NORD gratefully acknowledges Thomas D. Bird, MD, Seattle VA Medical Center, Departments of Neurology and Medicine, University of Washington, for assistance in the preparation of this report.
Myotonic dystrophy refers to two rare genetic disorders of muscle that actually affect multiple systems of the body. The disorder is abbreviated DM, which is for dystrophia myotonia. This is the Latin name for the disorder. There are two main types DM. DM type 1 (DM1) can be further classified as mild DM1, classic DM1 and congenital DM1. Mild DM1 is characterized by clouding of the lenses of the eyes (cataracts) and sustained muscle contractions (myotonia), in which the muscles do not relax after use. Classic DM1 is characterized by muscle weakness and wasting (atrophy), myotonia, early-onset cataracts (i.e. before the age of 50), and abnormalities in the heart’s conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness (hypotonia), difficulty breathing, intellectual disability and early death. DM type 2 (DM2) causes similar symptoms to DM1, but is generally a less severe disorder and does not cause congenital disease. DM1 is caused by an alteration in the DMPK gene. DM2 is caused by an alteration in the CNBP gene. These alterations are inherited in an autosomal dominant manner.
DM is a type of muscular dystrophy. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Each disorder is characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from patients. DM1 is also known as Steinert disease, named after Dr. Steinert who, along with colleagues, first described the classic form in the medical literature in 1909. DM2 is also known as Ricker syndrome or proximal myotonic dystrophy or PROMM.
The signs and symptoms of DM1 or DM2 can vary greatly among affected individuals. This is true even among members of the same family. Many people will not develop all of the symptoms discussed below. Every person is unique and how these disorders affect a person can be very different. In addition, DM1 and DM2 have many symptoms that overlap, but there are also symptoms unique to each disorder, clearly marking them distinct disorders.
DM1 can develop at birth (congenital form), during childhood (juvenile form) and during adulthood (adult form). The adult form is the most common form and usually begins in a person’s 30s. Generally, the signs and symptoms of these disorders progress slowly.
This is the most common form of myotonic dystrophy. People may have mild disease or severe complications. Mild DM1 may be associated with cataract, mild myotonia and sometimes diabetes. Men with the mild form have an increased likelihood of going bald. Affected individuals may have fully active lives with little impact on the lifespan or quality of life.
Individuals with a more severe form of DM1 (commonly referred to as the classic form) have muscle weakness that most often affects certain muscles including a muscle that elevates the upper eyelid, a muscle that helps people to chew (masticate), a muscle that helps to move the neck, the muscles of the forearm closest to the hands, certain muscles in the hands, and muscles of the lower legs that help to move the ankles. Less often, muscles around the eyes (extraocular), a group of muscles located on the front of the thighs (quadriceps) and various muscles of the respiratory tract are affected. Muscle weakness and wasting is progressive. Muscle pain and fatigue are common.
For some people, it may take longer for their muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Myotonia is usually mild or moderate in severity. Two common examples of myotonia are being unable to release a doorknob after opening or shutting a door, or taking a moment to be able to release a person’s hand after shaking hands.
Because of weakness of facial muscles, affected individuals may not have facial expressions or have a mask-like facial appearance. Because of weakness of the muscle that elevates the upper eyelids, the eyelids may droop and hang partially in front of the eyes (ptosis). Some individuals may have slurred speech because of weakness of muscles required to speak.
Many people with DM1 have conduction defects of the heart. This means that there are problems with the transfer of electrical impulses (conduction) that regulate the normal, rhythmic pumping action of the heart. The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. Within the right atrium of a normal heart is a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the pacemaker (sinoatrial or SA node) to the ventricles along a very specific path consisting of conducting tissue and known as the AV (atrioventricular) node. If the electrical impulse is transmitted normally, the heart behaves normally. If the transmission of the signal is impeded, the blocked transmission is known as a heart block or an AV block. People with DM1 may have irregular heartbeats (arrhythmias), disease of the heart muscle (cardiomyopathy), overgrowth of the left ventricle (ventricular hypertrophy). The various heart abnormalities potentially associated with DM1 can lead to life-threatening complications.
