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 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, may appear in newborns of mothers who have DM. Congenital means that the condition is present from birth.

DM occurs in about 1 of 20,000 people and has been described in people from all over the world.

— Karen M. Krajewski, M.S., C.G.C.

(medicine) A hereditary disease, transmitted as an autosomal dominant, characterized by lack of normal relaxation of muscles after contraction, slowly progressive muscular weakness and atrophy, especially of the face and neck, cataract formation, early baldness, gonadal atrophy, abnormal glucose tolerance curve, and, frequently, mental deficiency.

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: Colleen_DonlinSmith@urmc.rochester.edu; Eileen Eastwood, telephone 585-275-6372; email: Eileen_Eastwood@urmc.rochester.edu).

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. mda@mdausa.org. 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. info@muscular-dystrophy.org. http://www.muscular-dystrophy.org.

Bryan Richard Cobb, PhD

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.

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." GeneReviews [cited August 9, 2004]. Available online at: www.genetests.org/profiles/myotonic_d/details.html.

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

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

[Article by: Tish Davidson, A.M. Karen M. Krajewski, M.S., C.G.C.]

Myotonic dystrophy
Classification and external resources
ICD-10	G71.1
OMIM	160900 602668
DiseasesDB	8739
MeSH	D009223

Myotonic dystrophy (dystrophia myotonica, DM) is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles (muscular dystrophy), posterior subcapsular iridescent cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age.

Contents 1 Classification 2 Epidemiology 3 Symptoms 4 Genetics 4.1 DM1 4.2 DM2 5 Diagnosis 6 Management 7 Screening 8 References 9 Further reading 10 External links

Classification

Comparison between myotonic dystrophy subtypes

Type	Gene	Repeat	Anticipation	Severity
DM1	DMPK	CTG	Yes	Moderate-severe
DM2	ZNF9	CCTG	Minimal/none	Mild-moderate

Two types of adult onset myotonic dystrophy exist. Type 1 (DM1), also called Steinart's disease, has a severe congenital form and a milder childhood-onset form. Also called proximal myotonic myopathy (PROMM), myotonic dystrophy type 2 (DM2) is due to a different mechanism than DM1 and generally manifests with milder signs and symptoms.

Other forms of myotonic dystrophy (DM3, DM4, and DMX) may also exist.^{[citation needed]} One recent case was proposed as a candidate for the "DM3" label,^[1] but was later characterized as a form of Paget's disease.^[2][3]

Epidemiology

Myotonic dystrophy is the most common form of muscular dystrophy affecting adults.^{[citation needed]} It is the second most common form of any skeletal muscle disease after Duchenne muscular dystrophy.^{[citation needed]}

Type 1 accounts for 98% of all myotonic dystrophy cases. Estimates of the the prevalence of type 2 muscular dystrophy may be erroneously low as the various atypical presentations of this subtype may evade diagnosis.^{[citation needed]}

Symptoms

Presentation of symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with myotonia, disabling distal weakness and severe cognitive problems. DM2 patients commonly present with muscle pain, stiffness, fatigue, or the development of proximal lower extremity weakness (Day & al, 2003). The characteristic pattern of weakness is different for DM1 and DM2: In DM1, it is noted in face and jaw muscles, the drooping of the eyelids (ptosis), weakness of the neck muscles, hands and lower legs. In DM2, the weakness is more evident in proximal muscles, those closer to the trunk of the body: neck, shoulders, hip flexors and upper legs.

Symptoms classically asssociated with DM1 are generally more mild and involve the smooth muscle (including G.I. symptoms), hypersomnia (daytime sleepiness), muscle wasting, dysphagia, and respiratory insufficiency. In addition, DM1 may manifest with a cognitive abnormalities including developmental delays, learning problems, language, speech, behaviour, apathy or hypersomnia. Cognitive manifestations for DM2 include problems with executive function (eg, organization, concentration, word-finding) and hypersomnia. Conduction abnormalities are more common in DM1 than DM2, but all patients are advised to have an annual ECG. Both types are also associate with insulin resistance.

DM2 is generally milder than DM1, with generally fewer DM2 patients requiring assistive devices than DM1 patients.^{[citation needed]} In addition, the severe congenital form that affects babies in DM1 has not been found in DM2 and the early onset of symptoms is rarely noted to appear in younger patients in the medical literature.

Genetics

Myotonic dystrophy is inherited in an autosomal dominant pattern.

Myotonic dystrophy is a genetic condition which is inherited in an autosomal dominant pattern and thus will be passed along to 50% of a carrier's offspring, on average.

Myotonic dystrophy is one of several known trinucleotide repeat disorders. Certain areas of DNA have repeated sequences of two or three nucleotides.

