Welcome to the WCN 2023 Interactive Program

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In this workshop, I will discuss ataxia phenotypes, dominant genes, and methods to detect genetic variation in these genes.

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Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease caused by mutations in the SACS gene. The first two mutations were identified in French-Canadian populations 20 years ago. The disease is now known as one of the most frequent recessive ataxia worldwide. Prominent features include cerebellar ataxia, pyramidal spasticity, and neuropathy. Neuropathological findings also revealed a cerebellar atrophy of the anterior vermis associated with Purkinje cell death. No effective therapy is available for ARSACS patients but, the last two decades has seen significant advances in our understanding of the disease. New approaches in ARSACS, such as the reprogrammation of induced pluripotent stem cells derived from patients, open exciting perspectives of discoveries. Several research questions are now emerging. The talk will review clinical features of ARSACS. It aims to provide a targeted overview of the essentials that every neurologist should know in order to evaluate a patient. We present a stepwise approach to the clinical evaluation and genetic testing, with an emphasis on recently described clinical features, potential biomarkers, and therapies.

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Friedreich ataxia (FA) is an autosomal recessive multisystem disorder characterized by neurological impairment, hypertrophic cardiomyopathy, skeletal abnormalities, and carbohydrate intolerance. It is caused by a hyperexpansion of a GAA repeat in the FXN gene, which inhibits frataxin production and leads to mitochondrial dysfunction, oxidative stress, and altered iron metabolism.

Therapeutic approaches for FA aim to increase frataxin expression and reduce oxidative stress. Histone deacetylase inhibitors, although currently on hold due to toxicity concerns, have shown potential in modifying the chromatin associated with FA. Another approach under phase 1 clinical trial involves a synthetic transcription elongation factor that promotes transcription across repressive chromatin.

Protein replacement therapy delivers frataxin to the mitochondria by fusing it with the HIV TAT protein. Gene replacement therapy using adeno-associated viral vectors is also being explored, with promising results in mouse models of FA cardiomyopathy and neurological disease. While a phase 1 study in FA cariomyopathy is ongoing, further development is required to target gene therapy to the neurological components of FA addressing issues such as capsid selection, construct design, and route of administration.

Targeting oxidative stress has shown promise in FA treatment. Omaveloxolone, an activator of the oxidative stress response, has demonstrated significant improvements in the Friedreich Ataxia Rating Scale. Omaveloxolone is the first FDA-approved drug for FA. Leriglitazone, a PPARγ activator, has shown positive results in imaging biomarkers, while PTC-743, an antioxidant, has shown promise in secondary outcomes.