Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelinesfor clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.
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There are two types of Myotonic Dystrophy
DM1 is known as Type 1
DM2 is known as Type 2, and also known as PROMM or “Proximal Myotonic Myopathy“ DM1 is caused by an expanded repeat of CTG on Chromosome 19
DM2 is caused by an expanded quadruplet repeat of CTG on Chromosome 3 Differences in DM1 and DM2
DM2 does not seem to cause the severe congenital form when the mother that has the disease has an infant. Also the apathetic personality traits with DM1 do not seem to be associated with DM2. People with DM2 will have more weakness in the trunk of the body (proximal) versus DM1 will have more weakness in the distal parts of the body like legs and arms. The incidence of DM2 is unknown. There is a genetic test for DM2 just available from Athena Diagnostics. Estimation is that the incidence is less than 2% (QUEST Feb 2002) but it may be much higher.
A deficient gene causes DM1. This is an alteration in the myotonin protein kinase gene, specifically in the APOC2 locus located on the proximal long arm of chromosome 19. DM is an autosomal dominant condition; this means that only one copy of the gene with a genetic alteration is necessary for DM to occur. The genetic alteration found in the myotonin protein kinase is a repeating sequence of three specific nucleotides (these are the ‘building blocks’ which make up DNA). Normally in gene 19 the sequence of cytosine-thymidine-guanine (CTG) repeats itself from 5-37 times in a row, however in an altered DM gene this CTG sequence repeats 50+ times and in some cases it can exceed 2000. The number of repeats effects when the age of onset occurs and the severity of DM. The table below shows how the CTG repeat length/numbers effects the clinical symptoms
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| Table 1: Correlation of CTG repeat numbers with clinical symptoms | |||||||||||||||||||
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The numbers of CTG repeats are stable from generation to generation when they are in the normal 5-30 repeats. The number of CTG repeats may change in number from generation to generation when they are in the range of 50+. The number of repeats will rarely decrease in number from parent to child. Figure 1 shows the difference between the normal and the altered CTG repeats |
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Some authorities maintain that the correlation between the number of repeats and the severity of the illness is not absolute. A key factor they maintain is the age when the first symptoms appear. The earlier the symptoms appear the more likely that the disease may have a more severe manifestation. The affected mother has a 50% chance of transmitting the mutation to each child. The underlying Myotonic Dystrophy that the mother has is inherited as a “autosomal dominant trait” However, there is some thought that the mother has a “maternal factor” that passes through the placenta and thus is the cause of fetal muscle maturation arrest. (Farkas-Bargeton). There have a a very few documented cases of paternal (father’s) transmission of the congenital form. Click here for more info. Congenital Myotonic Dystrophy is related and linked very strongly to Myotonic Dystrophy. In virtually all cases the mother must be affected and have Myotonic Dystrophy. Myotonic Dystrophy is a genetic disease that is more progressive between generations. This is called anticipation; that means that each son or daughter that is affected may have the disease slightly worse. The CMD condition is potentially the worst outcome of this disease. Myotonic Dystrophy has the anticipation or amplification factor. Each succeeding generation may have the disease slightly worse. The number of repeats of the CTG sequence gets longer. The onset of Myotonic Dystrophy gets earlier as a general rule as the number of repeats increases. In this family of disorders the number of repeats tend to increase with succeeding generations. Again, this is known as “genetic anticipation” There also has been a report from England that there can be regression (shrinkage) as the MD allele is passed on to successive generations; this is mostly seen with paternal (through the father which is rare) transmission. The is also some reports of regression to a repeat number within the normal range Myotonic and CMD belong to a growing family of disorders where the genetic mutation involves unstable Trinucleotide repeats (C_G) These letters correspond to amino acids which form the basis of DNA. More information on Triplet Repeat Disorders or Triplet Repeat Information. A few related disorders: Fragile X Syndrome CGG |
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| CTG Repeat Numbers | |||||||||||||||||||
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5 repeat and 16-30 repeat alleles have been shown to share the same linkage disequalibrium as DM. It is proposed that the 5 repeat allele expands to alleles in the 16-30 repeat range which then form a pool for recurrent DM mutations. In the absence of a high new mutation rate, this theory explains why myotonic dystrophy is maintained in the population and not lost via the congenital form. |
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| Diagram of How the disease may affect transcription
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Click below for a great booklet on Whether to test for Myotonic Dystrophy |
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| myotonic dystrophy an informed choice of testing | |||||||||||||||||||
(EDITORS NOTE THIS IS AN OLDER PAMPHLET UPDATED INFORMATION IS IN BOLD)
MYOTONIC DYSTROPHY An informational booklet for individuals and families
Written by: Wendy C. McKinnon, M.S., Genetic Counselor Vermont Regional Genetics Center
Introduction
This booklet is written for individuals and families with Myotonic Dystrophy, also known as Steinert’s disease or Dystrophia Myotonica (DM). The booklet describes what DOM is, how it is inherited, and recent discoveries about DM.
DM is an inherited disorder that affects about one in every 8000 people. In general, DM consists of muscle weakness and myotonia (inability of muscles to relax after use) which gets more severe over time. Specific problems in other systems of the body can also occur. Since DM can affect many tissues and organs it is called a “multisystem” disorder.
Myotonic Dystrophy is an extremely variable condition. It can vary in severity, the systems of the body it affects, and the age of onset, even in the same family. People with milder symptoms may never require special medical attention and thus never be diagnosed as having DM. On the other hand, newborn babies who are more severely affected may die during infancy without the diagnosis of DM ever having been made. If a newborn is diagnosed with DM, this may be the first time the family learns about the condition. Recent discovery of the gene alteration which causes DM helps explain this condition’s incredible variation.
What are the clinical features of Myotonic Dystrophy?
It is important to realize that any one individual with DM is unlikely to have all of the features described here, but will probably have some of them and these may vary greatly from one individual to another.
Personal Stories ::: What are the clinical features of Myotonic Dystrophy?
It is important to realize that any one individual with DM is unlikely to have all of the features described here, but will probably have some of them and these may vary greatly from one individual to another.
DM primarily affects muscles and these will be described first. Myotonia refers to the slow relaxation of muscle following contraction, resulting in muscle stiffness. For example, following a forceful grip, the individual with DM may have delayed release of their grip. This may cause difficulty in releasing objects such as door handles, cups, tools, or bowling balls. Cold weather can make this worse. While myotonia is most obvious in the hands, it can affect other muscles as well. Some individuals with DM have little or no myotonia. Myotonia can be confirmed by an Electromyogram (EMG). An electromyogram involves insertion of a fine needle into the muscle and recording electrical activity, looking for evidence of myotonia.
Facial muscle weakness can be one of the earliest and most constant features of DM. There may be weakness and lack of movement of the facial muscles. Some individuals with DM are unable to whistle or retain air in their cheeks. Some people with DM describe difficulty drinking through a straw or blowing up a balloon, or getting food stuck in their cheeks. Facial muscle weakness may also make it difficult to smile.The muscles of the eyes can be weak, resulting in a “droopiness” of the eyelids which is called ptosis.Involvement of jaw muscles may give the face a hollow cheek appearance. More severe jaw muscle weakness may cause the jaw to hang open, dislocation of the jaw, locking of the jaw, difficulty in chewing, or “clicking” of the jaw.
The sternocleidomastoids are muscles in the neck and shoulder. Some people with DM have trouble lifting their head when they get out of bed due to weakness in these muscles. In addition, weakness of the shoulder muscles makes it difficult for some individuals with DM to lift their arms over their head for an extended period.DM commonly involves the distal (end) limb muscles. These include the forearm and hand muscles, as well as the muscles of the feet and ankles. Weakness of the hand and forearm can affect coordination and grip. Symptoms might include difficulty opening jars or holding small objects tightly. Weakness in the muscles of the feet and ankle may result in unsteady gait, tripping or stumbling.
What other muscles are affected in DM?
Speech requires the coordination of the muscles of the voice box (larynx), the throat , the tongue, the lips, and the roof of the mouth (palate). If any of these muscles are affected by DM, speech may sound slurred or indistinct. It is also common for individuals with DM to have somewhat “nasal” speech.
Speech requires the coordination of the muscles of the voice box (larynx), the throat , the tongue, the lips, and the roof of the mouth (palate). If any of these muscles are affected by DM, speech may sound slurred or indistinct. It is also common for individuals with DM to have somewhat “nasal” speech.
