Myotonic Dystrophy

Myotonic Dystrophy is caused by a trinucleotide repeat expansion in the DMPK gene (DM1) or CNBP gene (DM2). In DM1, a CTG repeat expands in the 3' untranslated region, while DM2 involves CCTG repeats. The pathophysiology involves toxic accumulation of mutant mRNA, which sequesters RNA-binding proteins and disrupts normal RNA splicing and protein production. This leads to dysfunction of multiple proteins, including myosin, chloride channels, and sarcoplasmic reticulum calcium release channels, resulting in muscle damage and myotonia. The trinucleotide repeat number correlates with disease severity and age of onset, with longer repeats generally causing more severe disease with earlier presentation. DM1 shows two main phenotypes: classic form with adult onset and congenital form with severe neonatal presentation and intellectual disability. DM2 generally has milder symptoms than DM1. Beyond skeletal muscle, MD affects smooth muscle, cardiac muscle, and the brain. Cardiac involvement ranges from conduction abnormalities to arrhythmias and dilated cardiomyopathy. Cerebral manifestations include intellectual disability in congenital forms, behavioral changes, cognitive decline, and increased risk of central sleep apnea. Cataracts are common, developing in teenagers with DM1. Endocrine dysfunction includes testicular atrophy, insulin resistance, and thyroid abnormalities.