Myotonic Dystrophy Foundation

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The myotonic dystrophies (DM) are caused by expanded tracts of repeated short DNA sequences:

• (CTG)n trinucleotide repeat, localized to the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19q13.3 for DM1.

• (CCTG)n tetranucleotide repeat, localized in intron 1 of the transcription factor cellular retroviral nucleic acid-binding protein 1 (CNBP1) gene on chromosome 3q21 for DM2.

Once repeat counts reach an approximate threshold (>35 repeats for DM1 and >75 repeats in DM2), these sequences become highly unstable in both the soma and germ line. Although the mutational mechanism is not well understood, DNA replication and DNA repair are likely to be responsible for the changes in the number of repeat units in myotonic dystrophy patients.

As a result, a single individual may have cells and tissues that differ in repeat count (referred to as somatic mosaicism); i.e. the number of repeats is different between and within each tissue of the same individual. This somatic mosaicism is age and size-dependent, and very likely contributes toward the tissue-specific and progressive nature of the symptoms seen in patients with myotonic dystrophy. 

Several features of somatic mosaicism have been observed:

• The repeats show an expansion bias; i.e. the number of repeats tends to increase instead of decrease.

• The changes in repeat counts accumulate over time, so the expanded regions tend to grow through the life of in individuals with myotonic dystrophy.

• The rate of change depends primarily on the inherited size of the rmutation, with more repeats being more unstable and showing faster increases in the number of repeats.

• The level of mosaicism varies between tissues. In particular, the number of repeats in muscle cells are typically greater than those seen in circulating lymphocytes (white blood cells).

• The level of mosaicism can vary within a tissue (i.e. different cells within the same tissue have different number of repeats).

It is possible that individual specific factors (genetic and/or environmental) play an important role in the somatic dynamics of the repeat and that the process of somatic expansion may be very likely correlated with the clinical progression of the disease.

The number of repeats shows a positive correlation with the severity of the disease (i.e. the more repeats and individual has the more severe their symptoms are likely to be). In addition, the number of repeats shows a negative correlation with the age of onset (i.e. the more repeats and individual has, the earlier the age of onset of symptoms is likely to be).

However, these correlations are not very precise and it is not possible to accurately predict how severely and when an individual will be affected.  This is due at least in part to the fact that the number of repeats changes, is different in different cells and increases in number throughout the lifetime of the individual. Thus, the number of repeats reported in a diagnostic test will depend on how old the individual was when he was sampled, which tissue was tested and then, will only measure the average number of repeats.

As a result, the use of pre-symptomatic testing in this disorder should be carefully considered. The size of repeat expansions (measured by the standard method) in white blood cells should not be considered predictive of the age of onset and severity of symptoms.  New assays that allow us to measure age-independent repeat expansions are required and are being developed.

The molecular mechanisms underlying somatic mosaicism are not completely understood. Difficulties exist in obtaining samples from a full range of somatic tissues at multiple time points during a patient’s lifetime. Comprehensive tissue-by-tissue comparisons in humans have not been conducted to date. By doing this, it might be possible to gain better insights about how somatic mosaicism contributes to the age of onset and progression of the disease in myotonic dystrophy patients.

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