MYOTONIC DYSTROPHY DEFINITION
An inherited disease in which the muscles contract but have decreasing power to relax — this phenomenon is termed myotonia (irritability and prolonged contraction of muscles). The disease also leads to a mask-like expressionless face, premature balding, cataracts, and heart arrhythmias (abnormalities in heart rhythm). The onset of such problems is usually in young adulthood. However, onset can be at any age and the disease is extremely variable in the degree of severity.
Myotonic dystrophy is due to a trinucleotide repeat (a “stuttering” sequence of three bases) in the DNA. The myotonic dystrophy gene (called DM1), found on chromosome 19q13.3, codes for a protein kinase (an enzyme) that is found in skeletal muscle.
An unusual feature is that the signs and symptoms of the disease usually become more severe with each successive generation. This is because mistakes in the faithful copying of the gene from one generation to the next result in the amplification of a genomic “AGC/CTG triplet repeat.” Unaffected individuals have between 5 and 27 copies of AGC/CTG, myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have an expansion of up to several kilobase pairs.
Myotonic dystrophy is not genetically homogeneous; it is more than one genetic entity. Some families with myotonic dystrophy have a mutation in a gene on chromosome 3q21 (at the DM2 locus). The DM2 mutation is a huge expansion of a tetranucleotide repeat (CCTG) in a noncoding region of the ZNF9 gene. Both DM1 and DM2 appear to cause disease through the effects of the mutant RNA (that contains abnormal repeating sequences).
Myotonic dystrophy is not to be confused with muscular dystrophy. They are distinct and different diseases.
MYOTONIC DYSTROPHY CAUSES
Myotonic dystrophy (DM) was the first autosomal dominant disease found to be caused by a repeat expansion that is transcribed into RNA, but is not translated into protein. Transcriptions of the repeat expansion accumulate and, as toxic RNAs, disrupt the function of up to twenty other genes, causing the multiple symptoms of the disorder.
Although the two types of myotonic dystrophy present with similar symptoms, they have fundamentallly different origins. The two forms (DM1 and DM2) are caused by distinct microsatellite expansions that occur in the non-coding regions of different genes. (The existence of other forms, caused by mutations at different sites, is currently being investigated.) Click here for the chart: Commonalities Between DM1 and DM2, used with permission of the authors Bjarne Udd and Ralf Krahe, 2009.
Causes of DM1
The genetic defect for this form of the disorder results in an expanded and unstable (CTG) trinucleotide repeat, localized to the 3′ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19q13.3. Once there are more than 37 triplet repeats in the DMPK gene, the expanded sequence becomes unstable and slippage is more frequent. Disease symptoms are apparent in individuals once the CTG expansion exceeds 50 repeats. Disease severity roughly correlates with the number of repeats:
Individuals with 5 to 37 repeats in the 3′ UTR region are unaffected.
Individuals with 38-50 repeats are said to carry the pre-mutation. These individuals are asymptomatic and are unlikely ever to show symptoms. However, these repeats are unstable and very likely to expand during meiosis. As a result, such individuals are at risk of having affected children.
Individuals with >50 repeats to 4000 repeats have myotonic dystrophy. These individuals are symptomatic or likely to develop symptoms in later life. A looser correlation is seen between the form of the disease and repeat count in these individuals:
- 50-150 repeats are consistent with the mild adult-onset form of myotonic dystrophy.
- 100-1000 repeats are consistent with the classic adult or childhood onset form of myotonic dystrophy.
- 750 or more repeats are consistent with the congenital form of myotonic dystrophy and often result in severe neonatal complications.
Causes of DM2
Also known as proximal myotonic myopathy (PROMM), this form is caused by an expanded and unstable (CCTG) tetranucleotide repeat in the first intron of the zinc finger 9 (Znf9 also known as Cnbp) gene on chromosome 3. The repeat structure in DM2 is more complex than the triplet repeat seen in DM1.
