Causes/Inheritance

What causes MMD?

Type 1 myotonic dystrophy (MMD1) and type 2 myotonic dystrophy (MMD2) dystrophy are both caused by abnormally expanded stretches of DNA. The expansions occur in two different genes but appear to have similar effects on various cells, particularly the cells of the voluntary and involuntary muscles, including the heart and some nerve cells.

DNA expansion in DMPK gene causes MMD1

In MMD1, the abnormal DNA expansion is in the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19. The defect was identified as the cause of MMD1 in 1992.

The DNA building blocks cytosine, thymine and guanine (abbreviated as CTG) are repeated many more times than average in this disorder. The normal number of "CTG repeats" in the DMPK gene is three to 37.

In MMD1, there can be hundreds or even thousands of CTG repeats in the DMPK gene. In general, the number of repeats correlates with the age of onset and the severity of the disorder, with the highest numbers correlating with the congenital-onset form, the lower numbers correlating with the adult-onset form, and mid-range numbers correlating with the juvenile-onset form. However, these correlations are by no means perfect and should not be taken as absolute predictors of the course of the disease.

Another unusual feature of the genetic defect that causes MMD1 is that it can change size over time in the same person and when it's being transmitted from parent to child. When the DMPK gene expansion is transmitted from parent to child, it often expands, causing the disease to manifest earlier with each generation in a family.

The congenital-onset form of MMD1 appears to occur only when the DMPK gene flaw comes from the mother. A mother with a small CTG repeat expansion and few or no noticeable symptoms can give birth to a baby with a large CTG expansion and the congenital-onset form of MMD1.

At first, it was believed that the main effects of the expanded DNA in the DMPK gene were that it decreased the amount of available DMPK protein in cells. While this may be a factor in the causation of MMD1, it is now believed that there are widespread effects of the CTG expansions on many cellular processes.

For more on the underlying causes of MMD1, see MMD Research: Seeking to Free Proteins from a "Toxic Web" (part of Quest's In Focus: Myotonic Muscular Dystrophy series).

DNA expansion in ZNF9 gene causes MMD2

The underlying cause of MMD2 was identified in 2001 as an expanded DNA section in the ZNF9 (zinc finger 9) gene on chromosome 3.

In this disorder, the expansion contains four DNA building blocks — two cytosine molecules followed by a thymine and a guanine (abbreviated CCTG) — repeated far more times than average.

As in MMD1, the effects of the ZNF9 gene abnormality appear to be widespread, affecting many cellular processes.

However, the correlation between repeat length and disease severity or age of onset is not clear in MMD2.

For an in-depth look at MMD research, read MMD Research: Seeking to Free Proteins from a "Toxic Web."

MMD1 and MMD2 are dominantly inherited

Both MMD1 and MMD2 are inherited in an autosomal dominant pattern, meaning it takes only one flawed gene (in MMD, one gene carrying the abnormal expansion) to cause symptoms of the disease. If one parent has the disorder, every child of that person has a 50 percent chance of inheriting the gene flaw that causes it.

If either the type 1 (DMPK) or the type 2 (ZNF9) genetic abnormality is passed on, the child will almost certainly develop the disease. MMD1 symptoms very often are milder in the parent than in the child. In MMD2, this increase in severity between generations does not seem to occur, at least most of the time.

Genetic testing for the expanded DNA that leads to either type of MMD can be performed in several laboratories.

For more on genetic testing, read MDA Genetic Counseling Webinar Answers Key Questions and Facts About Genetics and Neuromuscular Diseases.

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