely affect both autonomic neurogenic and myogenic regulation of GI motility, contributing to the symptoms. This study examined if carriers of m.3243A>G exhibit GI dysmotility, characterized as prolonged segmental transit times and decreased motility indices.

Twenty-two Danish carriers of m.3243A>G and 22 healthy, sex- and age-matched controls with body mass index < 26 kg/m² were included. Symptoms were assessed using the validated questionnaires Gastroparesis Cardinal Symptoms Index (GCSI) and Gastrointestinal Symptom Rating Scale (GSRS). GI segmental transit times and motility indices were measured using the ingestible SmartPill, which records pressure, temperature, and pH throughout the GI tract.

Median [interquartile range] GI symptoms were higher in carriers of m.3243A>G assessed with GCSI (1.3 [0.4-1.9] vs. 0.2 [0.0-0.4], p < 0.001) and GSRS (2.1 [1.4-3.3] vs. 1.1 [1.0-1.2], p < 0.001). m.3243A>G carriers further exhibited prolonged median [interquartile range] gastric emptying time (221 min [150-348] vs. 165 min [137-199], p = 0.02), colonic transit time (2283 min [1082-5153] vs. 1014 min [840-2451], p = 0.03) and decreased mean [confidence interval] colonic motility index (114.7 mmHg*s/min [86.2; 143.3] vs. 168.6 mmHg*s/min [129.9; 207.3], p = 0.03) compared to controls. However, these measures were not associated with the perceived GI symptoms.

Carriers of m.3243A>G demonstrated gastroenteropathy, evident as prolonged gastric and colonic transit time and decreased colonic motility index. It is plausible that the negative effect of impaired mitochondrial ATP production impacts the regulation of GI motility.