Myotonic dystrophy

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Autosomal trisomies: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
Miscellaneous genetic disorders: Pathology review

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Myotonic dystrophy

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Myotonic dystrophy

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Myotonic dystrophy is of genetic inheritance.

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USMLE® Step 2 style questions USMLE

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A 44-year-old man comes to his primary care physician because of muscle pain, increased difficulty concentrating, and sleeping too much. The patient states that these symptoms have been present over the last six months, and is getting worse, interfering with his work. He says that his sleep quality has been very poor. In addition, he also noticed that he has been having difficulty getting up from sitting down or squatting, and picking up his dog is harder than it used to be. Physical examination shows decreased muscle strength in upper and lower extremities bilaterally with slowed relaxation after contraction. An eye examination shows a pathognomonic pattern of iridescence on his lens as shown below. Which of the following is the most likely diagnosis?

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Transcript

Content Reviewers:

Rishi Desai, MD, MPH

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 DMPK 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.