Myotonic Dystrophy

Definition

Myotonic dystrophy is a progressive disease in which the muscles are weak and are slow to relax after contraction.

Description

Myotonic dystrophy (DM), also called dystrophia myotonica, myotonia atrophica, or Steinert's disease, is a common form of muscular dystrophy. DM is an inherited disease, affecting males and females approximately equally. About 30,000 people in the United States are affected. Symptoms may appear at any time from infancy to adulthood. DM causes general weakness, usually beginning in the muscles of the hands, feet, neck, or face. It slowly progresses to involve other muscle groups, including the heart. DM affects a wide variety of other organ systems as well.

A severe form of DM, congenital myotonic dystrophy or Thomsen's disease, may appear in newborns of mothers who have DM. Congenital means that the condition is present from birth. The incidence of congenital myotonic dystrophy is thought to be about 1:20,000.

DM occurs in about 1 per 7,000-8,000 people and has been described in people from all over the world.

Causes and symptoms

The most common type of DM is called DM1 and is caused by a mutation in a gene called myotonic dystrophy protein kinase (DMPK). The DMPK gene is located on chromosome 19q. When there is a mutation in this gene, a person develops DM1. The specific mutation that causes DM1 is called a trinucleotide repeat expansion.

Some families with symptoms of DM do not have a mutation in the DMPK gene. As of early 2001, scientists have found that the DM in many of these families is caused by a mutation in a gene on chromosome 3. These families are said to have DM2.

Congenital myotonic dystrophy has been linked to a region on chromosome 7 that contains a muscle chloride channel gene.

Trinucleotide repeats

In the DMPK gene, there is a section of the genetic code called a CTG repeat. The letters stand for three nucleotides (complex organic molecules) known as cytosine, thymine, and guanine, and are repeated a certain number of times. In people who have DM1, this sequence of nucleotides is repeated too many times—more than the normal number of 37 times—and thus this section of the gene is too big. This enlarged section of the gene is called a trinucleotide repeat expansion.

People who have repeat numbers in the normal range will not develop DM1 and cannot pass it to their children. Having more than 50 repeats causes DM1. People who have 38-49 repeats have a premutation and will not develop DM1, but can pass DM1 onto their children. Having repeats numbers greater than 1000 causes congenital myotonic dystrophy.

In general, the more repeats in the affected range that someone has, the earlier the age of onset of symptoms and the more severe the symptoms. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age they will begin to have symptoms or how their condition will progress.

Exactly how the trinucleotide repeat expansion causes myotonia, the inability to relax muscles, is not yet understood. The disease somehow blocks the flow of electrical impulses across the muscle cell membrane. Without proper flow of charged particles, the muscle cannot return to its relaxed state after it has contracted.

Since 2001 it has been discovered that DM2 is caused by a CCTG (cytosine-cytosine-thymine-guanine) expansion on chromosome 3 at locus 3q21, but as of 2004 it is not known how this repeat affects muscle cell function.

Anticipation

Sometimes when a person who has repeat numbers in the affected or premutation range has children, the expansion grows larger. This is called anticipation. A larger expansion can result in an earlier age of onset in children than in their affected parent. Anticipation happens more often when a mother passes DM1 onto her children then when it is passed from the father. Occasionally repeat sizes stay the same or even get smaller when they are passed to a person's children.

Inheritance

DM is inherited through autosomal dominant inheritance. This means that equal numbers of males and females are affected. It also means that only one gene in the pair needs to have the mutation in order for a person to be affected. Since a person only passes one copy of each gene onto their children, there is a 50% or one in two chance that a person who has DM will pass it onto each of their children. This percentage is not changed by results of other pregnancies. A person with a premutation also has a 50%, or one in two, chance of passing the altered gene on to each of their children. However, whether or not their children will develop DM1 depends on whether the trinucleotide repeat becomes further expanded. A person who has repeat numbers in the normal range cannot pass DM1 onto their children.

There is a range in the severity of symptoms in DM and not everyone will have all of the symptoms listed here.

Myotonic dystrophy causes weakness and delayed muscle relaxation called myotonia. Symptoms of DM include facial weakness and a slack jaw, drooping eyelids called ptosis, and muscle wasting in the forearms and calves. A person with DM has difficulty relaxing his or her grasp, especially in the cold. DM affects the heart muscle, causing irregularities in the heartbeat. It also affects the muscles of the digestive system, causing constipation and other digestive problems. DM may cause cataracts, retinal degeneration, low IQ, frontal balding, skin disorders, atrophy of the testicles, and diabetes. It can also cause sleep apnea—a condition in which normal breathing is interrupted during sleep. DM increases the need for sleep and decreases motivation. Severe disabilities do not set in until about 20 years after symptoms begin. Most people with myotonic dystrophy maintain the ability to walk, even late in life.

A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM1. Congenital myotonic dystrophy is marked by severe weakness, poor sucking and swallowing responses, respiratory difficulty, delayed motor development, and mental retardation. Death in infancy is common in this type.

Some people who have a trinucleotide repeat expansion in their DMPK gene do not have symptoms or have very mild symptoms that go unnoticed. It is not unusual for a woman to be diagnosed with DM after she has an infant with congenital myotonic dystrophy.

Predictive testing

It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms, or the course of the disease.

Diagnosis

Diagnosis of DM is not difficult once the disease is considered. However, the true problem may be masked because symptoms can begin at any age, can be mild or severe, and can occur with a wide variety of associated complaints. Diagnosis of DM begins with a careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes. A family history of DM or unexplained weakness helps to establish the diagnosis.