DM1

In DM1, the affected gene is called DMPK, which codes for myotonic dystrophy protein kinase,^[4] a protein expressed predominantly in skeletal muscle.^[5] The gene is located on the long arm of chromosome 19.^[6]

In DM1, there is a repeat of the triplet cytosine-thymine-guanine (CTG) in the DMPK gene. The number of repeats varies greatly, but the average number in a healthy person is between 5 and 37. Additional trinucleotide repeats inserted during cell division can produce protein instability.^{[citation needed]} Consequently, the repeat size of an individual with DM1 will become larger usually during gametogenesis or early embryonic development. This explains the phenomenon of anticipation, as each child of an affected adult will have a larger expansion than their parent. Individuals with larger expansions have an earlier onset of the disorder and a more severe phenotype.

DM2

DM2 is caused by a defect of the ZNF9 gene on chromosome 3.^[7] The specific defect is a repeat of the cytosine-cytosine-thymine-guanosine (CCTG) tetranucleotide in the ZNF9 gene.^[7] As it involves the repeat of four nucleotides, it is not a trinucleotide repeat disorder, but rather a tetranucleotide repeat disorder.^[8]

The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats.^[7] Unlike in DM1, the size of the repeated DNA expansion in DM2 does not appear to make a difference in the age of onset or disease severity.^{[citation needed]} Anticipation appears to be less significant in DM2 and most current reviews only report mild anticipation as a feature of DM2.^{[citation needed]}

Diagnosis

The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. More than 40 neuromuscular disorders exist with close to 100 variants.^{[citation needed]}

As a result, patients with multiple symptoms that may be explained by a complex disorder such as DM1 or DM2 will generally be referred by their primary care physician to a neurologist for diagnosis. Depending on the presentation of symptoms, patients may be referred to a number of medical specialists including cardiologists, ophthalmologists, endocrinologists, and rheumatologists. In addition, the clinical presentation is obscured by the degree of severity or the presence of unusual phenotypes.

It is common that the clinical presentation for both DM1 and DM2 patients does not conform to the perceptions of these diseases held by many neurologists. Clinicians who are less familiar with the myotonic dystrophies in their day to day practice may expect patients with both forms to present with the more severe classic symptoms of DM1. As a result, patients may remain undiagnosed or be misdiagnosed.

Even though there is presently no cure for DM and management is currently symptom based, a precise diagnosis is still necessary because of multiple other problems that may develop over time. Even mildly affected DM1 & DM2 patients should be routinely monitored for potentially fatal complications (i.e. cardiac conduction issues, insulin resistance, cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and medical management of symptoms. In addition, genetic counseling should be made available to all patients because of the high risk of transmission. Potentially serious anesthetic risks are important to note, so the presence of this disorder should be brought to the attention of all medical providers.

Management

There is currently no cure for or treatment specific to myotonic dystrophy. Complications of the disease, including heart problems, cataracts, and other abnormalities, can be treated but not cured. However there are medical interventions and medications that may relieve some of the symptoms such as myotonia, pain, and excessive sleepiness. Some treatments have been subject to systematic review for safety and efficacy through the Cochrane Reviews for symptoms such as hypersomnia (excessive daytime sleepiness), myotonia, strength training, aerobic exercise training, and foot drop.

Recent research has provided more information on the underlying molecular pathophysiologic mechanisms involved in myotonic dystrophy and has fueled interest and research into new approaches for more specific and effective treatment. Research in areas such as high-throughput screening and antisense therapy hold hope for more effective targeted treatments for the future. Altered splicing of the muscle-specific chloride channel 1 (ClC-1) has been shown to cause the myotonic phenotype of DM1 and is reversible in mouse models using Morpholino antisense to modify splicing of ClC-1 mRNA^[9].

Progress in this area is being fueled by the sharing of research by scientists and clinicians at biannual meetings by the International Myotonic Dystrophy Consortium (IDMC). The 7th biannual meeting IDMC-7 took place in Wurtzburg, Germany September 9-12 2009.

Screening

Screening for the repeat expansions on the DMPK gene for DM1 is targeted at chromosome 19, while the ZNF9 gene for DM2 is found on chromosome 3. Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard of diagnosis. Further forms of myotonic dystrophy (DM3, DM4, and DMX) are suspected by researchers with possible defects on chromosome 16 and chromosome 21.^{[citation needed]}

