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<p><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,&#xa0;<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.</p>

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Genotype and Age at Onset Drive Vermis Atrophy in CACNA1A- and GAA-FGF14-related Ataxias

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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  • Elisabetta Indelicato,
  • Wolfgang Nachbauer,
  • Matthias Amprosi,
  • David Pellerin,
  • Stephanie Mangesius,
  • Elke R. Gizewski,
  • Stefan Kiechl,
  • Bernhard Brais,
  • Sylvia Boesch,
  • Florian Krismer

摘要

CACNA1A- and GAA-FGF14-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 CACNA1A- (n = 16) and GAA-FGF14-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 (rs(26) = 0.47, p = 0.01). The cluster with most marked atrophy of the vermis comprised patients with missense CACNA1A 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 CACNA1A variants and GAA-FGF14-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 CACNA1A and GAA-FGF14-disease.