Advances in the understanding of hereditary ataxia – implications for future patients

ABSTRACT

Introduction: Hereditary ataxias are caused by mutations in a plethora of different genes. Advances in sequencing technologies have led to an exponential increase in novel gene discoveries, highlighted the genetic overlap with other neurological diseases and improved our understanding of genotype-phenotype relationships. Together, these developments allowed the identification of new therapeutic targets that are subsequently making their way into clinical trials.

Areas covered: This review focuses on the shared genetic characteristics and the latest insights into the molecular cause of the most prevalent hereditary ataxias. Furthermore, conventional genetic diagnosis and the gradual implementation of next-generation sequencing (NGS) approaches in clinical practice is discussed. Finally, the latest investigated disease-modifying therapeutic agents are reviewed. A literature search was performed in PubMed and the Cochrane Library. Additional information on previous and on-going trials was obtained from the ClinicalTrials.gov website.

Expert opinion: The implementation of NGS in clinical practice has led to an increase in detected sequence variants of unknown clinical significance. Determining their pathogenicity is an expensive and time-consuming process. In accordance with the progresses in genetics, there is a need for the simultaneous definition of novel biomarkers and functional assays that can assist in the interpretation of genetic tests.

KEYWORDS:

• Anticipation
• biomarkers
• hereditary ataxia
• next-generation sequencing
• gene panels
• polyglutamine diseases
• trinucleotide expansions

Article highlights

• Hereditary ataxias are mono-genetic diseases that show genetic and clinical heterogeneity with marked phenotypical overlap.

• The most prevalent dominant, recessive and X-linked ataxias are due to a trinucleotide repeat expansion in their respective genes.

• Depending on the disease-causing gene, the length and configuration of these trinucleotide repeat expansions variably influences age of onset, intergenerational instability and phenotypic presentation.

• Advances in sequencing technologies, such as next-generation sequencing, have revolutionised the genetic landscape of ataxias and are increasingly implemented in clinical practice.

• Disease-modifying treatments target the genetic cause of the disease directly or focus on shared pathological downstream mechanisms. Biomarkers could prove useful in monitoring therapeutic response.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

P Giunti works at University College London Hospitals/University College London, which receives a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding.