Autosomal and X-Linked Degenerative Ataxias: From Genetics to Promising Therapeutics

Abstract

Autosomal recessive cerebellar ataxias (ARCAs) refer to a large group of neurodegenerative disorders mainly affecting the cerebellum and the nervous system. ARCAs are characterized by important genetic heterogeneity and complex phenotypes. Because of their rarity and heterogeneity, it is challenging to rapidly advance our understanding in addition to discovering viable symptomatic and, most importantly, disease-modifying treatments. Significant advances have been recently achieved regarding the genetic basis of autosomal recessive and X-linked cerebellar ataxias. Unfortunately, the pathophysiology of most ARCAs is poorly characterized. For most ARCAs, clinical management consists in supplying symptomatic treatments. However, many new therapeutic strategies have emerged. They range from reducing the debilitating effects of ARCAs to exploring curative strategies. The aim of this chapter is to discuss fundamental and novel genetic aspects of ARCAs and X-linked cerebellar ataxias, focusing specifically on the fragile X tremor ataxia syndrome (FXTAS). We summarize clinical features, pathophysiology, diagnosis, currently available therapies, and novel research for the most frequent ARCAs. We also present examples of how novel and cutting-edge therapeutic tools including the clustered regularly interspaced short palindromic repeats (CRISPR) approach, antisense oligonucleotides (ASOs), and stem cells may lead to disease-modifying and ultimately curative treatment for ARCAs. The emphasis is made on new and ongoing research for the most frequent ARCAs. We will discuss promising future therapeutic strategies as well.