Myotonic dystrophy

Definitions & Key takeaways

Myotonic dystrophy is an autosomal dominant genetic disorder that is characterized by progressive muscle weakness and myotonia. Symptoms may include facial-muscle weakness, drooping eyelids, muscle stiffness, foot and hand contractures, cataracts, difficulty walking, and cardiac conduction defects. Treatment typically includes physical therapy, medications, and lifestyle modifications.

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With myotonic dystrophy, “myo” means muscle, “tonic” means spasm, “dys” means bad, and “troph” means nourish; so myotonic dystrophy refers to the muscle appearing poorly nourished and weak, and being contracted, without being able to relax.
Myotonic dystrophy is actually a group of disorders, all of which are caused by autosomal dominant genetic mutations. This means that one affected copy of a gene is enough to cause disease.
Affected people are typically present in each generation, because an affected person (male or female) has a 50% chance of passing on the affected gene to a child, which causes that child to have the disease.
There are two major types of myotonic dystrophy: type 1, or DM1 for short, also known as Steinert’s disease and type 2, or DM2 for short.
In myotonic dystrophy type 1, the affected gene is on the long arm of chromosome 19 and is called DMPK. The DMPK gene has a trinucleotide repeat, which means that a group of three DNA nucleotides is repeated multiple times in a row.
In DMPK, it’s the nucleotides cytosine, thymine, and guanine, or CTG. These CTGs are found in the 3’ untranslated region of DMPK.
The 3’ untranslated region is at the end of the DMPH gene that’s made into mRNA but not protein, and it helps modulate gene expression.
Expressed DMPK mRNA gets translated into a protein called myotonic dystrophy protein kinase, and it helps in the communication between muscle cells, but also heart and brain cells.
In the muscle, this kinase shuts off a muscle protein called myosin phosphatase, which is involved in muscle tensing or contraction and relaxation.
In myotonic dystrophy type 2, the affected gene is located on the long arm of chromosome 3 and is called CNBP. Instead of a trinucleotide repeat, the CNBP gene contains a tetranucleotide repeat where the nucleotides cytosine, cytosine, thymine, and guanine, or CCTG are repeated multiple times in a row.
These CCTGs are found in the first intron of CMBP, which is a part of the gene that’s made into mRNA but not protein, and helps modulate gene expression.
Expressed CNBP mRNA gets translated into a protein called Cellular nucleic acid- binding protein, which controls the function of various genes in the muscle and heart.
In both types of myotonic dystrophy, there is a repeat expansion, meaning there’s an increased number of CTG and CCTG repeats in the affected genes, respectively.
This repeat expansion is caused by slipped mispairing, which is where the enzyme DNA polymerase gets confused when copying a repetitive sequence.
DNA polymerase loses its place among the repeats and goes back to recopy what it already just copied. This is like getting lost in a video and watch the same part over and over.
But since DNA polymerase is making copies, the effect is an increase, or expansion, of the number of repeats. And once as a zygote develops into a fetus and eventually into a full adult, by the time sperm and eggs are created, several dozen cell divisions, each with a round of DNA replication have taken place, and so there have already been ample opportunities for repeat expansion, and the more repeats that’ re added, the more unstable it gets.
This expansion of the originally inherited gene means a child of a parent with myotonic dystrophy can inherit even more repeats than the parent did.
The higher the number of repeats in the protein, the earlier the age when a person starts having symptoms and the more severe these symptoms are.
This phenomenon is called anticipation, which means that families often show earlier symptom onset and increased severity with each generation.
So, in the DMPK gene the normal number of CTG triplets is 5 to 37 and in the CNBP gene, the normal number of CCTG tetranucleotide repeats is 11 to 26.
Alleles with 38 to 49 CTG repeats or 27 to 74 CCTG repeats are called “pre-mutation” alleles and they don’t cause the disease.
Finally, if an allele contains more than 50 CTGs or more than 75 CCTGs, then it’s considered a full mutation. Alleles can tend to get longer and longer as DNA polymerase becomes more and more unstable copying the longer stretches of repeats, so a pre-mutation allele is set up for giving rise to a full mutation.
The exact reason that extra CTG trinucleotides and CCTG tetranucleotides lead to disease isn’t fully worked out, but one clue is that the repeated regions have widespread hydrogen bonding between C and G base pairs.
This makes the RNA form into condensed clumps inside the nucleus. These RNA clumps attract RNA-binding proteins which are needed for processing a lot of other RNA molecules.
As a result, other genes can’t get expressed normally, such as the SIX5 gene, which is involved in the function of the eye, the insulin receptor gene, and cardiac troponin T gene which are in the heart muscle.
It’s thought that these genes deficiencies lead to myotonic dystrophy. Now, symptoms of myotonic dystrophy vary widely between the various types.
Type 1 has two forms- first, there’s a congenital one, where symptoms begin at birth with babies being too weak to even suck or breathe and these infants don’t survive for long.
Then, there’s an adult form, where muscle weakness occurs later in life, and primarily affects facial muscles, resulting in hollow cheeks and drooping eyelids, as well as distal hand muscles, and muscles of the lower leg, causing toe and foot drop.
Myotonic dystrophy type 2 only presents at adulthood. Muscle weakness is typically milder and mostly affects proximal muscles of the thighs and hips, causing difficulty climbing stairs or rising from a seated position.
It also affects shoulders and elbows, causing problems in holding or lifting an object. Both types of myotonic dystrophy cause myotonia, meaning sustained muscle contractions and difficulty relaxing these muscles after use.
For example, an individual may be unable to release their grip after they shake someone’s hand. In some cases, myotonic dystrophy also causes cataracts, or clouding of the lens of the eye, insulin resistance, meaning that cells don’t respond to the actions of insulin in transporting glucose from the bloodstream into tissues, which leads to high blood glucose, as well as cardiac conduction defects, or abnormalities in the electrical signals controlling the heartbeat.
Myotonic dystrophy is diagnosed with genetic testing to identify the number of CTG and CCTG repeats. Electromyography can be done to assess the electrical activity in a muscle, and a muscle biopsy can be done to distinguish muscle problems from nerve problems.
The diagnosis is particularly relevant in terms of counseling an individual about the risk of disease for current and future family members.
Treatment of myotonic dystrophy is directed at individual symptoms, especially focusing on mobility support that may include braces or wheelchairs, surgery to correct cataracts, and using a cardiac pacemaker - if needed.
All right, as a quick recap, myotonic dystrophy is an autosomal dominant genetic disorder that can be broken down into type 1, which is caused by the expansion of more than 50 CTG trinucleotide repeats in the DMPK gene, has a congenital and an adult form and is more severe and type 2, which is caused by the expansion of more than 75 CCTG tetranucleotide repeats in the CNBP gene, is adult- onset and is milder.
Both types cause muscle weakness, myotonia, cataracts, insulin resistance, and cardiac conduction defects.