High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study

Abstract

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). γGT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and γGT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and γGT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1.

MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility

“…To determine whether Mbnl KO alters GI motility as observed in DM1 ( 5 – 8 ), we performed separate in vivo assays to quantify upper and lower GI tract transit. Upper GI motility was assessed in 3-mo-old mice by measuring the distribution of cell-impermeable fluorescein isothiocyanate-70 kDa dextran conjugate (FITC-dextran) in the small intestine ( 55 ).…”

“…Eighty percent of individuals affected with DM1 experience GI symptoms that affect daily life ( 5 – 8 ) and the mechanisms of GI dysfunction remain unknown. Defects in multiple cell types within the GI system could lead to GI dysmotility, including disruption of the ENS, intestinal epithelium, or smooth muscle ( 73 ).…”

MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility

“…To determine whether Mbnl KO alters GI motility as observed in DM1 ( 5 – 8 ), we performed separate in vivo assays to quantify upper and lower GI tract transit. Upper GI motility was assessed in 3-mo-old mice by measuring the distribution of cell-impermeable fluorescein isothiocyanate-70 kDa dextran conjugate (FITC-dextran) in the small intestine ( 55 ).…”

“…Eighty percent of individuals affected with DM1 experience GI symptoms that affect daily life ( 5 – 8 ) and the mechanisms of GI dysfunction remain unknown. Defects in multiple cell types within the GI system could lead to GI dysmotility, including disruption of the ENS, intestinal epithelium, or smooth muscle ( 73 ).…”

Prevalence of gastrointestinal symptoms and their association with psychological problems in youths

“…Firstly, gastrointestinal symptoms are gender-specific. Females have a higher prevalence of gastrointestinal symptoms (22), probably because estrogens directly affect the intestinal microbes and immune cells (23), and the menstrual cycle affects gastrointestinal transit duration (24), then leading to gastrointestinal symptoms. In our study, the sophomore population had a predominance of females.…”

Intergenerational Influence of Gender and the DM1 Phenotype of the Transmitting Parent in Korean Myotonic Dystrophy Type 1

“…The pathogenesis of DM1 is complex, with a pivotal role played by the pathogenic effect of the mutant DMPK pre-mRNAs harboring the expanded CUG stretch, which will eventually interrupt the expression of other genes in different tissues by damaging the functions of specific transcription factors controlling alternative splicing. Because the DMPK mRNA is expressed widely in various tissues, this finding explains the multi-organ involvement in patients with DM1, including the associated development of gastrointestinal disturbances, endocrine dysfunction, cardiac conduction abnormalities, premature cataracts, and behavioral and cognitive impairments [ 15 ]. Male patients with DM1 tended to show more apparent classical DM1 phenotypes, such as cardiac and respiratory involvement, significant myotonia, and cognitive impairment; however, female patients with DM1 had late-onset disease and more extra-muscular clinical features, characteristics which are less suggestive of DM1.…”

MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility

“…To determine whether Mbnl KO alters GI motility as observed in DM1 ( 5 – 8 ), we performed separate in vivo assays to quantify upper and lower GI tract transit. Upper GI motility was assessed in 3-mo-old mice by measuring the distribution of cell-impermeable fluorescein isothiocyanate-70 kDa dextran conjugate (FITC-dextran) in the small intestine ( 55 ).…”

“…Eighty percent of individuals affected with DM1 experience GI symptoms that affect daily life ( 5 – 8 ) and the mechanisms of GI dysfunction remain unknown. Defects in multiple cell types within the GI system could lead to GI dysmotility, including disruption of the ENS, intestinal epithelium, or smooth muscle ( 73 ).…”

Prevalence of gastrointestinal symptoms and their association with psychological problems in youths

“…Firstly, gastrointestinal symptoms are gender-specific. Females have a higher prevalence of gastrointestinal symptoms (22), probably because estrogens directly affect the intestinal microbes and immune cells (23), and the menstrual cycle affects gastrointestinal transit duration (24), then leading to gastrointestinal symptoms. In our study, the sophomore population had a predominance of females.…”

Intergenerational Influence of Gender and the DM1 Phenotype of the Transmitting Parent in Korean Myotonic Dystrophy Type 1

“…The pathogenesis of DM1 is complex, with a pivotal role played by the pathogenic effect of the mutant DMPK pre-mRNAs harboring the expanded CUG stretch, which will eventually interrupt the expression of other genes in different tissues by damaging the functions of specific transcription factors controlling alternative splicing. Because the DMPK mRNA is expressed widely in various tissues, this finding explains the multi-organ involvement in patients with DM1, including the associated development of gastrointestinal disturbances, endocrine dysfunction, cardiac conduction abnormalities, premature cataracts, and behavioral and cognitive impairments [ 15 ]. Male patients with DM1 tended to show more apparent classical DM1 phenotypes, such as cardiac and respiratory involvement, significant myotonia, and cognitive impairment; however, female patients with DM1 had late-onset disease and more extra-muscular clinical features, characteristics which are less suggestive of DM1.…”

MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility

“…To determine whether Mbnl KO alters GI motility as observed in DM1 ( 5 – 8 ), we performed separate in vivo assays to quantify upper and lower GI tract transit. Upper GI motility was assessed in 3-mo-old mice by measuring the distribution of cell-impermeable fluorescein isothiocyanate-70 kDa dextran conjugate (FITC-dextran) in the small intestine ( 55 ).…”

“…Eighty percent of individuals affected with DM1 experience GI symptoms that affect daily life ( 5 – 8 ) and the mechanisms of GI dysfunction remain unknown. Defects in multiple cell types within the GI system could lead to GI dysmotility, including disruption of the ENS, intestinal epithelium, or smooth muscle ( 73 ).…”

Prevalence of gastrointestinal symptoms and their association with psychological problems in youths

“…Firstly, gastrointestinal symptoms are gender-specific. Females have a higher prevalence of gastrointestinal symptoms (22), probably because estrogens directly affect the intestinal microbes and immune cells (23), and the menstrual cycle affects gastrointestinal transit duration (24), then leading to gastrointestinal symptoms. In our study, the sophomore population had a predominance of females.…”

Intergenerational Influence of Gender and the DM1 Phenotype of the Transmitting Parent in Korean Myotonic Dystrophy Type 1

“…The pathogenesis of DM1 is complex, with a pivotal role played by the pathogenic effect of the mutant DMPK pre-mRNAs harboring the expanded CUG stretch, which will eventually interrupt the expression of other genes in different tissues by damaging the functions of specific transcription factors controlling alternative splicing. Because the DMPK mRNA is expressed widely in various tissues, this finding explains the multi-organ involvement in patients with DM1, including the associated development of gastrointestinal disturbances, endocrine dysfunction, cardiac conduction abnormalities, premature cataracts, and behavioral and cognitive impairments [ 15 ]. Male patients with DM1 tended to show more apparent classical DM1 phenotypes, such as cardiac and respiratory involvement, significant myotonia, and cognitive impairment; however, female patients with DM1 had late-onset disease and more extra-muscular clinical features, characteristics which are less suggestive of DM1.…”