Researchers from the University of Rochester recently summarized the “diagnostic odyssey” experienced by a group of 814 individuals with myotonic dystrophy enrolled in their national registry.  They focused on individuals with a confirmed diagnosis and with first symptoms starting after more than 4 weeks of age, and collected the age when the first symptom was observed, the type of symptom first experienced, any misdiagnoses, the age when a correct diagnosis was made, and the diagnostic tests administered.

This study found that members with myotonic dystrophy type 1 (DM1) experienced an average of 7 years delay to diagnosis, and members with myotonic dystrophy type 2 (DM2) had an even more stunning delay of 14 years to get a correct diagnosis.  On average, DM1 individuals experienced their first symptoms at age 26, whereas DM2 individuals had a later average age of onset at 34 years old.  In general, one quarter of the study’s myotonic dystrophy population experienced their first symptom before the age of 18.

Researchers determined that the type of symptom that manifests first can help dictate how quickly it will take for a correct diagnosis for DM1.  In DM1, members who reported weakness as their first symptom waited on average 6.6 years for their diagnosis, whereas a significantly longer delay in diagnosis was found when the first symptom was myotonia (7.6 years), fatigue (11.5 years), and sleep disturbance (15.6 years).  In DM2, a proper diagnosis was delayed on average 7 years, and was not significantly changed based on the type of symptom first observed.  The most common first symptom in DM1 was grip myotonia, followed by arm weakness, general weakness and leg weakness.  The most common first symptom in DM2 was leg weakness, followed by grip myotonia, general weakness and arm weakness.

Given that members with DM2 waited much longer for a correct diagnosis, the researchers further examined what caused the delay.  One quarter of DM2 members had an incorrect diagnosis, most often originating from a neurologist.  The most common misdiagnosis was limb-girdle muscular dystrophy, but others included chronic fatigue, fibromyalgia, arthritis, and multiple sclerosis.  DM2 members also underwent significantly more testing than DM1 members, having more EMGs, muscle biopsies and genetic testing.  Overall, 71% of DM2 members in this study had a confirmed genetic diagnosis, compared to 58% of DM1 members.

The authors stressed the need for a timely diagnosis to facilitate addressing the short term medical needs of people with DM, because many of the symptoms are disabling and reduce quality of life.  They also note that it is “imperative to diagnose patients earlier in the disease course if promising experimental therapies can reverse or delay onset of symptoms and potentially ward off the progression of many disabling manifestations”.  Now that genetic diagnoses have been available for DM1 and DM2 since 1992 and 2001, respectively, and much effort is being put into educating the community and medical trainees about DM, hopefully the diagnostic odyssey for people with DM will be improved.

An abstract of the original article can be found here.

08/22/2013

Maurice Swanson, Ph.D., Professor of Molecular Genetics and Microbiology at University of Florida, Gainesville, and a team of researchers have found that the muscleblind-like 2 (MBNL2) protein in the central nervous system (CNS) may be responsible for the neurological impacts of myotonic dystrophy (DM), providing hope for new treatments. Muscleblind is a type of protein that plays an important role in switching proteins typically found only in babies to proteins found in adults. If this switch isn’t made, an imbalance exists that leads to myotonic dystrophy.

Dr. Swanson states that the team’s work seeks to understand what causes myotonic dystrophy beyond the mutations in the DM1 and DM2 genes.

Dr. Swanson examined which genes were affected by loss of MBNL2 in the brain and found more than 800 affected genes. Many of them had one thing in common: the encoded protein could be made in both fetal and adult forms and MBNL2 appeared to regulate which version was created, according to an article in Neurology Today. One persistent concern that people living with DM1 and DM2 have is the effects of this disease on the brain. “People who don’t have DM usually feel refreshed after a night’s sleep. Myotonic dystrophy patients do not routinely achieve a normal sleep pattern; instead, they have an interrupted series of sleep-wake patterns that do not allow for deep, restful sleep cycles”.

Dr. Swanson created a mouse that lacks the MBNL2 protein as an animal model for DM effects on the CNS. These mice showed normal skeletal muscle structure and function. However, the mice did have DM-related sleep issues, such as a higher number of REM sleep episodes and more REM sleep in general, leading to less restful sleep. In mice lacking MBNL1, another member of the MBNL protein family, the skeletal muscle effects were similar to what is seen in DM. But the central nervous system was not affected, according to Dr. Swanson. 

“What we would like to do now is identify the specific cellular events that are abnormal in the DM brain and see if there is something we can do to treat these disease manifestations with focused therapy development. We would also like to understand the heart and muscle problems in DM. We have developed mice with DM-associated problems and we want to use these mouse models to develop effective drug treatments. Also, we want to understand what is so different about the congenital form of DM. Why does it manifest in babies and children? If we can develop animal models for congenital DM, then we can begin to address the important question of what goes wrong during fetal life,” explains Dr. Swanson.

Recently, therapy development for DM has accelerated and treatments based on anti-sense oligonucleotides will hopefully enter clinical trials in the near future. These new studies focused on the roles of MBNL proteins in CNS function should lead to alternative therapeutic strategies designed to reverse effects caused by expression of the mutant DM1 and DM2 genes.

04/16/2013