| Neurogenetics  

Expanding the expansions in hereditary ataxias

A recent paper from Cortese et al (2019) reported that a new intronic expansion may be a relevant cause of late-onset ataxia.

Coding and non-coding expansions are a frequent cause of hereditary ataxias. A coding CAG expansion is the most common cause of dominant ataxia including six different forms (SCA1-3; 6-7; 17). A GAA intronic expansion is the cause of the most common hereditary and recessive ataxia, Friedreich’s disease. Other non-coding expansions are responsible for other rare forms of dominant ataxias (SCA8-10-12-31-36).  Cortese et al (2019) by whole genome sequencing identified a new homozygous AAGGG repeat expansion in 29 patients from 11 families with CANVAS. The acronym stays for cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Onset is adult and progression slow. Other features are chronic coughing, cerebellar atrophy at MRI, and occasionally autonomic dysfunction. The pathological expansion that ranges between 400 to 2000 repeats occurs in intron 2 of the replication factor C subunit 1 (RFC1) gene, a gene possibly involved in DNA repair. Normal individuals carry combinations of similar pentanucleotide repeats (AAAAG or AAAGG) of variable length at this locus, but no homozygous AAGGG expansions. A further screening of 150 sporadic late-onset ataxics showed 22% carrying the homozygous expansion in RFC1 gene with highest yield if the core feature of CANVAS was present. The expansion does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. Finally, an allele frequency of 0.7% for the expanded AAGGG sequence in Europeans implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Key points:

  • a new intronic expansion responsible for sporadic late-onset cerebellar ataxia;
  • the major gene responsible for cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS);
  • first major ataxic gene discovered by whole genome sequencing.


Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019; 51:649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29.

Shakkottai V, Paulson H. Expanding the genetic basis of ataxia. Nat Genet. 2019; 51:580-581. doi: 10.1038/s41588-019-0387-x.

Harding AE. "Idiopathic" late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci. 1981;51:259-71.