A definitive diagnosis of DM1 is done by genetic testing, usually by taking a small amount of blood. The DNA in the blood cells is examined and the number of repeats in the DMPK gene is determined. Various other tests may be done to help establish the diagnosis, but only rarely would other testing be needed. An electromyogram (EMG) is a test is used to examine the response of the muscles to stimulation. Characteristic changes are seen in DM that helps distinguish it from other muscle diseases. Removing a small piece of muscle tissue for microscopic examination is called a muscle biopsy. DM is marked by characteristic changes in the structure of muscle cells that can be seen on a muscle biopsy. An electrocardiogram could be performed to detect characteristic abnormalities in heart rhythm associated with DM. These symptoms often appear later in the course of the disease.

Prenatal testing

Testing a pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10-12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.

There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

A group of researchers in Houston, Texas, reported in 2004 that they have successfully developed a technique for detecting the CCTG expansion that causes DM2 and estimating the size of the repeat expansion.

Treatment

Myotonic dystrophy cannot be cured, and no treatment can delay its progression. As of the early 2000s there is no standardized treatment for these disorders because the precise reasons for muscle weakness are not yet fully understood. However, many of the symptoms can be treated. Physical therapy can help preserve or increase strength and flexibility in muscles. Ankle and wrist braces can be used to support weakened limbs. Occupational therapy is used to develop tools and techniques to compensate for loss of strength and dexterity. A speech-language pathologist can provide retraining for weakness in the muscles controlling speech and swallowing.

Irregularities in the heartbeat may be treated with medication or a pacemaker. A yearly electrocardiogram is usually recommended to monitor the heartbeat. Diabetes mellitus in DM is treated in the same way that it is in the general population. A high-fiber diet can help prevent constipation. Sleep apnea may be treated with surgical procedures to open the airways or with nighttime ventilation. Treatment of sleep apnea may reduce drowsiness. Lens replacement surgery is available when cataracts develop. Pregnant woman should be followed by an obstetrician familiar with the particular problems of DM because complications can occur during pregnancy, labor and delivery.

Wearing a medical bracelet is advisable. Some emergency medications may have dangerous effects on the heart rhythm in a person with DM. Adverse reactions to general anesthesia may also occur.

Prognosis

The course of myotonic dystrophy varies. When symptoms appear earlier in life, disability tends to become more severe. Occasionally people with DM may require a wheelchair later in life. Children with congenital DM usually require special educational programs and physical and occupational therapy. For both types of DM, respiratory infections pose a danger when weakness becomes severe.

Resources

BOOKS

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Myotonic Disorders." Section 14, Chapter 184. In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

PERIODICALS

International Myotonic Dystrophy Consortium (IMDC). "New Nomenclature and DNA Testing Guidelines for Myotonic Dystrophy Type 1 (DM1)." Neurology 54 (2000): 1218-1221.

Meola, G., and V. Sansone. "Treatment in Myotonia and Periodic Paralysis." Revue neurologique (Paris) 160, no. 5, Part 2 (May 2004: S55-S69.

Meola, Giovanni. "Myotonic Dystrophies." Current Opinion in Neurology 13 (2000): 519-525.

Ranum, L. P., and J. W. Day. "Myotonic dystrophy: RNA Pathogenesis Comes into Focus." American Journal of Human Genetics 74 (May 2004): 793-804.

Sallinen, R., A. Vihola, L. L. Bachinski, et al. "New Methods for Molecular Diagnosis and Demonstration of the (CCTG)n Mutation in Myotonic Dystrophy Type 2 (DM2)." Neuromuscular Disorders 14 (April 2004): 274-283.

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. 〈http://www.mdausa.org〉.

OTHER

Gene Clinics. 〈http://www.geneclinics.org〉.

Myotonic Dystrophy Website. 〈http://www.umd.necker.fr/myotonic_dystrophy.html〉.

NCBI Genes and Disease Web Page. 〈http://www.ncbi.nlm.nih.gov/disease/Myotonic.html〉.

KEY TERMS

Electrocardiogram (ECG, EKG)— A test that uses electrodes attached to the chest with an adhesive gel to transmit the electrical impulses of the heart muscle to a recording device.

Electromyography (EMG)— A test that uses electrodes to record the electrical activity of muscle. The information gathered is used to diagnose neuromuscular disorders.

Muscular dystrophy— A group of inherited diseases characterized by progressive wasting of the muscles.

Nucleotide— Any of a group of organic molecules that link together to form the building blocks of DNA or RNA.

Sleep apnea— Temporary cessation of breathing while sleeping.

Trinucleotide repeat expansion— A sequence of three nucleotides that is repeated too many times in a section of a gene.

Myotonic dystrophy

Definition

Myotonic dystrophy is a progressive disease in which the muscles are weak and slow to relax after contraction.

Description

Myotonic dystrophy (DM), also called dystrophia myotonica, myotonia atrophica, or Steinert disease, is a common form of muscular dystrophy . DM is an inherited disease. It causes general weakness, usually beginning in the muscles of the hands, feet, neck, or face. It slowly progresses to involve other muscle groups, including the heart and a wide variety of other organ systems.

There are four types of DM as determined by when symptoms appear. These are:

• Congenital: Severe symptoms are apparent at birth.
• Juvenile: Symptoms appear between birth and adolescence.
• Adult: Symptoms appear in individuals ages 20–40.
• Late onset: Mild symptoms appear after age 40.

Transmission

DM is an inherited disease. It is passed from parent to child through an autosomal dominant pattern of inheritance. In the case of DM, one copy of each gene is inherited from each parent. In an autosomal dominant pattern of inheritance, only one of these two copies needs to have the mutation (change) or defect in order for the child to have DM. Therefore, there is a 50 percent chance that a parent who has DM will pass it onto each child. This percentage is not changed by results of other pregnancies. In each pregnancy, a parent with DM has a 50% chance of having a child with DM.

Demographics

Myotonic dystrophy is an uncommon disease occurring in about one out of every 8,000 individuals. It is found worldwide. The congenital form of DM is much rarer, occurring in only about one out of every 100,000 births. DM affects males and females approximately equally.

Causes and symptoms

The most common type of DM is called DM1, which is caused by a mutation in a gene called myotonic dystrophy protein kinase (DMPK). The DMPK gene is located on chromosome 19. The specific mutation that causes DM1 is called a trinucleotide repeat expansion. In people who have DM1, a particular unit of the gene is repeated too many times—more than the normal range of five to 38 times—and thus this section of the gene is too big and is unstable. The enlarged section of the gene is called a trinucleotide repeat expansion.

People who have repeat numbers in the normal range will not develop DM1 and cannot pass it to their children. Having more than 50 repeats causes DM1. People who have 38–49 repeats have what is called a premutation. They do not develop DM1, but can pass DM1 on to their children.

Myotonic dystrophy has an effect called "anticipation." This means that when a person with repeat numbers in the affected or premutation range (above 38) has children, the expansion grows larger, and the child has more of the repeated genetic unit (a higher repeat number). As a result, symptoms of the disease tend to appear at an earlier age in children than in their affected parent. Anticipation happens more often when a mother, rather than the father, passes DM1 to children. Occasionally, repeat sizes stay the same or even get smaller when they are passed to a person's children.

In general, the more repeats above 38 an individual has, the earlier the age of onset of symptoms and the more severe the symptoms. Having repeat numbers greater than 1,000 causes congenital myotonic dystrophy. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age he or she will begin to have symptoms or how the condition will progress.

Some families with symptoms of DM do not have a mutation in the DMPK gene. Instead, they have a mutation in a gene on chromosome 3 that causes four units within the gene to be repeated. This genetic defect is called DM2 or proximal myotonic myopathia (PROMM). Symptoms of DM2 are almost never apparent at birth. This defect has only been decoded since 2001; therefore, less is known about how it functions.

Symptoms of DM vary in severity, and not everyone will have all of the symptoms. In general, myotonic dystrophy causes weakness and delayed muscle relaxation called myotonia. Exactly how the repeat of genetic information causes myotonia, the inability to relax muscles, is not yet understood. The disease somehow blocks the flow of electrical impulses across the muscle cell membrane. Without proper flow of charged particles, the muscle cannot return to its relaxed state after it has contracted.

The most severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM1. Congenital myotonic dystrophy is marked by severe weakness, poor sucking and swallowing responses, respiratory difficulty, delayed motor development, and mental retardation . Death in infancy is common in babies with congenital DM.

Symptoms of juvenile and adult onset DM include facial weakness and a slack jaw, drooping eyelids called ptosis, and muscle wasting in the forearms and calves. A person with DM has difficulty relaxing his or her grasp, especially in the cold. DM affects the heart muscle, causing irregularities in the heartbeat. It also affects the muscles of the digestive system, causing constipation and other digestive problems. DM may cause cataracts in the eye, retinal degeneration, low IQ, early frontal balding, skin disorders, atrophy of the testicles, and diabetes. It can also cause sleep apnea, a condition in which normal breathing is interrupted during sleep. DM increases the need for sleep and decreases motivation. Often, severe disabilities do not set in until about 20 years after symptoms begin. Most people with myotonic dystrophy maintain the ability to walk, even late in life.

Some people who have a trinucleotide repeat expansion in their DMPK gene do not have DM symptoms or have very mild symptoms that go unnoticed. It is not unusual for a woman to be diagnosed with DM after she has an infant with congenital myotonic dystrophy.

When to call the doctor

Parents should let the doctor know as soon as possible if there is a family history of DM. Otherwise, they should contact their pediatrician if the child shows any signs of delayed or abnormal growth, or unexplained muscle weakness.

Diagnosis

Diagnosis of DM is not difficult once the disease is considered. However, the diagnosis may be masked because symptoms can begin at any age, can be mild or severe, and can occur with a wide variety of associated complaints. Diagnosis of DM begins with a careful medical history and a thorough physical examination to determine the distribution of symptoms and to rule out other causes. A family history of DM or unexplained weakness helps to establish the diagnosis.

Genetic testing, usually using a blood sample, establishes a definitive diagnosis of DM. The DNA in the blood cells is examined and the number of repeats in the affected gene is determined. Other tests may be done to help establish the diagnosis, but only rarely would other testing be needed. An electromyogram (EMG) is a test used to examine how muscles respond to stimulation. Characteristic changes revealed by this test, and seen in DM, help distinguish it from other muscle diseases. Removing a small piece of muscle tissue for microscopic examination is called a muscle biopsy. DM is marked by characteristic changes in the structure of muscle cells that can be seen on a muscle biopsy. An electrocardiogram could be performed to detect abnormalities in heart rhythm associated with DM. These symptoms often appear later in the course of the disease.

If genetic testing in a family has identified a DMPK mutation, it is possible to test a fetus during pregnancy. Testing can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the fetus and analyzing the cells in the fluid. Each of these procedures carries a small risk of miscarriage. Those who are interested in learning more should check with their doctor or genetic counselor.

