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Gastrointestinal System

Ask-the-Expert: Gastrointestinal (GI) Issues and Myotonic Dystrophy


Originally presented on October 18th, 2024.

Do you have questions for myotonic dystrophy (DM) doctors? Join gastroenterologist, Dr. Irene Sonu from Stanford Medicine, for an "Ask the Expert" webinar on gastrointestinal (GI) issues and DM!

Find all our upcoming Ask the Expert dates and previously recorded sessions! >>>

MDF Resources referenced in this video:

About our Myotonic Dystrophy Expert

Dr. Irene Sonu, Gastroenterologist, Stanford Medicine 

Dr. Irene Sonu is a Gastroenterologist at Stanford Medicine. She is passionate about gut health and strive to provide the best care to my patients. She specializes in complex motility disorders of the gastrointestinal tract. Her areas of clinical expertise include achalasia, dysphagia, eosinophilic esophagitis, gastroesophageal reflux disease, gastroparesis, functional dyspepsia, irritable bowel syndrome, and pelvic floor dysfunction. Dr. Sonu also sees patients in need of fecal microbiota transplant for recurrent C. difficile infection.

Ask-the-Expert: Gastrointestinal Tract (GI) & DM

 

Originally presented on April 16th, 2021.

Do you have questions for DM doctors and therapists? Join Leila Neshatian, MD, MSc of Stanford University for a “Ask-the-Expert” session on the GI tract. After the success of the Stump-the-Doctor session at the 2020 Virtual MDF Conference, MDF has created a series using the same format to connect families and DM experts.

Dr. Neshatian is a neurogastroenterologist and Gastrointestinal Director at Stanford University, Division of Gastroenterology and Hepatology. Her clinical areas of expertise and research include functional gastrointestinal and motility disorders. Click here to learn more about Dr. Neshatian.

Click here to find all our upcoming “Ask-the-Expert” question sessions!

 

Patterns:

  • Because both the smooth and skeletal muscles are involved in DM1, dysfunction along the entire gastrointestinal (GI) tract is common in this disorder. Children with CDM may have profound oral facial weakness that prevents oral intake and requires a gastrostomy tube. This will improve with age, though not completely.

Symptoms:

  • Gastrointestinal issues.

  • Constipation, diarrhea, fecal incontinence, which can result in fecal impaction and megacolon.

  • Gastrointestinal dysmotility that frequently results in pseudo-obstruction and can lead to aspiration.

  • Aspiration, abdominal pain and bloating.

  • While children with childhood-onset DM1 do not have neonatal feeding problems, they may have any of the other symptoms. Children may have urinary incontinence and difficulty toilet training. This may resolve, or partially resolve, with age.

Treatment:

  • Feeding support should be managed by nasogastric tube initially, as many children with CDM will improve in feeding function over time. Placement of a gastrostomy-tube for longer term feeding is warranted for those who do not show improvement by one month of age, corrected for prematurity if needed.

  • Fiber supplementation (more than 8 grams daily) for children with constipation or diarrhea.

  • Gentle laxatives for constipation:

    • First-line therapy recommendations: polyethylene glycol (Miralax), senna (Ex-Lax, Senokot), docusate (Colace) or lactulose (Cholac).

    • Second-line therapy recommendations: bisacodyl (Dulcolax, Correctol), lubiprostone (Amitiza) or linaclotide (Linzess).

    • Metoclopramide (Reglan) to reduce the symptoms of gastroparesis, pseudo-obstruction and gastric reflux. Long-term use is not recommended because this drug can cause tardive dyskinesia.

    • Antibiotics to reduce diarrhea if bacterial overgrowth is found on breath testing.

    • Referral to a gastrointestinal specialist for anal manometry should be considered if a patient does not respond to the first- or second-line recommendations above.

    • Oils should be avoided.

  • Mexiletine may be considered for refractory diarrhea or constipation.

  • Refer to speech therapy for children with a feeding tube. Children should be periodically re-assessed for improving dysphagia.

  • Children with CDM often benefit from dysphagia therapy. With aggressive dysphagia therapy, children with CDM often are able to PO feed within the first year of life.

Patterns:

  • Dysphagia, aspiration, abdominal pain and bloating, especially after eating, slow gastric emptying, gastroesophageal reflux, constipation, diarrhea and “irritable bowel” symptoms, gallstones, dilated colon which can result in fecal impaction, megacolon and even perforation of the bowel; and anal incontinence.

  • Elevated GGT, which is usually NOT an expression of a liver disease, is a common and early finding. However, liver steatosis and cholelithiasis are also common findings in DM2 and should be carefully monitored.

