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  • Review Article
  • Published:

Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions

Nature Reviews Neurology volume 18, pages 145–157 (2022)Cite this article

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Abstract

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.

Key points

  • Pathogenic non-coding CGG repeat expansions in different genes cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy and oculopharyngodistal myopathy, respectively.

  • CGG repeat expansion disorders have overlapping clinical, MRI and histopathological features, including parkinsonism, ataxia, dementia, autonomic dysfunctions, myopathy, ubiquitin-positive inclusion bodies, middle cerebellar peduncle hyperintensity and leukoencephalopathy.

  • RNA toxicity, disturbance of membraneless organelle function, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment are likely molecular mechanisms.

  • Development of novel disease models, single-cell expression profiling and greater understanding of pathophysiological mechanisms and the effects of various repeat lengths and repeat interruptions could facilitate the development of therapeutic approaches.

  • Short antisense oligonucleotides, CGG repeat binding molecules, histone acetyltransferase inhibitors, heat shock proteins and heat shock response inducers have therapeutic potential.

  • CGG repeat expansion diseases might represent manifestations of an underlying non-coding CGG expansion neuromyodegenerative syndrome in which different organs are affected to varying degrees according to the gene location of the repeat expansion.

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Fig. 1: Possible interventions in the pathogenesis of CGG repeat disease.

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Acknowledgements

We thank the Singapore National Medical Research Council for providing funding support to E.-K.T. and Z.-D.Z. The authors are supported by Singapore National Medical Research Council (NMRC) (Clinical and Translational Research in Movement Disorders, NMRC/STaR/0030/2018 and Singapore Parkinson’s Disease Translational Clinical Program (SPARK II), MOH-OFLCG18May-0002).

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Authors and Affiliations

  1. Department of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Singapore, Singapore

    Zhi-Dong Zhou & Eng-King Tan

  2. Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore

    Zhi-Dong Zhou & Eng-King Tan

  3. Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

    Joseph Jankovic

  4. Houston Methodist Research Institute, Houston, TX, USA

    Tetsuo Ashizawa

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E.-K.T. researched data for the article. Z.-D.Z. and E.-K.T. wrote the manuscript. All authors made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.

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Zhou, ZD., Jankovic, J., Ashizawa, T. et al. Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions. Nat Rev Neurol 18, 145–157 (2022). https://doi.org/10.1038/s41582-021-00612-7

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