Originally presented on November 15th, 2024.

Do you have questions for myotonic dystrophy (DM) doctors and therapists? Join Dr. Lorelei Thornburg, Obstetrician/Gynecologist, and Dr. Johanna Hamel, Assistant Professor in Neurology, Pathology, and Laboratory Medicine, from the University of Rochester for an "Ask the Expert" webinar on reproductive health and DM!

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

MDF Resources referenced in this video:

• Clinical Recommendations for People of Pregnancy Potential with Myotonic Dystrophy
• Toolkits & Publications
• Support Groups
• Calendar of Events
• DM Drug Development Pipeline
• Myotonic Dystrophy Family Registry
• 2025 MDF Annual Conference
• Sign up for My Dispatch, our monthly e-newsletter!

About our Myotonic Dystrophy Experts

Dr. Lorelei Thornburg, Obstetrician/Gynecologist, University of Rochester  

Dr. Thornburg joined the faculty of the University of Rochester in June 2008. She received her undergraduate degree from Kalamazoo College graduating cum laude, and her medical degree from Wayne State University in Detroit, Michigan where she received the David S. Diamond Memorial Award in Obstetrics and Gynecology and was elected to the Alpha Omega Alpha honor society. She completed her residency in Obstetrics and Gynecology at the University of Rochester in Rochester, New York in 2005, where she also served as administrative chief resident during the final year of her residency. Dr. Thornburg completed her fellowship in Maternal Fetal Medicine (Perinatology- High Risk Obstetrics) at the University of Rochester in Rochester, New York in 2008. She received the Ward L Ekas, the George C. Trombetta, the Obstetrical Perinatology, Dr. Curtis J. Lund, and the Creog Awards for leadership and teaching during the course of her residency, and the Todd Faculty Fellowship in Maternal Fetal Medicine Award during her fellowship. She is a board-certified Obstetrician/Gynecologist and Maternal Fetal Medicine and is a Fellow of the American College of Obstetrics and Gynecology. Active areas of research include maternal obesity, ultrasound and resident education.

Dr. Johanna Hamel, Assistant Professor in Neurology, Pathology, and Laboratory Medicine, University of Rochester  

Dr. Hamel is an Associate Professor of Neurology, Pathology and Laboratory Medicine and specializes in the diagnosis and treatment of neuromuscular diseases. Dr. Hamel cares for patients with acquired and hereditary neuromuscular diseases in clinic, with special expertise in myotonic dystrophy (DM) type 1 and type 2 and FSHD. Dr. Hamel also performs electrodiagnostic studies in the EMG lab and teaches residents about neuromuscular diseases. She graduated from medical school at the Martin-Luther-University Halle-Wittenberg in Germany and worked as a neurology resident and researcher at the Charité in Berlin before completing a neurology residency and a clinical neuromuscular fellowship at the University of Rochester.

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]

Dr. Nicholas Johnson and a research team from the Universities of Utah and Rochester partnered on a study commissioned by MDF to study how women with myotonic dystrophy (DM) are impacted by pregnancy. Data for the study were drawn from the Myotonic Dystrophy Family Registry and the National Registry for DM and FSHD. Previous studies have shown that women with DM may have pregnancy complications in excess of what is normally seen in women without DM. For example, pregnant women with DM1 experience more spontaneous abortions, polyhydramnios (excess amniotic fluid), ectopic pregnancies (fertilized egg implants outside the uterus), placenta previa (placenta covers the cervix) and early labor. Other studies focusing on DM2 showed that 21% of women with DM2 had their first symptom during pregnancy, and women with DM2 experienced more urinary tract infections and preterm labor.

This new study recruited 152 women from the two registries and collected data on their 375 pregnancies. Women with DM1 and DM2 had miscarriage rates of 32% and 37%, respectively, which is higher than the national average of 17%. All women with DM combined had a 10% rate of preeclampsia (high blood pressure and protein in urine) and a 14% rate of peripartum hemorrhage (bleeding before, during or after delivery), both of which are well above the national average of 3%. Many common symptoms of DM progressed during pregnancy, including mobility limitations, activity limitations, pain, emotional issues and myotonia. After delivery many of these symptoms reportedly did not return to the level experienced before pregnancy.

The authors summarize their findings by suggesting that “this research may be utilized by DM patients and family members seeking to better understand the risks and outcomes associated with pregnancy and DM.”

Reference:

The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study.
Johnson NE, Hung, M, Nasser, E, Hagerman, KA, Chen, W, Ciafaloni, E, and Heatwole, CR.
Journal of Neuromuscular Diseases. Oct 7, 2015.

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, has prepared the following summary of the recently published study, "Parental Age Effects, But No Evidence for an Intrauterine Effect in the Transmission of Myotonic Dystrophy Type 1" in the Journal of Human Genetics. 

Researchers from the laboratories of Fernando Morales from the University of Costa Rica, and Darren Monckton from the University of Glasgow collaborated in a recent study examining how the DNA mutation causing myotonic dystrophy type 1 (DM1) worsens from one generation to the next. Previous studies have shown that the DM1 mutation behaves differently depending on whether it is passed on from the father or mother. However, there has been conflicting information regarding whether the age of the parent’s symptom onset or parent’s age at conception of their affected child can change the degree to which the child is affected by DM1.

The conflict in research findings is likely the result of using different methods to assess the size of the DM1 mutation, and failing to account for the age of the parent at the time the blood was collected, since the mutation grows throughout their lifetime. This study uses a newer technique called "small pool PCR" to assess the mutation size, and a complex statistical analysis to predict what the original size of the repeat was at birth. This method clarified the relationship between parent and child with regard to CTG repeat size and symptom onset, confirming that children born with DM1 have an inherited repeat that is larger than their parent’s repeat about 95% of the time, and symptom onset comes earlier in the child than their affected parent around 86% of the time. Furthermore, the parent’s age of onset is correlated with the child’s age of onset, but the correlation is much stronger in affected mothers than fathers.

What really stood out in this paper was a completely new finding that the age of the affected parent at conception correlates with the repeat size in their child. In other words, as people with DM1 age, the size of the repeat in their eggs or sperm grows larger. Basic genetic principles dictate that there is a 50% chance of an affected parent passing on the mutation to their child.

This paper found that if the child inherits the mutation from their mother and gets DM1, there is a 64% risk of the child’s DM1 being congenital if the mother’s repeat size is above 164 CTGs. There are very few cases of an affected father having a congenitally affected child, and none were found in this study. Unfortunately, current procedures for diagnosing DM1 do not use the same experimental method as in this paper and do not predict what the individual’s repeat was at birth. Therefore this predicted risk cannot be applied to mothers whose repeat was sized using conventional methods for diagnosis.

The authors estimate that the diagnostic test most women get to determine the size of their repeat would also predict that if their offspring inherit the expanded repeat, they would be congenitally affected 64% of the time when the mother's repeat length is over 284 CTGs.

Genetic counseling for families with DM1 can be very complicated, as many factors such as the repeat size and sex of the DM1-affected parent can alter any predictions as to how severely a child may be affected. Overall, this study clarifies how the growing repeat size in adults with DM1 can affect their children, and brings to light a new factor to be considered by genetic counselors when advising families of the risks of transmitting DM1.

Click here to view the article abstract. Click here for an interview on genetic counseling with Carly Siskind of Stanford University Hospital and Clinics.

08/20/2014