The normal repeat structure is approximately 10-20 repeats of a complex motif that is 104 to 176 nucleotides long ((TG)12-26(TCTG)7-12(CCTG)3-9(g/tCTC)0-4(CCTG)4-15). Individuals with 22-33 uninterrupted CCTG repeats are said to carry a pre-mutation. These individuals are asymptomatic and are unlikely ever to show symptoms. However, these repeats are unstable and very likely to expand during meiosis. As a result, such individuals are at risk of having affected children. Unaffected individuals typically have less than 75 repeats. Once the repeat number exceeds 75, the expanded sequence becomes unstable and slippage is more frequent. Affected individuals can have between 75 and 11,000 copies of the repeat sequence.
The minimum pathogenic length of the expanded region appears to be 75 uninterrupted CCTG repeats. Repeat counts can increase to over 11,000 in affected individuals, with a mean repeat length of ~5000 repeats. The expanded region has been shown to display an even greater instability than the DM1 mutation.
Unlike DM1, the length of the DM2 repeated DNA expansion does not appear to correlate significantly with the age of onset or severity of disease symptoms.
MYOTONIC DYSTROPHY PATHOPHYSIOLOGY
The human genome initiative and other lines of genomics research have engendered powerful new research tools, such as microarray analysis of gene expression and transgenesis in mice. The candidate has taken a leading role ‘in developing a framework to incorporate these methods into patient-oriented research. He now seeks to extend this framework and devote more effort to mentoring new investigators in this underserved field. Myototuic dystrophy (DM), the most common inherited muscle disease in adults, has been adopted as a test case for this integrative approach. Although the pathophysiology of DM historicaly has been problematic, this approach is yielding rapid progress. DM is caused by expansion of a CTG repeat in the DM protein kinase (DMTK) gene. The repeat is located ‘in a region that is transcribed (as a CUG repeat) but not translated into protein. The candidate has developed evidence that the pathogenic effect of the expanded repeat is mediated at the level of RNA: transcripts with an expanded CUG repeat do not leave the nucleus, they accumulate in the nucleus in multiple discreet foci, and they are sufficient to generate a DM phenotype in transgenic mice. This work establishes a novel, RNA-mediated disease mechanism, provides the first animal model for DIM, and lays the groundwork for farther progress through parallel studies of human DM and the transgenic model.
Aim I is to elucidate the mechanism of myotonia. Preliminary data indicate that expanded CUG repeats trigger aberrant splicing of a chloride channel mRNA and corresponding loss of chloride conductance in the muscle membrane. an alteration sufficient to cause myotonia.
Aim 2 is to undertake a broad search for genes whose expression is altered in human and murine DM. Preliminary data indicate strong activation of genes that are involved in the genotoxic stress response.
Aim 3 is to identify proteins that colocalize with, and may be sequestered by the expanded CUG repeats. One such protein, EXP42, has already been identified. EYCP42 is the human homologue of a gene that causes muscle disease when mutated in Drosophi1a, making it a strong candidate for involvement in the pathogenesis of DM.
Aim 4 is tit determine whether deficiency of DMPK enhances the toxicity of expanded CUG repeats, and to explore the possibility that the mechanical and biochemical stress of myotonia contributes to the degeneration of muscle fibers. information from this study may have a therapeutic application.
MYOTONIC DYSTROPHY SYMPTOMS
The main sign of muscular dystrophy is progressive muscle weakness. Specific signs and symptoms begin at different ages and in different muscle groups, depending on the type of muscular dystrophy.
Duchenne Muscular Dystrophy
About half of people with muscular dystrophy have this variety. Although girls can be carriers and mildly affected, the disease typically affects boys.
About one-third of boys with Duchenne muscular dystrophy don’t have a family history of the disease, possibly because the gene involved may be subject to sudden abnormal change (spontaneous mutation).
Signs and symptoms typically appear between the ages of 2 and 3, and may include:
- Frequent falls
- Difficulty getting up from a lying or sitting position
- Trouble running and jumping
- Waddling gait
- Walking on the toes
- Large calf muscles
- Muscle pain and stiffness
- Learning disabilities
- Becker muscular dystrophy
Signs and symptoms are similar to those of Duchenne muscular dystrophy, but typically are milder and progress more slowly. Symptoms generally begin in the teens but may not occur until the mid-20s or even later.