  • Gastrointestinal dysmotility that frequently results in pseudo-obstruction and can lead to aspiration.

Symptoms:

  • Problems with chewing or swallowing, drooling, gastroesophageal reflux, bloating, abdominal pain, frequency and characteristics of bowel movements, diarrhea and fecal incontinence. Careful history should be taken to differentiate oropharyngeal dysphagia from esophageal dysphagia. Esophageal dysphagia sometimes causes chest pain due to acid reflux from the stomach.

  • Involuntary weight loss or weight gain; dysphonia or dysphagia that may indicate pharyngeal muscle weakness; frequent cough and recurrent broncho-pneumopathies that may indicate aspiration; abdominal pain on palpation (generally in, or in the area of, the gall bladder); and abdominal bloating during routine physical exams.

Diagnosis:

  • Discuss the following tests with your doctor:

    • Screening guidelines for colon cancer that apply to the general population.

Treatment:

  • If taking mexiletine, take with food to avoid dyspepsia and transient ‘dizzy feelings’. Food extends absorption and lowers the peak level in blood, and lessens the gastrointestinal side effects that can potentially occur with mexiletine.

  • If symptoms persist, refer to gastroenterologist for proper examinations which can include among others: ALT, AST, GGT, abdomen ultrasound and in some cases endoscopic evaluations.

  • Non-pharmacologic treatments for gastrointestinal symptoms:

    • High-fiber diet (15-20 grams per day) for diarrhea or constipation as first response. Increased fiber intake should be undertaken with increased water intake, with the exception of drinks that are high in caffeine and fructose.

    • Nutrition consultation for dysphagia, weight loss or weight gain, to assess nutritional adequacy.

    • Dysphagia therapy referral, including compensatory strategies and dietary modifications, for oral pharyngeal dysphagia.

  • Potential pharmacologic treatment for gastrointestinal symptoms:

    • Loperamide (Imodium), for diarrhea.

    • Gentle laxatives (see below) for constipation. Oils should be avoided. If no response to the first- or second-line recommendations below, a referral to a gastrointestinal specialist for anal manometry should be considered:

      • First-line therapy recommendations: polyethylene glycol (Miralax), senna (Ex-Lax, Senokot), docusate (Colace) or lactulose (Cholac).

      • Second-line therapy recommendations: bisacodyl (Dulcolax, Correctol), lubiprostone (Amitiza) or linaclotide (Linzess).

      • Metoclopramide (Reglan) may be used to reduce the symptoms of gastroparesis, pseudo-obstruction and gastric reflux. Long-term use is not recommended because this drug can cause tardive dyskinesia.

      • If bacterial overgrowth is found on breath testing, treating with antibiotics may reduce diarrhea.

    • Enteral feeding (tube feeding) for severe dysphagia, for example, dysphagia that causes weight loss or recurring pneumonia, if required.

Patterns:

  • Because the smooth, as well as the skeletal, muscles are involved in DM1, dysfunction along the entire gastrointestinal (GI) tract is common in this disorder. Weakness and myotonia of the smooth muscles occurs.

  • Among the common problems are dysphagia, aspiration, abdominal pain and bloating, especially after eating, slow gastric emptying, gastroesophageal reflux, constipation, diarrhea and “irritable bowel” symptoms, gallstones, dilated colon, which can result in fecal impaction, megacolon and even perforation of the bowel; and anal incontinence. GI symptoms are not only surprisingly common in DM1 but can also be the initial or dominant clinical characteristic. However, these symptoms may be underestimated or ignored.

  • Gastrointestinal dysmotility that frequently results in pseudo-obstruction and can lead to aspiration.

Symptoms:

  • Problems with chewing or swallowing, drooling, gastroesophageal reflux, bloating, abdominal pain, frequency and characteristics of bowel movements, diarrhea and fecal incontinence. Careful history should be taken to differentiate oropharyngeal dysphagia from esophageal dysphagia. Esophageal dysphagia sometimes causes chest pain due to acid reflux from the stomach. Food aspiration and resultant pneumonia are a leading cause of death in DM1 patients.

  • Involuntary weight loss or weight gain; dysphonia or dysphagia that may indicate pharyngeal muscle weakness; frequent cough and recurrent broncho-pneumopathies that may indicate aspiration; abdominal pain on palpation (generally or in the area of the gallbladder); and abdominal bloating during routine physical exams.

Diagnosis:

  • Discuss the following tests with your doctor:

    • Physical exams such as a rectal exam for constipation, including anal sphincter spasm and dyssynergic defecation for symptomatic individuals.

    • Acute abdominal symptoms:

      • Pseudo-obstruction in addition to mechanical obstruction.

      • If acute bowel obstruction is considered, CT enterography or MR enterography can distinguish pseudo-obstruction from the surgical emergency of true (mechanical) obstruction.

      • Foer acute abdominal pain, cholecystitis should be excluded.

      • Individuals without mechanical obstruction should be treated conservatively for pseudoobstruction and/or cholelithiasis.

      • Abdominal x-ray to evaluate abnormal bowel gas or stool, or free abdominal air.

      • Abnormal amounts of hydrogen with the glucose breath test. It is abnormal for individuals with lactose intolerance and bacterial overgrowth in their intestine.

    • Signs of abnormal bowel gas or stool, or free abdominal air in an abdominal x-ray study.

    • Dyssynergic movements, oral and/or pharyngeal weakness, or aspiration using a standard swallowing study or a modified barium swallow evaluation with consultation by a speech therapist.

    • Abnormalities in stomach, small bowel, large bowel or gallbladder anatomy with abdominal ultrasound or magnetic resonance imaging (MRI).

    • Lower esophageal function and reflux, gastric emptying, and small bowel anatomy and function using barium upper GI radiographic evaluation.

    • Weakness or disordered contraction of esophagus, gastroesophageal sphincter, stomach, small bowel, rectum or anal sphincter using manometry or functional motility testing in patients who do not respond to therapy.

    • Abnormal structure or function of pharynx, esophagus, stomach, small intestine or large intestine using endoscopy.

    • Cholestasis or hepatic involvement using specific blood tests (serum alkaline phosphatase and bilirubin elevation correlate with cholestasis in DM). Measure GGT levels because elevations of AST and ALT may be due to the skeletal muscle disease from DM1. Cholecystectomy is one of the most common reasons for general anesthesia and neuromuscular blocking agents; extreme care should be taken if general anesthesia is necessary to perform this procedure.

    • Follow screening guidelines for colon cancer that apply to the general population; epidemiological studies have shown a higher rate of malignancy for this cancer in DM1.

Treatment:

  • Early referral for consultation by a gastroenterologist should be considered for refractory symptoms. Care should be taken for those tests requiring anesthesia or sedation.

  • Non-pharmacologic treatments for gastrointestinal symptoms:

    • High-fiber diet (15-20 grams per day) for diarrhea or constipation as first response. Increased fiber intake should be undertaken with increased water intake, with the exception of drinks that are high in caffeine and fructose.

    • Nutrition consultation for dysphagia, weight loss or weight gain, to assess nutritional adequacy.

    • Dysphagia therapy referral, including compensatory strategies and dietary modifications, for oral pharyngeal dysphagia.

  • Potential pharmacologic treatment for gastrointestinal symptoms:

    • Loperamide (Imodium), with care, for diarrhea.

    • Gentle laxatives (see below) for constipation. Oils should be avoided. If not response to the first- or second-line recommendations below, a referral to a gastrointestinal specialist for anal manometry should be considered.

    • First-line therapy recommendations: polyethylene glycol (Miralax), senna (Ex-Lax, Senokot), docusate (Colace) or lactulose (Cholac).

    • Second-line therapy recommendations: bisacodyl (Dulcolax, Correctol), lubiprostone (Amitiza) or linaclotide (Linzess).

    • Metoclopramide (Reglan) may be used to reduce the symptoms of gastroparesis, pseudo-obstruction and gastric reflux. Long-term use is not recommended because this drug can cause tardive dyskinesia.

    • If bacterial overgrowth is found on breath testing, treating with antibiotics may reduce diarrhea.

  • Enteral feeding (tube feeding) may be required in for severe dysphagia, for example, dysphagia that causes weight loss or recurring pneumonia. Tube feeding is not commonly needed. Nutrition via gastrostomy tube is acceptable for hospice care.

  • Probiotic regimens (many are over the counter) may be tried under a physicians supervision.

DM and Dental Care: the Neglected Health Risk

Darcy Trill, RDHAP, mobile dental hygenist who specializes in the treatment of people with disabilities and special needs in their homes, provides a compelling overview of the risks of ignoring dental health for DM patients, and strategies for achieving and maintaining oral health. From the 2017 MDF Annual Conference.

Risk of GI Manifestations in DM1 and DM2

Published on Mon, 09/18/2017

GI Symptoms Are an Important Component of DM Disease Burden

The involvement of gastrointestinal functions in all types of myotonic dystrophy is well documented (see MDF’s summary). Common GI symptoms include difficulties in chewing or swallowing, GI reflux, abdominal or chest pain, gallstones, constipation, diarrhea, impaired/painful bowel movements, and incontinence. GI manifestations have been treated by repurposing existing drugs (e.g., mexiletine, metoclopramide, cholestyramine) or behavioral modifications. Awareness of the types and breadth of GI manifestations from appropriately powered studies is vital to inform patient management.

Report on GI Manifestations from a Registry-based Study

James Hilbert and colleagues have reported findings of the frequency, progression and management of GI manifestations using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. The investigators evaluated Gi manifestations in a cohort of adult patients (913 DM1 and 180 DM2) enrolled in a patient-reported registry, analyzing data collected between 2002 and 2016, with annual updates on registrants.

GI Manifestations Represent a Substantial Factor in the Burden of Disease.

GI involvement was already prevalent among registrants at initial data entry, as 79% of DM1 and 77% of DM2 registrants reported one or more manifestations. Less than 2% of DM1 and none of the DM2 patients reported GI involvement as the first sign of their disease. In order of descending frequency, trouble swallowing, acid reflux, and constipation were most commonly reported for DM1, while constipation, acid reflux, and trouble swallowing were most commonly reported for DM2. Abnormal liver problems were in sufficient numbers (6-8% of DM1 and DM2) to potentially be a factor for clinical trials. As in prior reports of gender differences, female sex was associated with a higher frequency of GI manifestations in both DM1 and DM2 (constipation and gallbladder problems in this study)Analysis of management practices for GI manifestations included 59 medications used in DM1 and 28 medications in DM2. 

Analysis of disease progression in this studied was based on the approximately 50% of DM1 and DM2 registrants with data available at baseline and year 5. For DM1, trouble swallowing (the most frequent symptom at baseline) and acid reflux were the most frequently reported manifestation not previously present at baseline. Likewise, for DM2, manifestations of constipation and swallowing (the first and third most frequent symptoms, respectively, at baseline) were most frequent new reports at year 5.

Better Understanding of Causes, Consequences and Treatment of GI Manifestations Will Require International Collaboration

The research team notes that GI manifestations have complicating consequences for disease management and patient quality of life. Disease duration was associated with GI manifestations, confirming prior findings in DM1. The pathogenic mechanisms and putative biomarkers for many of the GI manifestations are poorly understood—this group noted no association with repeat length—and treatments are symptomatic. Often symptomatic treatments haven’t been systematically studied in DM. Finally, these researchers note the importance of data sharing to assess GI manifestations, and their progression and treatment, across a larger, better powered cohort.

Reference:

High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2.
Hilbert JE, Barohn RJ, Clemens PR, Luebbe EA, Martens WB, McDermott MP, Parkhill AL, Tawil R, Thornton CA, Moxley RT 3rd; National Registry Scientific Advisory Committee/Investigators.
Neurology. 2017 Aug 30. pii: 10.1212/WNL.0000000000004420. doi: 10.1212/WNL.0000000000004420. [Epub ahead of print]

 

Gender-Related Cancer Risk in DM1

Published on Thu, 09/22/2016

A recent study corroborated increased susceptibility to cancer in DM1, for women in particular, and linked the elevated risk to depressed levels of a tumor suppressor microRNA (miRNA). The association between DM1 and increased risk of certain types of cancer was first recognized in 1965. Recent studies have validated these initial findings and suggested that cancer risks in DM1 were greater in women, but the causative mechanisms remained unknown. 

Dr. Adolfo López de Munain (Donostia University Hospital, San Sebastián, Spain) and colleagues have now corroborated gender differences in susceptibility to cancer and identified potential molecular mechanisms behind the cancer risk in DM1. In a publication in Neurology, Dr. López de Munain’s team quantified cancer risk in a well-characterized cohort of 424 patients with DM1, representing > 18,000 patient years of data, and explored the potential molecular links between DM1 and cancer prevalence.

All patients in the study had molecular confirmation of DM1 and substantial longitudinal phenotypic data available. The observed numbers of cancers in the DM1 cohort were compared against the numbers that would be expected, as calculated from the Basque region’s overall prevalence numbers, in order to determine standardized cancer incidence ratios. The investigators also performed gene expression analyses as a first step to understand molecular mechanisms behind the cancer prevalence data.

When compared to a general, geographically controlled population, DM1 patients showed a 2-fold increased risk of developing cancer. Mean age of malignant cancer detection in the DM1 cohort was 47 years. Gastrointestinal, genitourinary, skin and thyroid were the most frequent sites for malignant tumors. Increased risk was stronger in women with DM1.

