The autosomal dominant spinocerebellar ataxias (SCAS) and episodic ataxias (EAs) are a group of adult- and juvenile-onset neurodegenerative diseases characterized by progressive or intermittent dysarthria and incoordination due to degeneration of the cerebellum and brainstem. Advances in the genetic understanding of these diseases have established that, despite similar clinical presentations, there are at least 9 genetically distinct subtypes, SCAI-SCA7, EA-1 and EA-2. Clinical observations suggest that eye movements and postural stability are universally but differentially impaired in the SCAs, presumably due to regional differences in brainstem and cerebellar involvement in the disease. The voluntary and reflexive control of oculomotor and vestibular function rely heavily on the normal function of the cerebellum and its interaction with brainstem neurons. A precise understanding of extraocular movements and vestibular dependent reflexes in SCA may identify both common abnormalities useful for comparative scoring among kindreds, and abnormalities that are unique to a given SCA subtype. In this project the applicants propose to take advantage of a large database of SCA patients, and recent developments in both the genetics of autosomal dominant ataxia, and in the technology for recording and analyzing eye movements and the dynamic control of posture to address the question of whether specific patterns of eye movement abnormalities and postural instability characterize genetically-defined SCAs. These studies will allow them to assess the functional integrity of widespread areas of the brainstem and cerebellum. These measurements are non-invasive, more sensitive than static magnetic resonance imaging, and can be applied to a larger number of genetically defined ataxia patients than could be possible using pathological studies. They propose to: 1) Determine the genetic status of all SCA and EA (episodic ataxia) patients in the University of Minnesota Ataxia Database. 2) Determine whether genetically homogeneous forms of SCA manifest unique patterns of oculomotor and vestibular abnomalities. 3) Determine whether the length of CAG repeat expansions in SCA 1, 2, 3 and 6 correlate with the profile of oculomotor and vestibular abnormalities. 4) Define the progression of oculomotor, vestibular and postural abnormalities as a function of disease duration for SCA 1-7.

These studies may identify diagnostic features for some SCA types and provide valuable information about selective vulnerability of CNS neurons and the pathogenesis of CAG repeat diseases. They also may identify traits common to all patients with ataxia that will be useful quantitative measures for therapeutic trials. These studies will test the hypothesis that sensitive measures of eye movements and balance can be used to detect and quantify ataxia from its earliest stages.

R01NS037211

1998-08-01

2004-07-31