Disease Mechanism

Myotonic dystrophy is one of the most complex disorders known. In addition to the incredible variability of clinical symptoms the disease also has unique mechanistic features:

  • True autosomal inheritance. The disease phenotype of patients who are homozygous for myotonic dystrophy is essentially the same as those who are heterozygous.
  • Variable penetrance. Considerable variability is seen between affected individuals, even within the same family. Somatic mosaicism is common, where the genetic defect can be significantly different in various tissues in a single individual and can change over time.
  • Anticipation. The disease symptoms tend to be more severe and occur earlier in successive generations.
  • Maternal transmission bias for the congenital form. In the most severe form of myotonic dystrophy (congenital myotonic dystrophy: DM1), transmission is nearly always maternal and does not appear to be related to the severity of the disease in the mother. The mutated gene is only very rarely inherited from the father in newborns with myotonic dystrophy.

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Because expansion of the CTG repeats commonly occurs during meiosis, 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. 

The molecular cause of anticipation is based on the instability of long stretches of repeated nucleotide sequences. These repeats occur naturally, but are present in greater copy numbers in individuals with myotonic dystrophy. Once repeat counts reach a predictable threshold (>38 repeats for DM1 and >75 repeats in DM2), the sequences become highly unstable. The cellular machinery for DNA replication begins to slip across the expanded region, generating extra copies of the repeated sequence. The length changes caused by this slippage are relatively large, often with gains of 100 repeats or more. 

These expansions occur in both somatic and germline tissues. Because the expanded repeats are particularly unstable in meiotic cells, slippage during gametogenesis is common. The resulting eggs or sperm have dramatically higher repeat counts than somatic parental cells. Repeat count tends to increase over successive generations as a result. Nearly all pedigrees show this progressive expansion, although decreases in copy number have been reported in rare cases. 

The few reported decreases are 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 sampled, which tissue was tested and then will only measure the average number of repeats. 

Symptomatic Consequences of Anticipation

DM1. The repeat length shows a positive correlation with the severity of the disease. In addition, the number of repeats shows a negative correlation with the age of onset. As repeat counts increase over successive generations, the progeny tend to experience more severe symptoms at an earlier age. However, these correlations are not very precise, and it is not possible to accurately predict how severely and when an individual will be affected. 
Therefore, 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 can measure age-independent repeat expansions are required and are being developed. 

DM2. Repeat expansions tend to be more extensive than those seen in DM1. However, anticipation is less pronounced as repeat length does not correlate strongly with increases in severity or earlier onset of disease symtpoms. The degree of anticipation may be underestimated, however, as the extensive somatic mosaicism seen in DM2 patients confounds assessment of the phenomenon.

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 increases 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. 

Causes of Myotonic Dystrophy

Myotonic dystrophy (DM) was the first autosomal dominant disease found to be caused by a repeat expansion that is transcribed into RNA, but is not translated into protein. Transcriptions of the repeat expansion accumulate and, as toxic RNAs, disrupt the function of up to twenty other genes, causing the multiple symptoms of the disorder.

Although the two types of myotonic dystrophy present with similar symptoms, they have fundamentallly different origins. The two forms (DM1 and DM2) are caused by distinct microsatellite expansions that occur in the non-coding regions of different genes. (The existence of other forms, caused by mutations at different sites, is currently being investigated.)  Click here for the chart: Commonalities Between DM1 and DM2, used with permission of the authors Bjarne Udd and Ralf Krahe, 2009.

Causes of DM1

The genetic defect for this form of the disorder 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:
1. 50-150 repeats are consistent with the mild adult-onset form of myotonic dystrophy.
2. 100-1000 repeats are consistent with the classic adult or childhood onset form of myotonic dystrophy.
3. 750 or more repeats are consistent with the congenital form of myotonic dystrophy and often result in severe neonatal complications.

Causes of DM2

Also known as proximal myotonic myopathy (PROMM), this form is caused by an expanded and unstable (CCTG) tetranucleotide repeat in the first intron of the zinc finger 9 (Znf9 also known as Cnbp) gene on chromosome 3. The repeat structure in DM2 is more complex than the triplet repeat seen in DM1.

The normal repeat structure is approximately 10-20 repeats of a complex motif that is 104 to 176 nucleotides long ((TG)12-26(TCTG)7-12(CCTG)3-9(g/tCTC)0-4(CCTG)4-15). Individuals with 22-33 uninterrupted CCTG repeats are said to carry a 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. Unaffected individuals typically have less than 75 repeats. Once the repeat number exceeds 75, the expanded sequence becomes unstable and slippage is more frequent. Affected individuals can have between 75 and 11,000 copies of the repeat sequence. 

The minimum pathogenic length of the expanded region appears to be 75 uninterrupted CCTG repeats. Repeat counts can increase to over 11,000 in affected individuals, with a mean repeat length of ~5000 repeats. The expanded region has been shown to display an even greater instability than the DM1 mutation. 
Unlike DM1, the length of the DM2 repeated DNA expansion does not appear to correlate significantly with the age of onset or severity of disease symptoms. 

Clinical Presentation

Although the most pronounced characteristic of myotonic dystrophy is skeletal and smooth muscle dysfunction (weakness, stiffness, and pain), the condition can be present with issues such as reduced cognitive function, vision impairment, gastrointestinal disturbances, endocrine deficiency, fertility issues, cardiovascular dysfunction, personality abnormalities, and respiratory insufficiency, in addition to muscle complaints. 

The range of systems affected and the severity of symptoms seen can vary greatly between patients, even in the same family. However, an affected person does not typically exhibit all, or even most, of the possible symptoms. Often the disorder is mild and only minor muscle weakness or cataracts are seen late in life. At the opposite end of the spectrum, life-threatening neuromuscular, cardiac, and pulmonary complications can occur in the most severe cases when children are born with the congenital form of the disorder.

Somatic Mosaicism

Tissues in affected individuals can have unstable expanded regions. 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. As a result, a single individual may have cells and tissues that differ in repeat count (referred to as somatic mosaicism). Somatic mosaicism is age and size-dependent, and a likely contributor to the tissue-specific and progressive nature of the myotonic dystrophy symptoms. 

Several features of somatic mosaicism have been observed:

  • Repeats show an expansion bias; i.e. the number of repeats tends to increase instead of decrease.
  • Changes in repeat counts accumulate over time, so the expanded regions tend to grow through the life of individuals with myotonic dystrophy.
  • Rate of change depends primarily on the inherited size of the mutation, with more repeats being more unstable and showing faster increases in the number of repeats.
  • 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).
  • Level of mosaicism can vary within a tissue (i.e. different cells within the same tissue have different number of repeats).

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. 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. 

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