Genotype and Age at Onset Drive Vermis Atrophy in CACNA1A- and GAA-FGF14-related Ataxias.
Authors
Affiliations (7)
Affiliations (7)
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
- Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33101, USA.
- Department of Radiology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
- Neuroimaging Research Core Facility, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
- VASCage, Centre On Clinical Stroke Research, Innsbruck, Austria.
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. [email protected].
Abstract
<i>CACNA1A</i>- and GAA-<i>FGF14</i>-related channelopathies are among the most frequent genetic etiologies of cerebellar ataxia. They display overlapping features consisting of both chronic and episodic neurological symptoms and usually show only a mild cerebellar atrophy in imaging studies, with prevalent involvement of the vermis. To evaluate cerebellar volumetry as a biomarker for distinguishing between these disorders and for understanding their neuroanatomical correlates. We applied a deep learning method (CerebNet) for the lobular segmentation and volumetry assessment of the cerebellum on 3.0 Tesla MRI scans of patients with genetically confirmed <i>CACNA1A</i>- (n = 16) and GAA-<i>FGF14</i>-related (n = 12) ataxia. K-means clustering and principal component analysis were employed to assess infratentorial atrophy patterns. Three distinct clusters based on the patterns of infratentorial volume loss were established, with vermian atrophy contributing the most. The degree of vermian atrophy was not correlated with the clinical severity of chronic ataxia, but with age at disease onset (<i>r</i><sub><i>s</i></sub>(26) = 0.47, <i>p</i> = 0.01). The cluster with most marked atrophy of the vermis comprised patients with missense <i>CACNA1A</i> variants who exhibited an early disease onset and migraine with aura as episodic manifestation. Conversely, there was an increase in the frequency of episodic ataxia and both loss-of-function <i>CACNA1A</i> variants and GAA-<i>FGF14</i>-expansions as genotypes when progressing from clusters with more to less severe vermian atrophy. Age at onset and the modality of channel dysfunction are key determinants of cerebellar volume loss in <i>CACNA1A</i> and <i>GAA-FGF14</i>-disease. The online version contains supplementary material available at 10.1007/s12311-026-01966-8.