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Recessive cerebellar and afferent ataxias — clinical challenges and future directions

Nature Reviews Neurology volume 18, pages 257–272 (2022)Cite this article

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Abstract

Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. In this Review, we discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype–phenotype correlations. We review the main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms. Finally, we discuss disease-modifying therapeutic advances in Friedreich ataxia, highlighting the most promising candidate molecules and lessons learned from previous clinical trials.

Key points

  • Cerebellar and afferent ataxias have a wide range of aetiologies, including paraneoplastic syndromes, infections, autoimmune disorders, drugs, toxicities, vitamin deficiencies and genetics.

  • Autosomal recessive disorders that have cerebellar involvement and a dorsal root ganglionopathy include Friedreich ataxia, cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), ataxia with vitamin E deficiency, and POLG-related neuropathy–ataxia spectrum disorders.

  • CANVAS is caused by biallelic intronic expansions in the RFC1 gene and can present as unexplained, late-onset ataxia or idiopathic sensory neuronopathy.

  • The main pathophysiological mechanisms of cerebellar and afferent ataxias are mitochondrial dysfunction and DNA break repair defects, possibly owing to the high energy demands of sensory and cerebellar neurons.

  • Promising therapies in Friedreich ataxia aim to increase FXN transcription, increase levels of frataxin, reduce oxidative stress, reduce iron levels or replace the mutated gene.

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Fig. 1: Cellular pathways involved in recessive cerebellar and afferent ataxias.
Fig. 2: Therapeutic targets of experimental therapies in Friedreich ataxia.

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Authors and Affiliations

  1. Axe Neurosciences, CHU de Québec–Université Laval, Québec, QC, Canada

    Marie Beaudin & Nicolas Dupre

  2. Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada

    Marie Beaudin & Nicolas Dupre

  3. Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium

    Mario Manto

  4. Service des Neurosciences, Université de Mons, Mons, Belgium

    Mario Manto

  5. Ataxia Center, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Jeremy D. Schmahmann

  6. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Massimo Pandolfo

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M.B. wrote the manuscript. All authors researched data for the article, made substantial contributions to discussion of the content, and reviewed and edited the manuscript before submission.

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Correspondence to Nicolas Dupre.

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Competing interests

M.P. has received grants and personal fees from Biomarin, Minoryx and Voyager Therapeutics, and has received, grants from the European Commission — 7th Framework Programme, Fonds National de la Recherche Scientifique (Belgium) and the Friedreich’s Ataxia Research Alliance, and personal fees from Apopharma, Exicure, Design Therapeutics, Aavanti Bio, and UCB. He has a patent for methods to diagnose Friedreich ataxia (WO1997032996A1), royalties for which have been paid by Athena Diagnostics. None of these disclosures represent a conflict of interest that may be perceived as biasing the content of this manuscript. All other authors declare no competing interests.

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Glossary

R-loops

Three-stranded DNA–RNA hybrid structures that can occur during transcription and cause replication stress, gene silencing, chromatin alterations and genome instability.

Pes cavus

Deformation of the foot with a high plantar longitudinal arch, which can be associated with equinus deformity and clawing of the toes.

Crus I

A hemispheric subdivision of cerebellar lobule VII, located above the horizontal fissure.

Bergmann gliosis

A distinctive reactive histological pattern that occurs after cerebellar insult with hyperplasia of radial astrocytes following Purkinje cell loss.

H reflex

A late-response electrophysiological test performed at the soleus muscle that assesses the integrity of the Aα muscle spindles as afference and α motor neurons as efference.

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Beaudin, M., Manto, M., Schmahmann, J.D. et al. Recessive cerebellar and afferent ataxias — clinical challenges and future directions. Nat Rev Neurol 18, 257–272 (2022). https://doi.org/10.1038/s41582-022-00634-9

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