Other Types Of Muscular Dystrophy
Some types of muscular dystrophy are defined by a specific feature or by where in the body symptoms first begin. Examples include:
- Myotonic. Also known as Steinert’s disease, this form is characterized by an inability to relax muscles at will following contractions. Myotonic muscular dystrophy is the most common form of adult-onset muscular dystrophy. Facial and neck muscles are usually the first to be affected.
- Facioscapulohumeral (FSHD). Muscle weakness typically begins in the face and shoulders. The shoulder blades might stick out like wings when a person with FSHD raises his or her arms. Onset usually occurs in the teenage years but may begin in childhood or as late as age 40.
- Congenital. This type affects boys and girls and is apparent at birth or before age 2. Some forms progress slowly and cause only mild disability, while others progress rapidly and cause severe impairment.
- Limb-girdle. Hip and shoulder muscles are usually the first affected. People with this type of muscular dystrophy may have difficulty lifting the front part of the foot and so may trip frequently. Onset usually begins in childhood or the teenage years.
When To See A Doctor
Seek medical advice if you notice signs of muscle weakness — such as increased clumsiness and falling — in yourself or your child.
MYOTONIC DYSTROPHY DIAGNOSIS
Your doctor is likely to start with a medical history and physical examination.
After that, your doctor may recommend:
- Enzyme tests. Damaged muscles release enzymes, such as creatine kinase (CK), into your blood. In a person who hasn’t had a traumatic injury, high blood levels of CK suggest a muscle disease — such as muscular dystrophy.
- Electromyography. An electrode needle is inserted into the muscle to be tested. Electrical activity is measured as you relax and as you gently tighten the muscle. Changes in the pattern of electrical activity can confirm a muscle disease.
- Genetic testing. Blood samples can be examined for mutations in some of the genes that cause different types of muscular dystrophy.
- Muscle biopsy. A small piece of muscle can be removed through an incision or with a hollow needle. Analysis (biopsy) of the tissue sample can distinguish muscular dystrophies from other muscle diseases.
- Heart-monitoring tests (electrocardiography and echocardiogram). These tests are used to check heart function, especially in people diagnosed with myotonic muscular dystrophy.
- Lung-monitoring tests. These tests are used to check lung function.
MYOTONIC DYSTROPHY TREATMENTS
There’s no cure for any form of muscular dystrophy. But treatment can help prevent or reduce problems in the joints and spine to allow people with muscular dystrophy to remain mobile as long as possible. Treatment options include medications, physical therapy, and surgical and other procedures.
Your doctor may recommend:
- Corticosteroids, such as prednisone, which can help improve muscle strength and delay the progression of certain types of muscular dystrophy. But prolonged use of these types of drugs can cause weight gain and weaken bones, increasing fracture risk.
- Heart medications, such as angiotensin-converting enzyme (ACE) inhibitors or beta blockers, if muscular dystrophy damages the heart.
Several types of therapy and assistive devices can improve quality and sometimes length of life in people who have muscular dystrophy. Examples include:
- Range-of-motion and stretching exercises. Muscular dystrophy can restrict the flexibility and mobility of joints. Limbs often draw inward and become fixed in that position. Range-of-motion exercises can help to keep joints as flexible as possible.
- Exercise. Low-impact aerobic exercise, such as walking and swimming, can help maintain strength, mobility and general health. Some types of strengthening exercises also might be helpful. But it’s important to talk to your doctor first because some types of exercise might be harmful.
- Braces. Braces can help keep muscles and tendons stretched and flexible, slowing the progression of contractures. Braces can also aid mobility by providing support for weakened muscles.
- Mobility aids. Canes, walkers and wheelchairs can help maintain mobility and independence.
- Breathing assistance. As respiratory muscles weaken, a sleep apnea device may help improve oxygen delivery during the night. Some people with severe muscular dystrophy may need to use a machine that forces air in and out of their lungs (ventilator).
Surgery may be needed to correct a spinal curvature that could eventually make breathing more difficult.