A genetic stutter that grows longer, and harsher, with each generation
In myotonic dystrophy type 1, a three-letter DNA sequence repeats itself too many times, and the run tends to lengthen as it passes from parent to child. Longer runs mean earlier and more severe disease, so a grandparent with mild cataracts can have a grandchild born struggling to breathe.
The hallmark is myotonia: muscles that contract normally but are slow to let go, so a gripped hand may not release promptly. Muscles also weaken and waste over time, and the condition reaches well beyond them, bringing early cataracts, heart rhythm and conduction problems, insulin resistance, excessive sleepiness and, in men, early balding and infertility. Symptoms usually appear in the 20s or 30s. First described in 1909, it affects about 1 in 2,100 people, far more than the long-quoted 1 in 8,000, because many cases go unrecognised for years. It is the commonest muscular dystrophy that starts in adulthood.
Type 1 comes from an expanded CTG repeat at the end of the DMPK gene on chromosome 19, a cause identified in 1992. Between 5 and 37 copies is normal; beyond 50 almost always brings symptoms. Stretches longer than 37 are unstable and can grow during cell division, a process called anticipation. The severe congenital form, with floppy muscles and breathing failure at birth, is usually passed on by mothers; paternal transmission accounts for only 13% of those cases. One published report described a newborn with roughly 1,500 repeats whose diagnosis revealed the mother's unsuspected condition.
Type 2 involves a four-letter CCTG repeat in the CNBP gene on chromosome 3, ranging from 75 to more than 11,000 copies. Despite that size it is generally milder, targets muscles nearer the trunk, causes more pain, and shows no anticipation. In both types, the faulty RNA forms hairpin loops that trap the splicing regulator MBNL1. One consequence is that a chloride channel called ClC-1 is built in its fetal form, and losing that channel produces the myotonia.
Diagnosis often lags, by an average of seven years for type 1 and fourteen for type 2 in one study; genetic testing confirms it. There is no cure. Care targets symptoms, with pacemakers, breathing support and drugs such as mexiletine to ease stiffness, and anaesthetists need to know about the condition.
Source: Myotonic dystrophy
