Cause of Myotonic Dystrophy: DM1
Myotonic dystrophy type 1 (DM1) is one of a class of triplet repeat diseases. In these diseases, a short stretch of DNA that is normally repeated several times undergoes dynamic or expansion mutation. During DNA replication, the cellular machinery slips and generates extra copies of the triplet repeat. The disease occurs once the expansion exceeds a threshold number of repeats. Other triplet repeat diseases include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and fragile X syndrome.
In DM1, the genetic defect results in an expanded and unstable (CTG) trinucleotide repeat, localized to the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19q13.3.
Once there are more than 37 triplet repeats in the DMPK gene, the expanded sequence becomes unstable and slippage is more frequent. Disease symptoms are apparent in individuals once the CTG expansion exceeds 50 repeats.
Disease severity roughly correlates with the number of repeats:
- Individuals with 5 to 37 repeats in the 3’ UTR region are unaffected.
- Individuals with 38-50 repeats are said to carry the pre-mutation. These individuals are asymptomatic and are unlikely ever to show symptoms. However, these repeats are unstable and very likely to expand during meiosis. As a result, such individuals are at risk of having affected children.
- Individuals with >50 repeats to 4000 repeats have myotonic dystrophy. These individuals are symptomatic or likely to develop symptoms in later life. A looser correlation is seen between the form of the disease and repeat count in these individuals:
- ~ 50 to 150 repeats are consistent with the mild adult-onset form of myotonic dystrophy.
- ~100 to 1000 repeats are consistent with the classic adult or childhood onset form of myotonic dystrophy.
- > 750 repeats are consistent with the congenital form of myotonic dystrophy and often result in severe neonatal complications.
Anticipation
Because expansion of the CTG repeats commonly occurs during meiosis (cell division that produces an egg or sperm), the repeat count tends to increase over successive generations. As a result, children of affected individuals (including those with the pre-mutation) tend to experience more severe symptoms at an earlier age than their parent. This parent-to-child amplification of repeat count is termed anticipation.
Maternal transmission of congenital DM1
Anticipation occurs differently in males and females. Extreme amplifications are seen during gametogenesis in females with DM1, elevating their risk of having a child with congenital DM1. These large increases in repeat count are only rarely seen in males. It is hypothesized that maternal imprinting plays a role in the difference seen, although minimal methylation evidence exists to support this conclusion.
As a result of this anticipation bias, newborns with the severe congenital form of myotonic dystrophy are almost always the offspring of affected mothers. Because the increase in repeat count can be dramatic, the mothers may be asymptomatic or have symptoms so mild that they are unaware they have the disease. In such cases, the child is often the index case in the extended family and other relatives may be subsequently identified as having the disease.
Somatic mosaicism
Tissues in affected individuals can have variable expanded regions. Repeat count can increase in the order of 50 to 100 repeats per year in certain tissues, but no increase may be seen in others. The resulting somatic mosaicism can lead to diagnostic and treatment challenges. The repeat count seen in one tissue at a given point in time cannot be predictive of prognosis for the individual. The presence of somatic mosaicism helps explain in part the variability seen between individuals, including members of the same family, who appear to have similar repeat counts.
Origins
The mutation involved in DM1 does not arise spontaneously. It appears that all affected individuals share a common ancestor. With the exception of one sub-Saharan family, the presence of DM1 has been associated with a single haplotype within and flanking the DMPK gene. This suggests predisposition for CTG instability has resulted from a single mutation event, which occurred after the migration from Africa to Europe.
A second alternative exists, where predisposition to CTG instability is due to elements within the haplotype. Individuals who do not possess this specific set of genetic alleles would have a stable number of repeats and not develop the disease.
Genetic tests
Genetic testing is available for myotonic dystrophy DM1 using standard DNA diagnostic protocols (PCR and southern blot) to determine definitively whether or not an individual has myotonic dystrophy.
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