Treatment

Myotonic dystrophy cannot be cured, and no treatment can delay its progression. However, many of its symptoms can be treated. Physical therapy can help preserve or increase strength and flexibility in muscles. Ankle and wrist braces can support weakened limbs. Occupational therapy is used to develop tools and techniques to compensate for loss of strength and dexterity. A speech-language pathologist can provide retraining for weakness in the muscles controlling speech and swallowing.

Irregularities in heartbeat may be treated with medication or a pacemaker. A yearly electrocardiogram is usually recommended. Diabetes mellitus in DM is treated in the same way that it is in the general population. A high-fiber diet can help prevent constipation. Sleep apnea may be treated with surgical procedures to open the airways or with nighttime ventilation. Treatment of sleep apnea may reduce drowsiness. Lens replacement surgery is available when cataracts develop.

Prognosis

The course of myotonic dystrophy varies. When symptoms appear earlier in life, disability tends to become more severe. Occasionally people with DM may require a wheelchair later in life. Children with congenital DM often die in infancy. If they survive, they usually require special educational programs and physical and occupational therapies. Respiratory infections pose a danger if weakness becomes severe.

Prevention

There is no way to prevent the genetic mutations that cause DM. However, it is possible to test someone who is at risk for developing DM1 before symptoms arise, to see whether he or she inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age at which someone will begin to have symptoms or the course of the disease.

Another procedure, called preimplantation diagnosis, allows a couple to have a child that does not have the genetic condition. This procedure is still experimental. Those interested in learning more about the procedure should check with their doctor or genetic counselor.

Parental concerns

Pregnant woman should be cared for by an obstetrician familiar with the particular problems of DM because complications can occur during pregnancy, labor, and delivery.

It is advisable for children or adults with DM to wear a medical alert bracelet. Some emergency medications may have dangerous effects on the heart rhythm in a person with DM. Adverse reactions to general anesthesia may also occur.

KEY TERMS

Electrocardiagram (ECG, EKG) —A record of the electrical activity of the heart, with each wave being labeled as P, Q, R, S, and T waves. It is often used in the diagnosis of cases of abnormal cardiac rhythm and myocardial damage.

Electromyography (EMG) —A diagnostic test that records the electrical activity of muscles. In the test, small electrodes are placed on or in the skin; the patterns of electrical activity are projected on a screen or over a loudspeaker. This procedure is used to test for muscle disorders, including muscular dystrophy.

Muscular dystrophy —A group of inherited diseases characterized by progressive wasting of the muscles.

Sleep apnea —A sleep disorder characterized by periods of breathing cessation lasting for 10 seconds or more.

Trinucleotide repeat expansion —A sequence of three nucleotides that is repeated too many times in a section of a gene.

See also Muscular dystrophy.

Resources

PERIODICALS

The International Myotonic Dystrophy Consortium (IDMC). "New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1)." Neurology 54 (2000): 1218–21.

Meola, Giovanni. "Myotonic Dystrophies." Current Opinion in Neurology 13 (2000): 519–25.

ORGANIZATIONS

International Myotonic Dystrophy Organization. P.O. Box 1121, Sunland, CA 91041-1121. (866) 679-7954 or (818)951-2311. Web site: <www.myotonicdystrophy.org>.

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. Web site: <www.mdausa.org>.

WEB SITES

Bird, Thomas D. "Myotonic Dystrophy Type 1." Gene Reviews [cited August 9, 2004]. Available online at: <www.genetests.org/profiles/myotonic_d/details.html>.

Smith, Corrine O'Sullivan. Myotonic Dystrophy: Making an Informed Choice About Genetic Testing. University of Washington. Available online at: <www.depts.washington.edu/neurogen/Myotonic.pdf>.

"What Is Myotonic Muscular Dystrophy?" Muscular Dystrophy Association [cited October 9, 2004]. Available online at: <www.mda.org/publications/fa-mmd-qa.html>.

Tish Davidson, A.M. Karen M. Krajewski, M.S., C.G.C.

Myotonic dystrophy

Definition

Myotonic dystrophy is a progressive disease in which the muscles are weak and are slow to relax after contraction.

Description

Myotonic dystrophy (DM), also called dystrophia myotonica, myotonia atrophica, or Steinert disease, is a common form of muscular dystrophy . DM is an inherited disease, affecting both males and females. About 30,000 people in the United States are affected. Symptoms may appear at any time from infancy to adulthood. DM causes general weakness, usually beginning in the muscles of the hands, feet, neck, or face. It slowly progresses to involve other muscle groups, including the heart. DM affects a wide variety of other organ systems as well.

A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital means that the condition is present from birth.

Genetic profile

The most common type of DM is called DM1 and is caused by a mutation in a gene called myotonic dystrophy protein kinase (DMPK). The DMPK gene is located on chromosome 19. When there is a mutation in this gene, a person develops DM1. The specific mutation that causes DM1 is called a trinucleotide repeat expansion.

Some families with symptoms of DM do not have a mutation in the DMPK gene. As of early 2001, scientists have found that the DM in many of these families is caused by a mutation in a gene on chromosome 3. However the specific gene and mutation have not yet been identified. These families are said to have DM2.

Trinucleotide repeats

In the DMPK gene, there is a section of the genetic code where the three letters CTG are repeated a certain number of times. In people who have DM1, this word is repeated too many times—more than the normal number of 37 times—and thus this section of the gene is too big. This enlarged section of the gene is called a trinucleotide repeat expansion.

People who have repeat numbers in the normal range will not develop DM1 and cannot pass it to their children. Having more than 50 repeats causes DM1. People who have 38–49 repeats have a premutation and will not develop DM1, but can pass DM1 onto their children. Having repeats numbers greater than 1,000 causes congenital myotonic dystrophy.