Weakness of muscles necessary for breathing can occur and can lead to hypoventilation, which is the insufficient exchange of carbon dioxide and oxygen in the lungs. People with hypoventilation breathe at a slower rate and there is an increased about of carbon dioxide in the blood. It is possible for respiratory failure to occur, particularly late in life.
Individuals with DM1 can develop problems in the gastrointestinal system. This involves the smooth muscle of the stomach and intestines. Affected individuals may have abdominal pain, gallstones, constipation, diarrhea, loss of bladder control (incontinence), and pseudo-obstruction, which is caused by abnormalities in the involuntary, coordinated muscle contractions (peristalsis) of the gastrointestinal tract. Peristalsis propels food and other material through the digestive system. Because of weakened muscles, peristalsis becomes altered and inefficient. Symptoms of pseudo-obstruction resemble those caused by mechanical obstruction of the small bowel. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. With pseudo-obstruction, no such physical obstruction is present. Common symptoms include nausea, vomiting, abdominal pain, abdominal swelling (distention) and constipation.
Some individuals with DM1 have difficulty swallowing (dysphagia). Dysphagia may result in aspiration pneumonia, an infection that develops when food, saliva and bacteria are inhaled into the lungs. This can potentially be a life-threatening complication.
Men who have DM1 have changes in hormones that cause balding. Some men are unable to father a child (infertility) due to underdevelopment of the testes (hypogonadism). People with the classic or adult form of DM are also at a greater risk of developing diabetes. Some individuals have problems with their sleep including sleep apnea, and episodes of drowsiness, tiredness and lack of energy during the day (excessive daytime sleepiness). Some individuals have small, benign growths called pilomatrixomas and epitheliomas, particularly on the scalp. Behavioral issues including obsessive-compulsive disorder and passive-aggressive personality have been reported.
Some medical sources classify certain individuals with DM1 as having juvenile DM1. Onset is often before the age of 12. They may or may not have signs of muscle weakness or myotonia. Affected individuals usually have some intellectual and behavioral issues such as learning disabilities and difficulties with socialization at school. Difficulty with speech (dysarthria), hearing problems, and problems with coordination may also occur. Heart issues including heart rhythm disturbances and irregular heartbeats (arrhythmias) have been reported. Heart issues have occurred in adolescents who did not have any other symptoms.
This is the most severe form of DM. Infants show signs and symptoms of the disorder at birth (congenital) including severe muscle weakness and hypotonia. Hypotonia is when an infant lacks muscles tone; such infants are described as ‘floppy’. Some infants have muscle weakness affecting both sides of the face (facial diplegia). Clubfoot (talipes equinovarus), in which the foot appears to be turned in toward the body, is also common at birth.
Some infants have a low clarity of vision (visual acuity), farsightedness (hyperopia), and an abnormal curving of the lenses of the eye (astigmatism), which can contribute to poor or blurred vision. Mild to moderate intellectual disability can also occur in infants and children with congenital DM1. Learning and behavioral disabilities may become apparent as children grow older.
Poor feeding is common in affected infants and they often fail to grow and gain weight as expected (failure to thrive). Some infants have gastroparesis, a condition in which there is sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach. This can result in persistent digestive symptoms, especially nausea.
Infants and children with congenital DM1 may have breathing difficulties due to muscle weakness. Breathing difficulties are often severe and can lead to respiratory failure, which is a common cause of mortality in congenital DM1.
Infants and children with congenital DM1 who survive early, severe complications will go on and develop symptoms of adult onset DM1 including heart (cardiac) abnormalities. Cardiac issues can begin as early as the second decade of life. In rare instances, severely affected infants can have cardiac abnormalities in the newborn (neonatal) period.
MYOTONIC DYSTROPHY TYPE 2 (DM2)
The onset of DM2 is typically in the third decade, but anywhere between the second and sixth decade of life is common. The signs and symptoms are highly variable. The most common symptoms are muscle weakness and pain, myotonia, and cataracts. However, some people will not develop these symptoms. Sometimes, the severity of these symptoms change in a person. For example, myotonia may worsen or improve. Symptoms do not appear in the congenital or juvenile ages.
The muscles of the neck and fingers are often the first muscles affected in DM2. Muscle weakness slowly affects other muscles including muscles of the elbows and hips. About one-third of affected individuals develop muscle weakness in the hips after the age of 50. Less commonly affected are facial muscles and muscles of the ankles. The muscles of the thighs are commonly affected and some people may have stiffness and weakness of these muscles when running up stairs. Muscle pain may come and go and can fluctuate in severity. Sometimes, muscle pain can be debilitating. Fatigue is common.
In addition to muscle weakness and pain, it may also take longer for the muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Although uncommon, myotonia has been reported to occur as early as the first decade of life. Some individuals with DM2 will not develop myotonia.
Cataracts are common and can develop as early as the second decade of life. Affected individuals are at a greater risk than the general population of developing diabetes. Some affected men may be unable to father a child (infertility). Excessive sweating and difficulty swallowing (dysphagia) are also common in DM2. Some people may have problems with concentration, organization and finding the right word when writing or speaking (word finding).
Heart (cardiac) abnormalities are less severe in DM2 than in DM1, and they occur with less frequency as well. Conduction defects, irregular heartbeats (arrhythmias), and disease of the heart muscle (cardiomyopathy) are potential complications. Sudden death because of heart abnormalities is possible in some people, but is a rare occurrence.
DM1 is caused by a change or alteration in the myotonic dystrophy protein kinase (DMPK) gene. DM2 is caused by a change or alteration in the nucleic acid-binding protein (CNBP) gene; this gene is also called the ZNF9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The change or alteration that affects these genes is called a repeat expansion. This means that a segment of DNA in the gene is repeated many times. In DM1, the segment that is repeated contains three building blocks of DNA (nucleotides). This segment is written as CTG and in most people is repeated anywhere from 5 to 34 or 37 times. If this segment is repeated more than 34 times, that is considered abnormal. If a person has between 38-49 CTG repeats, they will usually not develop symptoms, but their children will be at risk of developing myotonic dystrophy. In general, the more repeats there are, the more severe the symptoms will be. For example, people with the mild form of DM1 have fewer repeats than people with classic or congenital forms. People with the congenital form have the most.
In DM2, the segment that is repeated contains four building blocks of DNA and is written as CCTG. The number of repeats can range from about 75 to more than 11,000. The mean is approximately 5,000. In DM2 there is no correlation between severity of symptoms and size of the repeat expansion.
The DNA repeat expansions seen in DM1 and DM2 do not actually affect the genes they are connected with. Instead they work through a genetic mechanism called “RNA gain of function” in which they interfere with the coding of several other more distant genes such as a muscle chloride channel, an insulin receptor and a cardiac muscle protein gene. This explains the systemic effects of the disease on skeletal muscle, risk for diabetes and heart problems.
In addition, DM1 is associated with a phenomenon called “anticipation.” In genetics, anticipation refers to the finding that children of parents with a disorder have symptom onset at a significantly early age and more severe symptoms. This may be partly because the expanded CTG and CCTG repeats are unstable and likely to expand further over time and with successive generations. Researchers have also noted that women with DM are more likely to have a child with congenital DM (the most severe form). The reason for this is not fully understood. There are no reports of anticipation in DM2.
DM1 and DM2 are inherited in an autosomal dominant fashion. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
DM1 is estimated to affect about 1 in 8,000-20,000 people in the general population. However, the prevalence of DM1 and DM2 vary greatly among different countries and different ethnic groups. The incidence of DM2 is higher in Germany and Finland. Because some people with DM may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. Researchers have determined that DM is the most common form of adult onset muscular dystrophy.
A diagnosis of myotonic dystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient and family history, and identification of characteristic physical findings. A family history of muscle weakness and myotonia is a strong indicator of a diagnosis for DM.
Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis of DM1 or DM2. Molecular genetic testing looks for changes or alterations in the DMPK gene known to cause DM1, or in the CNBP gene for DM2. However, this testing is available only as a diagnostic service at specialized laboratories.
An electromyography (EMG) is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate characteristic changes that indicate the presence of myotonia or myopathy. This was a common test for DM before molecular genetic testing was developed. The EMG changes are not specific for DM1 or DM2.
Individuals with DM may have mildly or moderately elevated levels of a muscle enzyme called creatine kinase or CK in their blood serum. Some individuals have low levels of immunoglobulin G. Immunoglobulins are specialized proteins produced by certain white blood cells. They play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.
A specialized imaging technique called magnetic resonance imaging or MRI can be used to create images of the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In DM, this can show characteristic changes in the brain including degeneration (atrophy) of the cerebellum, the area of the brain that controls movement and balance.
Liver function tests may show elevated levels of liver enzymes in some people. The cause of this elevation is unknown. The liver function test abnormalities in DM1 and DM2 may be misinterpreted as a sign of hepatitis or other liver disease.
There is no cure yet for myotonic dystrophy, but researchers are studying ways to help people with these disorders. Current treatment is directed toward the specific symptoms that are apparent in each individual.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), specialists who assess and treat problems of the brain and central nervous system (neurologists), specialists who assess and treat problems of the heart (cardiologists), specialists who assess and treat problems of the lungs (pulmonologists), specialists who asses and treat eye problems (ophthalmologists), speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families.
There is no specific treatment for muscle weakness. Physical and occupational therapy can be of benefit. Some individuals may need braces, ankles supports, or walkers. In severe instances, a wheelchair may become necessary. Children with skeletal malformations may require orthopedic surgery. These interventions are commonly needed in DM1 than DM2.
Myotonia is usually not severe enough to require treatment. However, certain medications have been reported in the medical literature as being effective. The most commonly used is mexiletine which has been shown to be moderately effective. (See Investigational Therapies below)
Pain medications are sometimes recommended. A variety of medications have been used including nonsteroidal anti-inflammatories (NSAIDs), gabapentin, tricyclic antidepressants, mexiletine, and low-doses of glucocorticoids such as prednisone.
Cataracts can be removed surgically if they affect vision. However, there have been reports that cataracts can recur after removal.
Drooping of the upper eyelid (ptosis) can be treated by an eyelid crutch, which is a small device added onto to existing glasses to prop the eyelid up. Sometimes blepharoplasty is required. This surgery involves removing excess muscle, fat and other tissue.
Some people with breathing problems during sleep may require non-invasive ventilation, which involves breathing support with a mask or similar device.
Some individuals have a pacemaker or implantable cardioverter defibrillator (ICD). A pacemaker sends pulses to speed up a heart when there is an abnormally slow heartbeat or rhythm. An ICD sends a shock to the heart if it is beating irregularly in order to return the heartbeat to normal.
Some infants with congenital DM1 require ongoing breathing support with a machine. Some infants require a gastronomy tube, which is a thin tube that is inserted directly into the stomach through a small surgical opening. This ensures that infants receive the required nutrients, but avoid the risk of aspiration.
Some affected individuals may develop hypothyroidism, a condition characterized by underactivity of the thyroid gland. This means that the thyroid produces low levels of thyroid hormone. Hypothyroidism has been shown to worsen myotonic dystrophy. Hypothyroidism is treated by medications that replace the activity of the underproduced hormones.
Men who experience hypogonadism are treated with hormone replacement therapy.
People with DM1 are at risk for complications involving the use of anesthesia. Close consultation among the medical team and the anesthesiologist should be recommended before a person with DM1 undergoes any procedure that requires anesthesia. An anesthesiologist experienced with treating individuals with muscle disorders like DM1 is recommended.
A medication called modafinil has been used to treat excessive daytime sleepiness in a few small studies. They demonstrated that the medication show modest benefit for affected individuals.
The drug mexiletine has been used to treat myotonia that is severe enough to interfere with their daily functions. In some small studies, the drug shows benefit. However, adults and children should have a heart evaluation before going on to the drug. Mexiletine can worsen irregular heartbeats and should not be used if people have second or third degree heart block.
A registry has been established for myotonic dystrophy called the Myotonic Dystrophy Family Registry. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information on this registry, contact:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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