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American Society for Experimental Neurotherapeutics Abstracts
August 2001

Hereditary Ataxias

Arch Neurol. 2001;58(8):1315-1316. doi:

Ataxia can result from lesions at nearly any point along the neuroaxis. Moreover, every possible mode of inheritance has been shown to underlie hereditary ataxia. Thus, it is not surprising that more than 400 ataxic disorders are listed in the Online Mendelian Inheritance in Man. Fortunately, recent molecular genetic advances have markedly increased our knowledge about the mechanisms of disease, in the process simplifying classification schemes for these ataxias and suggesting promising therapeutic strategies. Because many of the more common inherited ataxis are caused by triplet repeat expansions, diagnostic testing is often straightforward, sensitive, and specific. A common theme among adult-onset hereditary ataxia is expansion of a CAG triplet repeat that encodes polyglutamine in the disease protein. To date, 5 dominantly inherited ataxias (spinocerebellar ataxia types 1, 2, 3, 6, and 7) fall within this category, comprising the so-called polyglutamine diseases along with Huntington disease and other neurodegenerative disorders. Despite their clinicopathologic differences, these diseases likely share certain pathogenic features, raising the possibility that therapies can be developed that apply to most or all diseases within this class. Here I will discuss the shared pathogenic features and important differences among the polyglutamine ataxias and review recent successes in modulating disease in animal models. Among early-onset ataxias, which typically are recessively inherited, the most common is Friedreich ataxia. Also a triplet repeat disease, Friedreich ataxia is caused by reduced expression of the disease protein frataxin, a mitochondrial protein that regulates iron homeostasis. I will discuss potential disease mechanisms and the different therapeutic strategies considered for this recessive disease, ranging from gene replacement therapy to antioxidants. Because recent advances in understanding the pathogenesis of inherited ataxias will lead to potential therapies, the field now confronts the welcome, but difficult, task of developing quantifiable phenotypic measures with which clinicians can measure the efficacy of potential therapies.