RNA-based disorders of muscle and brain

The RNA-based disorders of muscle and brain include myotonic dystrophy type 1 and type 2 (dystrophia myotonica, DM) and fragile X-associated tremor/ataxia syndrome (FXTAS). These disorders reflect an emerging concept in the pathogenesis of genetic disease, namely, that an expanded repeat element within a noncoding portion of an RNA transcript can be directly responsible for a disease phenotype. DM is an autosomal-dominant disorder and the most common form of muscular dystrophy in adults. The DM protein kinase gene (DMPK) and the zinc-finger protein 9 gene (ZNF9) are responsible for DM type1 and DM type 2 respectively. The discovery of the second gene (ZNF9) on a separate chromosome from the DMPK gene, which gives rise to many of the same clinical features, considerably strengthened the argument for an RNA-based mechanism for DM pathogenesis. FXTAS is caused by an RNA-based pathogenesis due to an expanded (noncoding) trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene. Abnormal expression of the fragile X mental retardation 1 (FMR1) gene leads to both the neurodegenerative FXTAS and fragile X syndrome. FXTAS is a movement disorder that affects some carriers of premutation alleles of the FMR1 gene. The disorder generally presents with progressive intention tremor and/or gait ataxia and Parkinsonism.