The CAG-polyglutamine repeat diseases: a clinical, molecular, genetic, and pathophysiologic nosology

Handb Clin Neurol. 2018;147:143-170. doi: 10.1016/B978-0-444-63233-3.00011-7.


Throughout the genome, unstable tandem nucleotide repeats can expand to cause a variety of neurologic disorders. Expansion of a CAG triplet repeat within a coding exon gives rise to an elongated polyglutamine (polyQ) tract in the resultant protein product, and accounts for a unique category of neurodegenerative disorders, known as the CAG-polyglutamine repeat diseases. The nine members of the CAG-polyglutamine disease family include spinal and bulbar muscular atrophy (SBMA), Huntington disease, dentatorubral pallidoluysian atrophy, and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17). All CAG-polyglutamine diseases are dominantly inherited, with the exception of SBMA, which is X-linked, and many CAG-polyglutamine diseases display anticipation, which is defined as increasing disease severity in successive generations of an affected kindred. Despite widespread expression of the different polyQ-expanded disease proteins throughout the body, each CAG-polyglutamine disease strikes a particular subset of neurons, although the mechanism for this cell-type selectivity remains poorly understood. While the different genes implicated in these disorders display amino acid homology only in the repeat tract domain, certain pathologic molecular processes have been implicated in almost all of the CAG-polyglutamine repeat diseases, including protein aggregation, proteolytic cleavage, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Here we highlight the clinical and molecular genetic features of each distinct disorder, and then discuss common themes in CAG-polyglutamine disease pathogenesis, closing with emerging advances in therapy development.

Keywords: Huntington disease; anticipation; autophagy; cerebellar ataxia; dosage reduction; mitochondrial dysfunction; polyglutamine; protein aggregation; proteolytic cleavage; repeat expansion; spinal and bulbar muscular atrophy; transcription dysregulation.

Publication types

  • Review

MeSH terms

  • Humans
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / physiopathology*
  • Neurodegenerative Diseases / therapy
  • Peptides / genetics*


  • Peptides
  • polyglutamine