In the digestive tract, the muscles of the pharynx and the esophagus are primarily affected. The pharynx is the first passageway food moves through on its way from the mouth to the stomach, and the esophagus is the tube connecting the pharynx to the stomach.
Dysphagia is the term used to describe difficulty in swallowing which is common in DM. This is due to the muscles of the pharynx and esophagus having difficultly contracting and relaxing which creates difficulty swallowing and delays the entry of food into the stomach. Some individuals describe dysphagia as a sensation of “sticking” of food in the throat. Difficulty swallowing can sometimes be understood better with a barium swallow examination or esophageal pressure recordings. Eating and drinking small quantities slowly may help dysphagia.Individuals with DM may have an increased chance of gallstones.
The respiratory system includes the trachea, the lungs and the diaphragm. The trachea is the tube that carries the air we breathe from the mouth and nose to the lungs. The lungs transfer oxygen from the air we breathe to the blood. The diaphragm is the muscle just below the lungs which expands and contracts with each breath. There can be weakness of the respiratory muscles in DM. Also, as discussed earlier, weakness in the muscles of the pharynx and esophagus can cause delayed entry of food into the stomach. This delay, combined with weakness of the respiratory muscles, can result in entry (aspiration) of food into the lungs. This can lead to infections in the lungs, including pneumonia. Avoiding hurried meals or large meals at night and elevating the head during sleep may help prevent this problem.Hypoventilation refers to shallow breathing and is due to abnormalities in respiratory muscle function. Smoking worsens breathing difficulties.
How are the heart and blood vessels affected?
There is nothing unusual about the structure of the heart muscles in individuals with DM. However, there can be abnormalities in how the heart beats. An irregular beat is referred to as a cardiac arrhythmia. Some people have no symptoms as a result of a cardiac arrhythmia. Other people have palpitations (“fluttering”), chest pain or tightness.
What other systems are affected by DM?
Individuals with DM can have abnormalities of the endocrine system. The endocrine system consists of a number of glands that produce substances called hormones which are carried by the bloodstream to various parts of the body.
What is the age of onset of Myotonic Dystrophy?
Symptoms of DM can first occur at various ages. In fact, there appear to be four stages of onset: congenital (at birth), juvenile (childhood), classic (20-40 years) and late (after 40 years of age).
Symptoms of DM can first occur at various ages. In fact, there appear to be four stages of onset: congenital (at birth), juvenile (childhood), classic (20-40 years) and late (after 40 years of age).
Congenital DM refers to the presence of symptoms in the first month of life. The major features may include facial weakness, hypotonia (low muscle tone), respiratory problems, feeding difficulties, talipes (clubfoot). Delays in motor skills such as rolling over, crawling, and walking may also occur. Some degree of mental impairment will occur in individuals with congenital DM. For reasons not yet clearly understood, congenital DM almost never occurs unless the baby’s mother has DM herself – although she may have only a mild version of DM.
Occasionally, a woman with DM may notice decreased fetal movements during pregnancy because the fetal muscles may be affected. In addition, polyhydramnios (increased amounts of amniotic fluid surrounding the fetus) may occur. A fetus normally swallows and urinates amniotic fluid continually. In a fetus exhibiting symptoms of DM, there may be difficulty swallowing, allowing extra amniotic fluid to accumulate. Juvenile DM has its onset between the ages of 1 and 20 years, and classic DM has onset between 21 and 40 years of age. Symptoms in these often consist of muscle weakness, myotonia, and possible involvement of other organ systems. There may also be an increased chance of learning problems in school.
The mildest form of DM first occurs after the age of 40 years and is usually accompanied by cataracts. Some minor muscle problems such as jaw tightness or cramps in the hands may be present, or there may be no muscle problems at all.There is wide variability in the age of onset and the severity of the condition. Individuals who develop symptoms early in life will likely have a more severe form of DM; while those whose symptoms do not appear until later usually have a milder form.
The genetic nature of Myotonic Dystrophy
DM is caused by a genetic alteration in the myotonin protein kinase gene located on chromosome 19. Since our chromosomes come in pairs, we have two copies of the myotonin protein kinase gene. A person with DM has a genetic change or alteration in one of their two copies of this gene.
