Myotonic dystrophy
Myotonic dystrophy is the most common form of muscular dystrophy that begins in adulthood and is characterized by an inability to relax muscles after contraction, a condition known as myotonia. There are two genetic forms: myotonic dystrophy type 1 (DM1) and type 2 (DM2), each caused by different mutations and exhibiting overlapping clinical features. DM1 is generally more severe than DM2 and is inherited in an autosomal dominant manner, meaning a child of an affected parent has a 50% chance of inheriting the condition. Symptoms can include progressive muscle wasting, cataracts, and life-threatening cardiac arrhythmias, particularly in DM1. Diagnosis typically requires molecular analysis of DNA, with prenatal testing available if a parent is affected. While there is currently no widely accepted cure, treatment focuses on managing symptoms and involves a multidisciplinary approach. Ongoing research into molecular therapies holds promise for future treatment options. Life expectancy may be reduced by up to two decades, with respiratory disease and cardiac issues being common causes of mortality.
Myotonic dystrophy
ALSO KNOWN AS: Dystrophia myotonica type 1 (DM1) and type 2 (DM2); Steinert’s disease, referring to DM1; proximal myotonic myopathy (PROMM) or proximal myotonic dystrophy (PDM), referring to DM2
DEFINITION Hans Steinert first described myotonic dystrophy as an independent syndrome in 1909. The most common form of muscular dystrophy that begins in adulthood, myotonic dystrophy presents in two distinct, but clinically similar, genetic forms, both affecting multiple body systems. Myotonia refers to difficulty of relaxing a muscle group after contraction.
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 underway is aimed at reversing the effects of the RNA disease mechanisms.
The FDA granted the breakthrough therapy designation to del-desirin, a drug used to treat myotonic dystrophy. The FDA fast-tracked the approval of the drug after it was shown to reverse the progression of the disease in a clinical trial presented at the 2024 Muscular Dystrophy Association Clinical and Scientific Conference. Researchers anticipated that del-desirin may be able to help those with no other treatment option.
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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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." Clinical Chemistry and Laboratory Medicine 51.12 (2013): 2239–2245. Print.
Harper, Peter S. Myotonic Dystrophy: The Facts. 2nd ed. Oxford: Oxford UP, 2009. Print.
Harper, Peter S., G. M. van Engelen Baziel, and Bruno Eymard, eds. Myotonic Dystrophy: Present Management, Future Therapy. New York: Oxford UP, 2004. Print.
Herpen, Robert. "FDA Grants Breakthrough Therapy Designation to Myotonic Dystrophy Type 1 Drug." Healio, 9 May 2024, www.healio.com/news/neurology/20240509/fda-grants-breakthrough-therapy-designation-to-myotonic-dystrophy-type-1-drug. Accessed 4 Sept. 2024.
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.
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