Simply Stated: What is Myotonic Dystrophy?
By Sujatha Gurunathan | Thursday, March 24, 2022
Myotonic dystrophy (DM) is a type of muscular dystrophy that affects about 1 in 8,000 people worldwide. The disease is known by several names, including Steinert disease, after the doctor that first described it, and “DM” in reference to its Greek name, dystrophia myotonica.
Similar to other forms of muscular dystrophy, DM is characterized by progressive muscle loss and weakness. DM is more than a muscle disorder, however. It can affect many organs in the body, and the non-muscle-related symptoms of DM are variable and differ greatly from those of other muscular dystrophies. This makes the journey to a diagnosis challenging for people with DM.
Symptoms of DM
DM typically begins in adulthood, usually in a person’s 20s or 30s. Disease symptoms and progression can be very different in each person with the disease, even among members of the same family. As a result, people with DM sometimes consult many physicians and specialties before considering a visit to a neurologist.
The most common symptoms of DM are muscle problems. People with DM generally experience muscle weakness (myopathy) of the skeletal muscles used for movement (voluntary muscles), though the degree of weakness and the muscles affected can vary greatly. A signature feature of DM in many cases is the inability to relax muscles at will (myotonia). For example, it may be difficult for someone with DM to let go of an object after gripping it. Many people with DM also experience muscle thinning or loss (atrophy) that gets worse over time.
In addition to muscle issues, DM can also affect the function of a person’s eyes, heart, endocrine system, and central nervous system. People with DM will have some combination of the possible symptoms, with disease severity ranging from mild to life-threatening.
There are two major forms of DM: DM1, also known as Steinert disease, and DM2, recognized as a milder version of DM1.
DM1 is classified in three main forms: mild, classic, and congenital.
- People with mild DM1 may develop cataracts, or clouding of the lens of the eye, that can interfere with their vision. They may also experience mild myotonia, and in some cases, develop diabetes mellitus (metabolic disorders that cause high blood sugar). People with mild DM1 often have fully active lives with little impact on the lifespan or quality of life.
- People with classic DM1 may experience muscle weakness and atrophy, myotonia,
cataracts, and abnormalities of a number of body systems. This form of the disease may begin earlier, in adolescence or young adulthood. The most common symptom is weakness in the distal muscles of the legs and hands, leading to distinctive signs such as a foot drop, abnormal gait when walking, and difficulty with dexterity of the hands/fingers. As the disease progresses, affected individuals may develop additional physical disabilities, experience impaired function of the heart, lungs, or gastrointestinal (GI) system, and have a shortened life span. Respiratory dysfunction is the most common cause of death in people with DM1.
- People with congenital DM1 typically experience poor muscle tone (hypotonia) and severe generalized weakness from the time of birth. These individuals often have impaired cognitive function, speech, and vision, and may experience serious breathing problems that can lead to an early death.
For more information, a clinical overview of DM1 can be found here.
The symptoms of DM2 are generally less severe than those of DM1, and unlike DM1, DM2 does not appear to cause developmental or childhood symptoms. The signs and symptoms of DM2 are highly variable. Beginning in the third or fourth decade of life, people with DM2 may experience myotonia and muscle dysfunction (e.g., weakness, fluctuating aches/pain, and stiffness), but are less likely to experience cataracts, heart problems, or endocrine issues. The pattern of muscle weakness in these individuals often begins in the neck and the hips and slowly moves to the arms and fingers as the disease progresses. Some people, however, may never develop these symptoms. A more in-depth clinical overview of DM2 can be found here.
Causes of DM
DM was first described by the German doctor Hans Steinert in 1909. The specific genetic causes for DM1 and DM2, however, were not identified until about 80-90 years later, in 1992 and 2001, respectively.
DM1 is caused by the abnormal expansion of a repeated DNA sequence (CTG) within the myotonic dystrophy protein kinase (DMPK) gene, while DM2 is caused by a similar change in the nucleic acid-binding protein (CNBP) gene (which is also known as ZNF9). The DMPK and CNBP genes encode proteins that are important for the proper functioning of voluntary muscles used for movement and involuntary muscles, such as the heart or the brain. Abnormal expansions in the DMPK or CNBP gene results in RNA copies of these genes that cannot produce proteins. Additionally, these defective RNA copies clump together, clogging the protein-making machinery and interfering with production of other important proteins in the cell. These defects lead to muscle dysfunction and the signs and symptoms of DM.
Normally, people will have between 5-34 CTG DNA repeats in the DMPK gene. People with DM1, however, may have ~50-1000 of these repeats. In DM1, the number of repeats correlates with the severity of symptoms. Furthermore, the number of repeats often increases in each subsequent generation. As a result, people with ~38-49 CTG repeats may not develop symptoms, but their children will be at high risk of developing DM1.
DM1 and DM2 are inherited in an autosomal dominant manner, meaning that only one flawed copy of the DMPK or CNBP gene is required to cause the disease. If one parent has DM, then every child of that person has a 50% chance of inheriting the disease. Children who inherit DM1 often have earlier onset and more severe disease than their affected parents due to the increases in genetic expansions in each subsequent generation. This is a phenomenon called “anticipation.” In DM2, there is no correlation between the number of repeats (the size of the expansion) and the severity of symptoms, and therefore, anticipation does not seem to occur in people with DM2.
Current management of DM
DM is suspected when a healthcare provider observes signs and symptoms of the disease, and the diagnosis can be confirmed with muscle function and genetic testing.
Though there is currently no cure for DM, multidisciplinary care of affected individuals can help manage symptoms and improve quality of life. Treatment is based on each person’s symptoms and may include physical therapy, medication for pain management, and consultation with specialists. Routine physical activity may be recommended to help maintain muscle strength and endurance. Ankle supports, leg braces, or a wheelchair may be recommended when muscle weakness worsens. Medications and other treatments can be used to lessen myotonia, and manage symptoms such as heart problems, cataracts, and endocrine issues.
A number of consensus-based care recommendations developed by physician and scientist experts in DM, in conjunction with the Myotonic Dystrophy Foundation, are available to guide physicians in evidence-based treatment of people living with DM
Evolving research and treatment landscape
While the standard of care is still symptom management, research advances and the promise of better therapeutics on the horizon offer hope for people living with DM. Preclinical research in DM is focused on strategies such as gene-editing technology or small molecules treatment to remove the RNA clumps that are thought to cause DM symptoms. However, these therapies are not yet available for clinical use in humans. Clinical research into DM is focused in three main areas: (1) physical/exercise interventions to improve DM symptoms, (2) therapeutic interventions to block the underlying disease processes, and (3) observational studies to identify markers of disease and measures that can be used to track improvements in clinical trials. To learn more about clinical trial and patient registry opportunities in DM1 and DM2, visit clinicaltrials.gov and search for “myotonic dystrophy” in the condition or disease field.
MDA is currently supporting research of DM1 and DM2 through the Myotonic Dystrophy Clinical Research Network led by Prof. Charles Thornton at the University of Rochester. The centers in this Network are distributed across the US to maximize the opportunity for individuals with DM to participate in research studies. One of the main goals of the Network is to optimize the methods for testing of new treatments. Another goal is to understand genetic factors that explain the tremendous variability of DM. The researchers in the Network are working together to develop standardized methods to assess DM. Ultimately these methods are expected to determine whether new medications have beneficial effects.
MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about myotonic dystrophy, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.
TAGS: Clinical Trials, Healthcare, Innovation, Research, Resources, Simply Stated
TYPE: Blog Post
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