References

1. ^ Le Ber I, Martinez M, Campion D, et al. (2004). "A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24". Brain 127 (Pt 9): 1979–92. doi:10.1093/brain/awh216. PMID 15215218. http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15215218. 
2. ^ "Myotonic Dystrophy Type 2". http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gene.chapter.myotonic-d2. Retrieved 2008-02-24. 
3. ^ Udd B, Meola G, Krahe R, et al. (2006). "140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management". Neuromuscul. Disord. 16 (6): 403–13. doi:10.1016/j.nmd.2006.03.010. PMID 16684600. http://linkinghub.elsevier.com/retrieve/pii/S0960-8966(06)00097-6. 
4. ^ Mahadevan M, Tsilfidis C, Sabourin L, et al. (March 1992). "Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene". Science (New York, N.Y.) 255 (5049): 1253–5. PMID 1546325. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1546325. 
5. ^ van der Ven PF, Jansen G, van Kuppevelt TH, et al. (November 1993). "Myotonic dystrophy kinase is a component of neuromuscular junctions". Human Molecular Genetics 2 (11): 1889–94. PMID 8281152. http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8281152. 
6. ^ Harley HG, Walsh KV, Rundle S, et al. (May 1991). "Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q". Human Genetics 87 (1): 73–80. PMID 2037285. 
7. ^ ^{a b c} Day JW, Ricker K, Jacobsen JF, et al. (February 2003). "Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum". Neurology 60 (4): 657–64. PMID 12601109. http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12601109. 
8. ^ Liquori CL, Ricker K, Moseley ML, et al. (August 2001). "Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9". Science (journal) 293 (5531): 864–7. doi:10.1126/science.1062125. PMID 11486088. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11486088. 
9. ^ Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA (2007). "Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy". J. Clin. Invest. 117 (12): 3952–7. doi:10.1172/JCI33355. PMID 18008009. 

Further reading

• Sir Peter S. Harper, (2002). Myotonic Dystrophy: The Facts : A Book for Patients and Families (Oxford Medical Publications). Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-852586-9. 
• Peter S. Harper... [et al.] (2004). Myotonic dystrophy: present management, future therapy. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-852782-9. 
• Robert D. Wells (Editor), Tetsuo Ashizawa (Editor) (2006). Genetic Instabilities and Neurological Diseases, Second Edition, 2006. Boston: Academic Press. ISBN 0-12-369462-0.  This book has chapters on multiple disorders including both Steinert’s (DM1) and PROMM (DM2). The revised 2006 edition is the first print resource to have a full chapter on DM2: Myotonic Dystrophy Type 2: Clinical and Genetic Aspects by Krahe, Bachinski, and Udd This book is intended to be a reference for medical professionals such as neurologists, neuroscientists, biochemists, geneticists, molecular biologists & human geneticists.

External links

Overview of condition at NLM Genetics Home Reference

• Searchable database at Dutch Neuromuscular Research
• 140th ENMC International Workshop 2006 Myotonic Dystrophy DM2/PROMM and other Myotonic dystrophies]
• Information from the Myotonic Dystrophy Foundation
• Information from the International Myotonic Dystrophy Organization
• MDSG Information
• Information from the Neuromuscular Disease Center
• DM Toolbox Research tools for Myotonic Dystrophy from the Marigold Foundation

v • d • e Muscular Dystrophy The Nine Primary Muscular Dystrophies Congenital • dystrophin (Becker's, Duchenne) • Distal • Emery-Dreifuss • Facioscapulohumeral • Limb-girdle muscular dystrophy • Myotonic • Oculopharyngeal Related topics National/International Organizations Muscular Dystrophy Association (USA) • Muscular Dystrophy Canada • Myotonic Dystrophy Foundation US government Institutes and Legislation NINDS • NIAMS • NICHD • MD CARE Act • Genetic Information Nondiscrimination Act • Americans with Disabilities Act of 1990 National/International Events Jerry Lewis MDA Telethon (USA) Recent or Ongoing Clinical Trials Stamulumab (MYO-029)

v • d • e Diseases of myoneural junction and muscle / neuromuscular disease (G70-G73, 358-359) Neuromuscular- junction disease autoimmune (Myasthenia gravis, Lambert-Eaton myasthenic syndrome) Myopathy/ congenital myopathy Muscular dystrophy (DAPC) AD Limb-girdle muscular dystrophy 1 · Oculopharyngeal · Facioscapulohumeral · Myotonic · Distal (most) AR Limb-girdle muscular dystrophy 2 · Congenital (Fukuyama, Ullrich) XR dystrophin (Becker's, Duchenne) · Emerin Emery-Dreifuss Other structural collagen disease (Bethlem myopathy) · PTP disease (X-linked MTM) · adaptor protein disease (BIN1-linked centronuclear myopathy) · cytoskeleton disease (Nemaline myopathy, Zaspopathy) Channelopathy Myotonia Myotonia congenita · Thomsen disease · Neuromyotonia/Isaacs syndrome · Paramyotonia congenita Periodic paralysis Hypokalemic · Hyperkalemic Other Central core disease Mitochondrial myopathy MELAS · MERRF · KSS · PEO Other Inflammatory myopathy muscle, DF+DRCT navs: anat/hist/physio, acquired myopathy/congenital myopathy/neoplasia, symptoms+signs/eponymous, proc

v • d • e Non-Mendelian inheritance: anticipation Trinucleotide repeat disorders Polyglutamine (PolyQ) Dentatorubral-pallidoluysian atrophy · Huntington's disease  · Kennedy disease · Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease) Non-Polyglutamine Fragile X syndrome · Friedreich's ataxia · Myotonic dystrophy type 1 · Spinocerebellar ataxia 8, 12 Four nucleotides Myotonic dystrophy type 2

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