Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions

Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2–3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases — similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.