In the overall DM1 population evaluated in this study, cancer represented the third leading cause of death, after respiratory and circulatory diseases. Analyses of molecular factors that may differentiate the at-risk DM1 population included CTG repeat length and genome-wide expression analysis of blood leukocytes using Affymetrix microarrays. The authors did not find a correlation between expanded CTG repeat length and cancer risk. Genome wide expression analysis did show differential expression of several genes that were previously linked to cancer (e.g., PDK4, DAPK1, CASP5, and PLA2G7).

Moreover, female patients with DM1 displayed significant down-regulation of the miRNA-200c/141 tumor suppressor family, while levels of this miRNA were elevated in men with DM1. Prior studies, in non-DM cohorts, have shown an association between declines in miRNA-200c and tumor progression/poor prognosis. Although further studies will be needed to mechanistically link changes in the DM1 transcriptome to increased cancer risk, the data from the San Sebastián group supports a compelling hypothesis linking reduction in tumor suppressor genes to cancer risk in women with DM1. The gender-specific differences in susceptibility to cancer, and the linkage to reduced levels of miRNA-200c, are particularly compelling findings for validation in independent DM1 cohorts and further mechanistic analyses.

Reference:

"Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation."
Fernández-Torrón R, García-Puga M, Emparanza JI, Maneiro M, Cobo AM, Poza JJ, Espinal JB, Zulaica M, Ruiz I, Martorell L, Otaegui D, Matheu A, López de Munain A.
Neurology. 2016 Aug 24. pii: 10.1212/WNL.0000000000003124. [Epub ahead of print]

MDF Fellow Profile: Dr. Melissa Hinman

Published on Thu, 09/10/2015

Although up to 25% of people with myotonic dystrophy report that gastrointestinal symptoms are their most troubling issue, we still understand little about their cause. MDF Fellow Dr. Melissa Hinman at the University of Oregon is tackling this issue with Dr. Andy Berglund of the University of Florida using zebrafish models.

Hinman, who received a Case Western University Doctoral Excellence award in 2014 for her work on the NF1 gene, says she was drawn to work on myotonic dystrophy for her postdoctoral fellowship because of the complicated nature of the pathology. “The mechanisms of most genetic diseases that you hear about are a bit boring to me,” she explains, “a mutation in DNA leads to loss or gain of function of some protein, which causes disease phenotypes. RNA-related diseases are much more creative in their mechanisms and it’s a fascinating puzzle try to figure out how they work.”

Focusing in on gastrointestinal (GI) changes in DM, she has hypothesized that inappropriate GI motility in DM causes changes in gut microbiota, which then feed back to impact disease phenotypes. To get at this question, Hinman will characterize whether and how gut motility differs in DM model zebrafish, and use tissue-specific expression of CUG repeats to narrow down the tissues that are responsible for gut phenotypes. She will then use established methods for manipulating zebrafish gut bacteria to determine whether microbiota are necessary for DM related phenotypes, and whether altered bacteria cause DM-related phenotypes in wild type fish.

“It is becoming increasingly clear that human health is influenced not just by our own genome, but also by the genes of the microbes that live on and within us, or the microbiom,” says Hinman. “Deviations from normal microbiota have been shown to contribute to many human disorders such as inflammatory bowel disease, cancer, and obesity. Individuals with diseases that impair gut motility, such as Hirschprung’s disease, often have altered microbiota, which are thought to influence disease severity. Since gut motility is also affected in DM, we are investigating whether there are associated changes in microbiota and how these changes might influence disease symptoms.”

After several months of prep work she is finally ready to start characterizing several new stable models of DM in zebrafish, and is looking forward to seeing what light they may be able to shed on gut phenotypes. Although mentor Andy Berglund’s focus on myotonic dystrophy matched her interests well, Hinman says that it’s an added bonus that the University of Oregon is the birthplace of the zebrafish as a model organism and home to many zebrafish experts, including her co-mentor Karen Guillemin (because Berglund has moved to the University of Florida, Hinman is finishing her project in Guillemin’s laboratory). In the future she would like to delve deeper into the molecular mechanisms behind myotonic dystrophy and speculates that zebrafish would be an ideal model for this goal, as well as for screening therapeutic compounds.

Hinman will be giving a talk about her work at the MDF Annual Conference in Washington, DC, on September 19th. She says she is most looking forward to meeting people who are living with the disease, saying “I never got the opportunity to meet anyone with NF1 (the disease that I studied in graduate school), and as a result I felt like I didn’t fully understand the disease.” Dr. Hinman’s talk will be recorded and available to view on the MDF website by the end of September.

09/15/2015

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