The neglected brain in myotonic dystrophy types 1 and 2

Myotonic dystrophy (DM), a dominantly inherited chronic progressive disease, is the most common cause of muscular dystrophy in adults, affecting 1 in 8,000 individuals worldwide. Different forms of the disease share similar features: DM1 (DM type 1) is caused by a trinucleotide (CTG) expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region on chromosome 19, and DM2 (DM type 2) is caused by a tetra-nucleotide (CCTG) expansion within intron 1 of the zinc finger 9 gene on chromosome 3. The RNA transcribed from the expanded allele contains long tracts of (CUG)(n) or (CCUG)(n). The mutant toxic-RNA alters the level of RNA-binding proteins (MBNL1 [muscleblind-like 1] and CUGBP1 [CUG-binding protein 1]), forms nuclear foci in various tissues including muscle and brain, and leads to a loss-of-function normally executed by the lost RNA-binding proteins. The recently discovered mechanisms underlying these RNA disorders are compatible with the widespread features of DM1 and DM2.1 Shared core clinical features of DM1 and DM2 are autosomal dominant inheritance, limb muscle weakness, myotonia, and multiorgan involvement, including cataract, cardiac conduction defects, insulin resistance, hypothyroidism, and gonadal atrophy. DM is one of the most variable diseases; DM2 probably more so than DM1,2 but in both DM1 and DM2 symptoms and severity vary greatly among family members and between generations. Muscle pain …