Anticipation in Myotonic Dystrophy
Over the last hundred years, a unique and perplexing feature has been seen in families with myotonic dystrophy (DM): members of the same family tended to exhibit a more severe disease phenotype with earlier onset of symptoms over successive generations. These changes were often dramatic: an individual whose only symptom was cataracts in later life could have a severely affected child with life-threatening complications present at birth (i.e. congenital myotonic dystrophy). However, these reports were discounted and often ascribed to ascertainment bias or the additive effects of multiple genes. It was not until recently that this phenomenon (termed anticipation) was confirmed.
Molecular Basis of Anticipation
The molecular cause of anticipation is based on the instability of long stretches of repeated nucleotide sequences:
- In DM1, an abnormal (CTG)n trinucleotide repeat is present in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19
- In DM2, an abnormal (CCTG)n tetranucleotide repeat is present in the first intron of the zinc finger 9 (Znf9 also known as Cnbp) gene on chromosome 3.
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.
Symptomatic Consequences of Anticipation
In DM1, repeat length correlates with severity of the disease and earlier age of onset. As repeat counts increase over successive generations, the progeny tend to experience more severe symptoms at an earlier age.
In 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 increased severity or earlier onset of disease symptoms. The degree of anticipation may be underestimated, however, as the extensive somatic mosaicism seen in DM2 patients confounds assessment of the phenomenon.
Read a list of references for this page here