DM is an autosomal dominant condition – only one copy of the gene with the genetic alteration is necessary for DM to occur. DM affects both males and females equally; however, females with DM are much more likely to have a child with congenital DM than are males with DM.
The inheritance of DM follows an autosomal dominant inheritance pattern as illustrated. An individual with the genetic alteration found in DM has a 50% chance of passing on the genetically altered myotonin protein kinase gene to any child.
A child who has inherited the genetically altered myotonin protein kinase gene will develop some or many features of DM. Their age of onset may be the same or different from the parent’s.
What is the genetic alteration in the myotonin protein kinase gene?
The genetic alteration found in the myotonin protein kinase gene is a repeating sequence of three specific nucleotides (the building blocks which make up DNA, which in turn make up genes).
Can the clinical features vary from person to person in the same family?
Problems can range from very mild to very severe even within the same family, and it is not always obvious who in the family has the DM gene alteration.
What if a doctor suspects an individual has Myotonic Dystrophy
If a doctor suspects that an individual has DM because features of the condition are present, genetic testing may be performed to confirm the diagnosis. Genetic testing involves obtaining about two teaspoons of blood. DNA is isolated from blood cells and then the number of CTG repeats in the DM gene can be determined. Testing takes an average of 2-3 weeks. Its cost varies somewhat but in 1994 is approximately $300.00
What if an individual has no clinical features of DM but has a family history of DM?
If an individual diagnosed with DM is identified as having the CTG repeat expansion, a family member who has no features of the condition may also consider having genetic testing.
What about having children?
When one member of a couple has DM, there are a number of options available when thinking about having children.When one member of a couple has DM, there are a number of options available when thinking about having children.
A couple can choose to have children and not have prenatal testing. If a couple decides not to have prenatal testing, they should inform the obstetrician and pediatrician of the family history. If the fetus inherits the DM gene, there could be complications during the pregnancy and/or in the newborn period.
A couple can choose to have a pregnancy and have prenatal testing for DM by either amniocentesis or chorionic villus sampling to find out if the fetus has inherited the DM gene. Prenatal testing is described in the next section.
A couple can choose to adopt children because they want to significantly reduce the chance of having a child with DM.
A couple can choose to use sperm from an unaffected donor when a man has DM, or an egg from an unaffected donor when a woman has DM. This would significantly reduce the chance of having a child with DM.
Now available a couple can choose to have pre-implant diagnosis and then invitro fertilization. The egg is fertilized outside of the body, then tested to see if it has the myotonic dystrophy gene. Only healthy non Myotonic dystrophy embryos are then implanted into the women’s uterus for development.
It is important to remember that there is no right or wrong choice to make with regards to having children. Everybody has different experiences, thoughts, ideas, and opinions about the various options available.
Prenatal Diagnosis
Prenatal diagnosis is available to couples who would like to know during a pregnancy whether their fetus has inherited the DM gene from an affected parent. Prenatal diagnosis can be discussed with a genetic counselor. Pre-Implant Diagnosis is also available
Genetic Counseling
Genetic counseling is often useful for individuals and families with questions and concerns about specific genetic conditions
Treatments
There are no specific treatments currently available for individuals with DM. It is hoped that with advances in research, a better understanding of the underlying cause of DM will lead to specific treatments for its symptoms. Medications are available that your doctor can prescribe to reduce myotonia, especially if it interferes with daily activities. Physical therapy and occupational therapy, as well as regular exercise may help minimize the progression of muscle weakness. Ankle and leg braces may help support these muscles.Drug Treatments are underdevelopment by Isis Pharmaceuticals and others. These treatments will not be commercially available until 2017 or 2018 at the earliest.
Additional Resources
Myotonic Dystrophy Foundation
Menlo Park, CA USA
Muscular Dystrophy Association (MDA)
National Headquarters
3300 East Sunrise Drive
Tucson, AZ 85718-3208
Telephone (602) 529-2000 / Fax (602) 529-5300 The National Society of Genetic Counselors (NSGC)
Executive Office
233 Canterbury Drive
Wallingford, PA 19086
Telephone (610) 872-7608
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