In general, the more repeats in the affected range that someone has, the earlier the age of onset of symptoms and the more severe the symptoms. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age they will begin to have symptoms or how their condition will progress.

Exactly how the trinucleotide repeat expansion causes myotonia, the inability to relax muscles, is not yet understood. The disease somehow blocks the flow of electrical impulses across the muscle cell membrane. Without proper flow of charged particles, the muscle cannot return to its relaxed state after it has contracted.

Anticipation

Sometimes when a person who has repeat numbers in the affected or premutation range has children, the expansion grows larger. This is called anticipation. A larger expansion can result in an earlier age of onset in children than in their affected parent. Anticipation happens more often when a mother passes DM1 onto her children then when it is passed from the father. Occasionally repeat sizes stay the same or even get smaller when they are passed to a person's children.

Inheritance

DM is inherited through autosomal dominant inheritance . This means that equal numbers of males and females are affected. It also means that only one gene in the pair needs to have the mutation in order for a person to be affected. Since a person only passes one copy of each gene onto their children, there is a 50% or one in two chance that a person who has DM will pass it onto each of their children. This percentage is not changed by results of other pregnancies. A person with a premutation also has a 50%, or one in two, chance of passing the altered gene on to each of their children. However, whether or not their children will develop DM1 depends on whether the trinucleotide repeat becomes further expanded. A person who has repeat numbers in the normal range cannot pass DM1 onto their children.

Demographics

DM occurs in about one of 20,000 people and has been described in people from all over the world.

Signs and symptoms

There is a range in the severity of symptoms in DM and not everyone will have all of the symptoms listed here.

Myotonic dystrophy causes weakness and delayed muscle relaxation called myotonia. Symptoms of DM include facial weakness and a slack jaw, drooping eyelids called ptosis, and muscle wasting in the forearms and calves. A person with DM has difficulty relaxing his or her grasp, especially in the cold. DM affects the heart muscle, causing irregularities in the heartbeat. It also affects the muscles of the digestive system, causing constipation and other digestive problems. DM may cause cataracts, retinal degeneration, low IQ, frontal balding, skin disorders, atrophy of the testicles, and diabetes. It can also cause sleep apnea—a condition in which normal breathing is interrupted during sleep. DM increases the need for sleep and decreases motivation. Severe disabilities do not set in until about 20 years after symptoms begin. Most people with myotonic dystrophy maintain the ability to walk, even late in life.

A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM1. Congenital myotonic dystrophy is marked by severe weakness, poor sucking and swallowing responses, respiratory difficulty, delayed motor development, and mental retardation. Death in infancy is common in this type.

Some people who have a trinucleotide repeat expansion in their DMPK gene do not have symptoms or have very mild symptoms that go unnoticed. It is not unusual for a woman to be diagnosed with DM after she has an infant with congenital myotonic dystrophy.

Predictive testing

It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms, or the course of the disease.

Diagnosis

Diagnosis of DM is not difficult once the disease is considered. However, the true problem may be masked because symptoms can begin at any age, can be mild or severe, and can occur with a wide variety of associated complaints. Diagnosis of DM begins with a careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes. A family history of DM or unexplained weakness helps to establish the diagnosis.

A definitive diagnosis of DM1 is done by genetic testing , usually by taking a small amount of blood. The DNA in the blood cells is examined and the number of repeats in the DMPK gene is determined. Various other tests may be done to help establish the diagnosis, but only rarely would other testing be needed. An electromyogram (EMG) is a test used to examine the response of the muscles to stimulation. Characteristic changes are seen in DM that helps distinguish it from other muscle diseases. Removing a small piece of muscle tissue for microscopic examination is called a muscle biopsy. DM is marked by characteristic changes in the structure of muscle cells that can be seen on a muscle biopsy. An electrocardiogram could be performed to detect characteristic abnormalities in heart rhythm associated with DM. These symptoms often appear later in the course of the disease.

Prenatal testing

Testing a pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.

Another procedure, called preimplantation diagnosis allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

Treatment and management

Myotonic dystrophy cannot be cured, and no treatment can delay its progression. However, many of the symptoms it causes can be treated. Physical therapy can help preserve or increase strength and flexibility in muscles. Ankle and wrist braces can be used to support weakened limbs. Occupational therapy is used to develop tools and techniques to compensate for loss of strength and dexterity. A speech-language pathologist can provide retraining for weakness in the muscles controlling speech and swallowing.

Irregularities in the heartbeat may be treated with medication or a pacemaker. A yearly electrocardiogram is usually recommended to monitor the heartbeat. Diabetes mellitus in DM is treated in the same way that it is in the general population. A high-fiber diet can help prevent constipation. Sleep apnea may be treated with surgical procedures to open the airways or with nighttime ventilation. Treatment of sleep apnea may reduce drowsiness. Lens replacement surgery is available when cataracts develop. Pregnant woman should be followed by an obstetrician familiar with the particular problems of DM because complications can occur during pregnancy, labor, and delivery.

Wearing a medical bracelet is advisable. Some emergency medications may have dangerous effects on the heart rhythm in a person with DM. Adverse reactions to general anesthesia may also occur.

Prognosis

The course of myotonic dystrophy varies. When symptoms appear earlier in life, disability tends to become more severe. Occasionally people with DM may require a wheelchair later in life. Children with congenital DM usually require special educational programs and physical and occupational therapy. For both types of DM, respiratory infections pose a danger when weakness becomes severe.

Resources

PERIODICALS

The International Myotonic Dystrophy Consortium (IDMC). "New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1)." Neurology 54 (2000): 1218–1221.

Meola, Giovanni. "Myotonic Dystrophies." Current Opinion in Neurology 13 (2000): 519–525.

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.

WEBSITES

Myotonic Dystrophy Website. <http://www.umd.necker.fr/myotonic_dystrophy.html>.

Smith, Corrine O'Sullivan. "Myotonic Dystrophy: Making an Informed Choice About Genetic Testing." University of Washington. <http://www.depts.washington.edu/neurogen/Myotonic.pdf>.

NCBI Genes and Disease Web Page. <http://www.ncbi.nlm.nih.gov/disease/Myotonic.html>.

Gene Clinics. <http://www.geneclinics.org>.

Karen M. Krajewski, MS, CGC

Myotonic dystrophy

Definition

Myotonic dystrophy is a progressive disease in which the muscles are weak and are slow to relax after contraction.

Description

Myotonic dystrophy (DM), also called dystrophia myotonica, myotonia atrophica, or Steinert disease, is a common form of muscular dystrophy . DM is an inherited disease, affecting both males and females. About 30,000 people in the United States are affected. Symptoms may appear at any time from infancy to adulthood. DM causes general weakness, usually beginning in the muscles of the hands, feet, neck, or face. It slowly progresses to involve other muscle groups, including the heart. DM affects a wide variety of other organ systems as well.

A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital means that the condition is present from birth.

Genetic profile

The most common type of DM is called DM1 and is caused by a mutation in a gene called myotonic dystrophy protein kinase (DMPK). The DMPK gene is located on chromosome 19. When there is a mutation in this gene, a person develops DM1. The specific mutation that causes DM1 is called a trinucleotide repeat expansion.

Some families with symptoms of DM do not have a mutation in the DMPK gene. As of early 2001, scientists have found that the DM in many of these families is caused by a mutation in a gene on chromosome 3. However the specific gene and mutation have not yet been identified. These families are said to have DM2.

Trinucleotide repeats

In the DMPK gene, there is a section of the genetic code where the three letters CTG are repeated a certain number of times. In people who have DM1, this word is repeated too many times—more than the normal number of 37 times—and thus this section of the gene is too big. This enlarged section of the gene is called a trinucleotide repeat expansion.

People who have repeat numbers in the normal range will not develop DM1 and cannot pass it to their children. Having more than 50 repeats causes DM1. People who have 38–49 repeats have a premutation and will not develop DM1, but can pass DM1 onto their children. Having repeats numbers greater than 1,000 causes congenital myotonic dystrophy.

In general, the more repeats in the affected range that someone has, the earlier the age of onset of symptoms and the more severe the symptoms. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age they will begin to have symptoms or how their condition will progress.

Exactly how the trinucleotide repeat expansion causes myotonia, the inability to relax muscles, is not yet understood. The disease somehow blocks the flow of electrical impulses across the muscle cell membrane. Without proper flow of charged particles, the muscle cannot return to its relaxed state after it has contracted.

Anticipation

Sometimes when a person who has repeat numbers in the affected or premutation range has children, the expansion grows larger. This is called anticipation. A larger expansion can result in an earlier age of onset in children than in their affected parent. Anticipation happens more often when a mother passes DM1 onto her children then when it is passed from the father. Occasionally repeat sizes stay the same or even get smaller when they are passed to a person's children.

Inheritance

DM is inherited through autosomal dominant inheritance . This means that equal numbers of males and females are affected. It also means that only one gene in the pair needs to have the mutation in order for a person to be affected. Since a person only passes one copy of each gene onto their children, there is a 50% or one in two chance that a person who has DM will pass it onto each of their children. This percentage is not changed by results of other pregnancies. A person with a premutation also has a 50%, or one in two, chance of passing the altered gene on to each of their children. However, whether or not their children will develop DM1 depends on whether the trinucleotide repeat becomes further expanded. A person who has repeat numbers in the normal range cannot pass DM1 onto their children.

Demographics

DM occurs in about one of 20,000 people and has been described in people from all over the world.

Signs and symptoms

There is a range in the severity of symptoms in DM and not everyone will have all of the symptoms listed here.

Myotonic dystrophy causes weakness and delayed muscle relaxation called myotonia. Symptoms of DM include facial weakness and a slack jaw, drooping eyelids called ptosis, and muscle wasting in the forearms and calves. A person with DM has difficulty relaxing his or her grasp, especially in the cold. DM affects the heart muscle, causing irregularities in the heartbeat. It also affects the muscles of the digestive system, causing constipation and other digestive problems. DM may cause cataracts, retinal degeneration, low IQ, frontal balding, skin disorders, atrophy of the testicles, and diabetes . It can also cause sleep apnea—a condition in which normal breathing is interrupted during sleep. DM increases the need for sleep and decreases motivation. Severe disabilities do not set in until about 20 years after symptoms begin. Most people with myotonic dystrophy maintain the ability to walk, even late in life.

A severe form of DM, congenital myotonic dystrophy, may appear in newborns of mothers who have DM1. Congenital myotonic dystrophy is marked by severe weakness, poor sucking and swallowing responses, respiratory difficulty, delayed motor development, and mental retardation. Death in infancy is common in this type.

Some people who have a trinucleotide repeat expansion in their DMPK gene do not have symptoms or have very mild symptoms that go unnoticed. It is not unusual for a woman to be diagnosed with DM after she has an infant with congenital myotonic dystrophy.

Predictive testing

It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms, or the course of the disease.

