MDF is pleased to announce that Dr. Melissa (“Missy”) Dixon, a Research Associate in the Deptartment of Neurology at the University of Utah, has been awarded a 2016-2017 postdoctoral fellowship.

Dr. Dixon’s research proposal is titled “Evaluation of Functional Connectivity as a Brain Biomarker in Congenital Myotonic Dystrophy.” In this study, she and her colleagues will use magnetic resonance imaging (MRI) to evaluate connectivity networks in the brains of children with congenital-onset myotonic dystrophy (CDM) to see if they differ from those of children without CDM, whether they change over a one-year time period, and whether the MRI results correlate with data from neuropsychological testing.

Dr. Dixon has an extensive background in clinical psychology, neuropsychological testing and clinical trial coordination. She received her doctorate in counseling psychology from the University of Utah in December 2015. We recently talked with Dr. Dixon to learn more.

MDF: There was a time when most children with CDM didn’t survive very long. Do they have a better prognosis now?

MD: Oh, absolutely. I would say that kids with this disorder have a better prognosis than they did a decade ago. We now know that respiratory and feeding problems can be life-threatening, and we’re better equipped to work with those issues from the start.

MDF: What is known so far about the neuropsychology and the brain abnormalities in children with congenital-onset myotonic dystrophy?

MD: Networks in the brain are kind of like a highway system. You can get from Illinois to Colorado by taking Interstate 80, but if there’s a block in that road or a piece of the road that’s missing, you have to take a different route to go around it. 

I don’t know if there are fewer “interstates” in the brains of children with CDM compared to those of children without CDM, but it may be that they’re using more roundabout pathways for getting from one place to another. I think the networks are different [from those in unaffected children.]  

People have used resting-state functional MRI [fMRI] during the resting state [without an attentional focus] to look at brain connectivity in kids who have autism, and they’ve found that it’s sensitive enough to show that there are differences in their connectivity networks. 

Earlier DM studies relied on structural imaging techniques. These can demonstrate a wide range of changes, but they’re not well correlated with clinical outcomes, such as IQ.

We think that by using fMRI we’ll be able to look at connectivity differences in these brain networks and see if they change over time in kids with CDM. 

MDF: Will this study be helpful in telling parents what to expect as their child matures?

MD: We’re hoping to be able to demonstrate changes over time by looking at blood flow in the brain using resting-state fMRI, at baseline and then at a year from baseline.

We’ll be tracking neuropsychological measures, such as executive function and IQ assessment. We’ll also look at adaptive behavior, at how a child is functioning, through a questionnaire that a parent or caregiver will fill out.  At the completion of the study, we would hope to tell parents where a child may have the most learning difficulty, and design interventions to approach those learning difficulties.  

MDF: If you do see abnormalities in connectivity in the brain, what are the possible implications?

MD: We know that cognition is impacted in CDM, but there is not a very sensitive way to see how this changes during the course of a short period of time, like during a drug trial. This technique could become an endpoint for a clinical trial to test the effect of a potential drug or therapy.

MDF: Is it possible that something like, say, DMPKRx, which is being developed by Ionis Pharmaceuticals, could have an effect on the brain, if it could be made to cross the blood-brain barrier?

MD: If not that particular therapeutic, then perhaps another, could potentially slow or halt the progression of the brain changes in this disease as we learn more about them.

MDF: Can you say more about the fMRI study?

MD: We’ll be enrolling 20 participants with CDM, ages 7 to 14, and we already have a control group for comparison. We’re not recruiting yet for the fMRI study; we’re still at the IRB [institutional review board] stage, applying for study approval. We hope to start recruiting in June 2016, and we’ll be posting that on the MDF site when we do. [Studies are listed at the MDF Study and Trial Resource Center under the Current Studies and Trials tab.]

We do, however, have an ongoing study of the natural history of CDM here at the University of Utah, and we hope to recruit some participants for the fMRI study from that group. [The natural history study, which is open, is Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy. Read more about it at the MDF Study and Trial Resource Center under Current Studies and Trials.]

We’ve done neuropsychological testing with the children in the natural history study. The children are all different, and that’s what makes CDM so interesting. The cognitive piece is fascinating. That profile for them is definitely varied, and I think that some of the measures that we’ve been using are just not sensitive enough to understand what’s going on.

I chose 7-year-olds as the lower cut-off age, because they have to stay in the fMRI scanner for 20 to 30 minutes. That can be difficult or scary for any child, and children with CDM sometimes have sensory issues. They’ll have something that’s like a fish tank for them to watch during the scan. It’s not like a movie, where they’d be actively thinking about things, but they’ll be looking at something.

MDF: You have a broad background in clinical psychology. What led you to study children with myotonic dystrophy?

MD: In 2013, when [neuromuscular disease specialist] Dr. Nicholas Johnson came here from the University of Rochester, I became interested in people who have myotonic dystrophy, particularly congenital myotonic dystrophy. I’m interested in understanding the neuropsychological differences in this population. There isn’t a whole lot of known information about congenital myotonic dystrophy and neuropsychological function.

MDF: Did you know that another MDF research fellow, Dr. Ian DeVolder, is doing a study of fMRI in adults with type 1 DM?

MD: Yes, I saw that. That was great to see that someone is doing something very similar in adults. I’m sure our paths will cross as we move forward in our careers. Hopefully, both of our efforts will better define the neuropsychological dysfunction throughout the life spectrum.

Community members discuss daily living strategies for motivating their adult children living with juvenile-onset DM1.

Please note: This is an audio recording only. To view the accompanying presentation, please click here.

Community members Penni Warford, Sarah Clarke and Ann Spaulding discuss best practices for planning and implementing your child's Individualized Education Plan.

This is an audio recording only. To see the handout that accompanied this presentation, please click here.

Dr. Craig Campbell, MD, of Western University in Ontario, Canada, has a discussion with audience members about congenital DM. In the video, Dr. Campbell does not follow a set slide show, but he created slides for additional viewing information. Please click here to see his slides.

Community-led session led by Sarah Berman, Erica Kelly, and Catherine Wycoff, DPT, GCFP, ABMCP. Parents of children living with DM and a hippotherapy specialist discuss the benefit that this type of therapy can often have.

View related web resources from this presentation

The Myotonic Dystrophy Family Registry currently has over 1,900 participants, making it one of the largest and most up-to-date myotonic dystrophy (DM) registries in the world. If you’ve been diagnosed with DM1 or DM2, including congenital or juvenile onset, or are the primary caregiver for some who has, and you haven’t already joined the Registry, we need you!

By participating in the Registry you can help researchers from industry and academia identify potential clinical trial participants and research study subjects, and increase understanding of the impact and complexity of this disease.

The Registry is patient-driven, which means you’re in charge of your information. You can opt out of the Registry at any time, and you can also visit the Registry website to review de-identified (anonymous) data and information the same way that registered researchers do. Your individual information is kept completely confidential. Data in patient registries is typically considered out of date and less useful if it is not updated at least every 18 months, so we’ll remind you to log back into the Registry to review and update your survey occasionally.

Click here to go to the Registry website, read and sign the consent form, and get started.

Questions? Contact the Registry Coordinator for more information.

08/20/2014

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