What is myotonic dystrophy?

Risk Factors

Each child of a parent with myotonic dystrophy has a 50 percent risk of
inheriting the disease. The severe congenital form (which occurs in DM1) is
inherited almost exclusively from the mother; however, paternal transmission of
the congenital form is possible.

Etiology and Genetics

Of the two myotonic dystrophy subtypes, type 1 (DM1) tends to be more severe
and more common than type 2. However, type 2 (DM2) may as common as type 1 in
individuals of German or Finnish descent. Both types are inherited as an autosomal
dominant trait. Individuals affected with myotonic dystrophy have also been
reported with genotypes that correspond to neither DM1 nor DM2 mutations.

Myotonic dystrophy was the first known RNA-mediated
disease and the first to challenge the premise that genetic diseases result from
DNA mutations translated into dysfunctional proteins.

The DM1 mutation is an expanded trinucleotide, or triplet, repeat
(cytosine-thymine-guanine, or CTG) in the gene DMPK, located on
chromosome 19. In most people, the number of CTG repeats in this gene ranges from
five to thirty-four, but individuals with DM1 have fifty to five thousand CTG
repeats in most cells. The DM2 mutation, which was not identified until 2001, is a
tetranucleotide repeat expansion called the CCTG sequence in the
CNBP gene (also called the ZNF9 gene) on
chromosome 3. In most people, the CCTG sequence is repeated fewer than twenty-six
times, but individuals with DM2 have more than seventy-five CCTG repeats. Both CTG
and CCTG repeats are unstable, tending to further expansion.

The mechanisms embedded in these mutations also dispelled the belief that RNA
is simply a molecular bridge between DNA and an encoded protein. Noncoding
RNAs, notably RNA binding proteins, are important in
regulating alternative splicing mechanisms in the human genome.
Splicing mechanisms normally generate a large variety of proteins specific to one
or another cell type at particular developmental stages.

When the expanded repeats are transcribed into RNA, the resulting RNA
transcripts alter the expression of specific RNA-binding proteins. The mutation
disrupts RNA processing from pre-message RNA splicing to protein translation.
Targeted messenger RNAs (mRNAs) with altered splicing mechanisms are
unable to encode functional protein.

Disease severity is related to the number of repeats in the RNA transcripts.
Mildly affected persons with DM1 will have upward of fifty copies of the CTG
triplet repeat, but those with severe symptoms may have two thousand to five
thousand repeats. CCTG repeats in DM2-affected persons range from seventy-five to
eleven thousand.

Although DM1 and DM2 are caused by mutations in unrelated genes occurring at
two different genetic loci, their clinical profiles overlap. This is because their
mutant RNA transcripts target the same mRNAs. Muscle cell
differentiation and insulin receptor function are compromised
in both DM type 1 and type 2, for example.

Genetic anticipation, in which disease severity increases and age of onset
occurs earlier in successive generations, is another feature of myotonic
dystrophy. Expanded repeat size and disease severity increase in successive
generations. The discovery of heritable, unstable DNA sequences provided a
molecular basis for anticipation. Although myotonic dystrophy introduced a new,
RNA-mediated disease category, the list has since grown to include many human
diseases.

Symptoms

Clinical profiles of DM1 and DM2 overlap, and both vary in severity. Multiple
organ systems are generally involved, but the DM hallmark is an impaired ability
to relax contracted muscles. Progressive muscle wasting is the most disabling
feature, and cataracts are common. Cardiac arrhythmias,
primarily in DM1, can be life-threatening.

Screening and Diagnosis

Molecular analysis of DNA is necessary to confirm a diagnosis of both DM1 and
DM2. Prenatal diagnosis (if a parent is affected) can be accomplished via
amniocentesis or chorionic villus sampling. Prenatal
diagnosis of congenital DM1 (when the mother is affected) can be complex, due to
inconsistent repeat size in various fetal tissues. Preimplantation diagnosis of
DM1 has also been reported.

Treatment and Therapy

Current treatment, which requires multispecialty management, is primarily
supportive and directed to specific symptoms. No widely accepted, effective
treatment strategies are available. Periodic monitoring of cardiac abnormalities
must be in place to prevent heart disease and cardiac events. Ventilatory support
may be needed for some patients with pulmonary failure. For the future,
molecular-based research that is under way is aimed at reversing the effects of
the RNA disease mechanisms.

Prevention and Outcomes

Prenatal diagnosis is the sole preventive strategy. Life expectancy can be reduced by as much as two decades. Adults with late-onset myotonic dystrophy may become wheelchair-bound. Respiratory disease and cardiac arrhythmias are the most frequent causes of death.

Bibliography

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Splicing Changes in Myotonic Dystrophy Type 1 and Type 2 Skeletal Muscle Are
Shared with Other Muscular Dystrophies." Neuromuscular
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Cardani, Rosanna, et al. "Overexpression of
CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 But
Not from Myotonic Dystrophy Type 2." PLoS One 8.12 (2013):
1–12. Print.

Esposito, Gabriella, et al. "Prenatal
Molecular Diagnosis of Inherited Neuromuscular Diseases: Duchenne/Becker
Muscular Dystrophy, Myotonic Dystrophy Type 1 and Spinal Muscular Atrophy."
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Harper, Peter S.
Myotonic Dystrophy: The Facts. 2nd ed. Oxford: Oxford
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Harper, Peter S.,
G. M. van Engelen Baziel, and Bruno Eymard, eds. Myotonic Dystrophy:
Present Management, Future Therapy. New York: Oxford UP, 2004.
Print.

Kurosaki, Tatsuaki, et al. "The Unstable CCTG
Repeat Responsible for Myotonic Dystrophy Type 2 Originates from an
AluSx Element Insertion into an Early Primate Genome."
PLoS One 7.6: E38379. Print.

Nussbaum, Robert
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