Diagnosis

Diagnosis of DM is not difficult once the disease is considered. However, the true problem may be masked because symptoms can begin at any age, can be mild or severe, and can occur with a wide variety of associated complaints. Diagnosis of DM begins with a careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes. A family history of DM or unexplained weakness helps to establish the diagnosis.

Relationship between phenotype and CTG repeat length in myotonic dystrophy

A definitive diagnosis of DM1 is done by genetic testing , usually by taking a small amount of blood. The DNA in the blood cells is examined and the number of repeats in the DMPK gene is determined. Various other tests may be done to help establish the diagnosis, but only rarely would other testing be needed. An electromyogram (EMG) is a test used to examine the response of the muscles to stimulation. Characteristic changes are seen in DM that helps distinguish it from other muscle diseases. Removing a small piece of muscle tissue for microscopic

examination is called a muscle biopsy. DM is marked by characteristic changes in the structure of muscle cells that can be seen on a muscle biopsy. An electrocardiogram could be performed to detect characteristic abnormalities in heart rhythm associated with DM. These symptoms often appear later in the course of the disease.

Prenatal testing

Testing a pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.

Another procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

Treatment and management

Myotonic dystrophy cannot be cured, and no treatment can delay its progression. However, many of the symptoms it causes can be treated. Physical therapy can help preserve or increase strength and flexibility in muscles. Ankle and wrist braces can be used to support weakened limbs. Occupational therapy is used to develop tools and techniques to compensate for loss of strength and dexterity. A speech-language pathologist can provide retraining for weakness in the muscles controlling speech and swallowing.

Irregularities in the heartbeat may be treated with medication or a pacemaker. A yearly electrocardiogram is usually recommended to monitor the heartbeat. Diabetes mellitus in DM is treated in the same way that it is in the general population. A high-fiber diet can help prevent constipation. Sleep apnea may be treated with surgical procedures to open the airways or with nighttime ventilation. Treatment of sleep apnea may reduce drowsiness. Lens replacement surgery is available when cataracts develop. Pregnant woman should be followed by an obstetrician familiar with the particular problems of DM because complications can occur during pregnancy, labor and delivery.

Wearing a medical bracelet is advisable. Some emergency medications may have dangerous effects on the heart rhythm in a person with DM. Adverse reactions to general anesthesia may also occur.

Prognosis

The course of myotonic dystrophy varies. When symptoms appear earlier in life, disability tends to become more severe. Occasionally people with DM may require a wheelchair later in life. Children with congenital DM usually require special educational programs and physical and occupational therapy. For both types of DM, respiratory infections pose a danger when weakness becomes severe.

Resources

PERIODICALS

The International Myotonic Dystrophy Consortium (IDMC). "New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1)." Neurology 54 (2000): 1218–1221.

Meola, Giovanni. "Myotonic Dystrophies." Current Opinion in Neurology 13 (2000): 519–525.

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.

WEBSITES

Gene Clinics. <http://www.geneclinics.org>.

Myotonic Dystrophy Web site. <http://www.umd.necker.fr/myotonic_dystrophy.html>.

NCBI Genes and Disease Web Page. <http://www.ncbi.nlm.nih.gov/disease/Myotonic.html>.

Smith, Corrine O'Sullivan. "Myotonic Dystrophy: Making an Informed Choice About Genetic Testing." University of Washington. <http://www.depts.washington.edu/neurogen/Myotonic.pdf>.

Karen M. Krajewski, MS, CGC

Myotonic dystrophy

Definition

Myotonic dystrophy is an inherited disorder that affects muscle tone, and hair loss and can involve varying degrees of impaired cognitive abilities. It is inherited as a dominant disorder, which means that individuals that carry the defective gene have the disease. The amount of symptoms exhibited in persons with myotonic dystrophy varies.

Description

Physical limitations resulting from myotonic dystrophy can be significant, involving muscle weakness and difficulty lifting items and performing certain routine daily tasks. There are many cases in which affected persons experience mental delays, and this usually correlates with the extent of the genetic defect. Myotonic dystrophy is a progressive disorder in terms of muscle weakness and muscle wasting.

Demographics

Myotonic dystrophy is relatively rare, occurring approximately once in 8,000 people. There is also a more rare, severe congenital form that occurs with an incidence of about 1 in 100,000.

Causes and symptoms

Myotonic dystrophy involves many different tissues within the body, including the eye, the heart, the endocrine system, and the central nervous system . The clinical manifestations in myotonic dystrophy span from mild to severe, leading to three separate categories with somewhat overlapping characteristics: mild, classical, and congenital (in which the clinical manifestations are evident at birth).

Mild myotonic dystrophy

In the mild form, persons usually develop cataracts and experience mild muscle tone dysfunction (myotonia). They normally do not experience clinical manifestations until they reach 20 years of age. Some patients do not develop symptoms until 70 years of age.

Classical myotonic dystrophy

In the classical form, patients can have generalized weakness, myotonia that is more severe than the mild form, cataracts, balding, and heart rhythm disturbances. The age of onset can be from 10 years until they are 30 years old.

Congenital myotonic dystrophy

Symptoms in the congenital form of myotonic dystrophy are evident at birth. Affected infants show muscle weakness, respiratory defects, and eventually, mental retardation . There are cases that appear after birth but before 10 years of age, although the symptoms might be slight and remain unnoticed. Congenital myotonic dystrophy is almost always inherited from the mother; however, inheritance from the father has occurred. Mental retardation is thought to be associated with early respiratory failure and the effects of the mutated gene on the brain.

