Clinical and Molecular Insights into Gastrointestinal Dysfunction in Myotonic Dystrophy Types 1 & 2

Abstract

Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and molecular analyses of GI dysfunction in both genetic forms of DM, DM type 1 (DM1) and DM type 2 (DM2). Based on current knowledge of DM primary pathological mechanisms in other affected tissues and GI tissue studies, we suggest that misregulation of alternative splicing in smooth muscle resulting from the dysregulation of RNA binding proteins muscleblind-like and CUGBP-elav-like is likely to contribute to GI dysfunction in DM. We propose that a combinatorial approach using clinical and molecular analysis of DM GI tissues and model organisms that recapitulate DM GI manifestations will provide important insight into defects impacting DM GI motility.

Mechanism of an alternative splicing switch mediated by cell-specific and general splicing regulators

“…Furthermore, the SMC transcription factor MYOCD was recently found to indirectly drive a set of SMC AS changes via changes in the expression levels of RBPMS, RBFOX2 and MBNL1 (Liu et al, 2022), and both Rbpms and Mbnl1 were found by scRNA-Seq to be part of a contractile VSMC gene signature (Dobnikar et al, 2018). Indeed, it has been suggested that gastrointestinal dysfunction in myotonic dystrophy is associated with dysregulation of an MBNL1 regulated splicing program in visceral smooth muscle cells (Peterson & Cooper, 2022). Our data suggest that this dysregulated program is likely driven by MBNL1-RBPMS coregulation.…”

Myotonic Dystrophy Type 1: A Comprehensive Literary Review

“…Abnormal gallbladder releases were found in individuals with DM1 administered with cholecystokinin to stimulate release and rates of cholelithiasis are increased in DM1 cohorts 2,16 . In the liver, abnormal levels of alkaline phosphatase, alanine aminotransferase, gamma-glutamyl transferase, and 5' nucleotidase were present 2,16 . Although relatively nonprogressive as a condition, such enzymes can lead to cholestasis and hepatocellular damage 2,16 .…”

“…Between 48-55% of individuals experience swallowing difficulties; between 33-46% experience constipation; between 38-39% of individuals experience acid reflux, making these the most common GI-related symptoms experienced 16 . Barium swallows (where barium is tracked via x-ray after being swallowed to discover abnormalities in esophageal movements) reveal difficulty in the closing of nasal passages, along with a tendency for individuals to retain meals in the oropharyngeal recess, and upper, and lower esophagus as well 16 . In the stomach, DM1 presents a lowered rate of digestion through higher meal lag phases and slower gastric emptying 16 .…”

“…Barium swallows (where barium is tracked via x-ray after being swallowed to discover abnormalities in esophageal movements) reveal difficulty in the closing of nasal passages, along with a tendency for individuals to retain meals in the oropharyngeal recess, and upper, and lower esophagus as well 16 . In the stomach, DM1 presents a lowered rate of digestion through higher meal lag phases and slower gastric emptying 16 . Abnormal gallbladder releases were found in individuals with DM1 administered with cholecystokinin to stimulate release and rates of cholelithiasis are increased in DM1 cohorts 2,16 .…”

“…In the stomach, DM1 presents a lowered rate of digestion through higher meal lag phases and slower gastric emptying 16 . Abnormal gallbladder releases were found in individuals with DM1 administered with cholecystokinin to stimulate release and rates of cholelithiasis are increased in DM1 cohorts 2,16 . In the liver, abnormal levels of alkaline phosphatase, alanine aminotransferase, gamma-glutamyl transferase, and 5' nucleotidase were present 2,16 .…”