Causes of myotonic dystrophy

Myotonic dystrophy is caused by a DNA alteration the in the Myotonin-protein kinase (DMPK) gene. This gene has been found to localize to specialized structures of the heart and skeletal muscle. Normal function is important for intercellular conduction and impulse transmission. It interacts with a variety of proteins that are important in signaling neurological messages. The abnormal gene product leads to disease but the mechanism is complex and in some tissues, it is relatively unclear. The alteration in the DNA leads to abnormal RNA processing, an important step in the production of proteins. This abnormal processing is felt to result in functional alterations of this protein that can lead to disease.

Diagnosis

Myotonic dystrophy is diagnosed clinically in individuals that have a specific type of muscle weakness. This is confirmed with molecular genetics testing, where the DMPK is analyzed. This gene is located on chromosome 19q13.2-13.3. Within the gene, there is a DNA sequence that is a string of three letters in the DNA alphabet (GTC, which are abbreviations for the nucleotides guanine, thymine, and cytosine) that are normally repeated up to 37 times. CTG repeats repeated greater than 50 times alters the function of the protein and can lead to disease. Individuals that have repeats from 38–49 times are considered to have permutations and in this range they generally do not produce symptoms, but their children are at risk for having repeats that expand into the disease causing range. Patients have more symptoms when they have repeat sizes greater than 50. DNA testing is 100% sensitive (able to determine the defect) and widely available. Prenatal diagnosis to determine if a fetus is affected is also available.

Myotonic dystrophy is suspected by physicians if patients experience muscle weakness in the lower legs, hands, neck, and face. The will experience a characteristic sustained muscle contraction whereby they have difficulty in quickly releasing their hand grip during a handshake. They also develop cataracts. Newborns usually have generalized and facial muscle weakness, club foot, and respiratory difficulties. Their muscles usually appear hypotonic (floppy).

Treatment team

A general practitioner may not see very many cases of myotonic dystrophy during his career, but may be the first physician to observe a patient. Usually, a neurologist and a geneticist are consulted. Depending on the age of onset, the extent of professional help varies. When the age of onset is a birth or infancy, a cardiologist and a pulmonologist will be necessary to evaluate and heart or respiratory deficiencies, respectively. These individuals usually also require special education, depending on the extent of the cognitive deficits.

Treatment

There is no specific treatment that has been identified to help the muscle weakness or prevent muscle wasting in myotonic dystrophy. Ankle and/or leg braces can be used to help support the muscles as the disease worsens. Heart problems, cataracts, and other abnormalities can often be treated. There are also medications that can help relieve the myotonia.

Recovery and rehabilitation

Although patients with this disorder do not recover, occupational and physical therapy is felt to be of benefit in many cases to help maintain optimum function for as long as possible.

Clinical trials

As of May 2004, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Neurological Disorders and Stroke (NINDS) were recruiting patients for a registry that will connect people with myotonic dystrophy with researchers studying these diseases. (Contact information: Colleen M. Donlin-Smith, MA, telephone: 585-275-6372, email: [email protected]; Eileen Eastwood, telephone 585-275-6372; email: [email protected]).

Prognosis

The prognosis for patients that are diagnosed with the mild form of the disease is quite good. They usually do not have mental retardation and can live a close to normal lifespan. Affected individuals that have the classic form have a more severe prognosis. They have more clinical manifestations and lifespan usually ranges 48–55 years. The congenital form is the most severe, although patients live, on average, until they are 45 years old. They have more severe mental retardation, respiratory deficits, and have clinical manifestations at birth.

Special concerns

As this disorder can be inherited, genetic counseling for at-risk families is recommended. Offspring of an affected individual, regardless of gender, have a 50% chance of inheriting the mutant gene. It is important to recognize that expanded repeats within the gene can expand even more in the gametes (sex cells—sperm or egg) from individuals with expansions, resulting in the transmission of even longer trinucleotide repeat genes. This expansion leading to longer repeats is associated with more severe disease that is observed in the parent. Therefore, affected individuals are more likely to have more offspring with a more serious form of the disorder. Premutation carriers, or individuals that have repeats that do not usually cause disease but are likely to expand in their offspring, should be identified (if possible) in cases where there is a family history of the disorder. These individuals are at risk for having affected offspring, although they may not themselves have the disorder.

Resources

BOOKS

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia: Saunders, 2001.

Rimoin, David L. Emery and Rimoin's Principles and Practice of Medical Genetics. London; New York: Churchill Livingstone, 2002.

PERIODICALS

Cobo, A. M., J. J. Poza, L. Martorell, A. Lopez de Munain, J. I. Emparanza, and M. Baiget. "Contribution of molecular analyses to the estimation of the risk of congenital myotonic dystrophy." J Med Genet 32 (1995): 105–108.

Redman, J. B., R. G. Fenwick Jr, Y. H. Fu, A. Pizzuti, C. T. Caskey. "Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring." JAMA 269 (1993): 1960–1965.

OTHER

"Myotonic Dystrophy; General Information." International Myotonic Dystrophy Association. <http://www.myotonicdystrophy.org/General%20Information.htm> (May 6, 2004).

"Myotonic Dystrophy." Gene and Disease. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.164 (May 5, 2004).

ORGANIZATIONS

Muscular Dystrophy Association (MDA). 3300 East Sunrise Drive, Tucson, AZ 85718-3208. (800) 572-1717 or (520) 529-2000; Fax: (520) 529-5300. [email protected]. <www.mdausa.org>.

Muscular Dystrophy Campaign. 7-11 Prescott Place, London SW4 6BS, UK. (+44) 0 020 7720 8055; Fax: (+44) 0 020 7498 0670. [email protected]. <http://www.muscular-dystrophy.org>.

Bryan Richard Cobb, PhD