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Background <p>Autosomal dominant spinocerebellar ataxia 27B (SCA27B), caused by an intronic (GAA•TTC) repeat expansion in <i>FGF14</i>, is a common cause of late-onset cerebellar ataxia, but its genotypic and phenotypic spectrum remains to be fully established.</p> Methods <p>We analysed the <i>FGF14</i> (GAA•TTC) repeat expansion in a cohort of 134 patients with ataxia and 822 controls from Quebec. We conducted segregation study in large families to further characterize intergenerational repeat instability.</p> Results <p>We found a significant enrichment of (GAA•TTC)<sub>≥200</sub> alleles in the ataxia cohort compared to controls (53.0%, 71/134, vs 3.6%, 30/822, <i>p</i> &lt; 0.0001), including for (GAA•TTC)<sub>200–249</sub> alleles (8.2% vs 2.6%, <i>p</i> = 0.0026). We identified 12 ataxic patients with a phenotype compatible with SCA27B carrying a (GAA•TTC)<sub>200–249</sub> expansion supporting the pathogenicity of these alleles in some patients. We further delineated the phenotype of 125 symptomatic individuals from 69 families who carried an <i>FGF14</i> (GAA•TTC)<sub>≥200</sub> repeat expansion. Patients with (GAA•TTC)<sub>200–249</sub>, (GAA•TTC)<sub>250–299</sub>, and (GAA•TTC)<sub>≥300</sub> had a similar phenotype. We observed that 14% of patients with episodic symptoms (13/92) had severe episodes that were initially misdiagnosed as stroke, vestibular neuritis, Wernicke’s encephalopathy, or seizures.</p> Discussion and conclusion <p>This large cohort demonstrates that (GAA•TTC)<sub>200–249</sub> alleles are enriched in patients with ataxia compared to controls and can be pathogenic for SCA27B, supporting the need to define a lower pathogenic threshold in the presence of specific clinical criteria.</p>

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Delineating the pathogenic threshold and phenotypic spectrum of SCA27B: findings from a large French–Canadian cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月20日

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  • Pablo Iruzubieta,
  • David Pellerin,
  • Catherine Ashton,
  • Felipe Villa,
  • Mathilde Renaud,
  • Marie-Josée Dicaire,
  • Matt C. Danzi,
  • Mayra Aldecoa,
  • Jean Mathieu,
  • Rami Massie,
  • Colin H. Chalk,
  • Anne-Louise Lafontaine,
  • François Evoy,
  • Marie-France Rioux,
  • Jean-Denis Brisson,
  • Kym M. Boycott,
  • Henry Houlden,
  • Matthis Synofzik,
  • Roberta La Piana,
  • Stephan Zuchner,
  • Antoine Duquette,
  • Bernard Brais

摘要

Background

Autosomal dominant spinocerebellar ataxia 27B (SCA27B), caused by an intronic (GAA•TTC) repeat expansion in FGF14, is a common cause of late-onset cerebellar ataxia, but its genotypic and phenotypic spectrum remains to be fully established.

Methods

We analysed the FGF14 (GAA•TTC) repeat expansion in a cohort of 134 patients with ataxia and 822 controls from Quebec. We conducted segregation study in large families to further characterize intergenerational repeat instability.

Results

We found a significant enrichment of (GAA•TTC)≥200 alleles in the ataxia cohort compared to controls (53.0%, 71/134, vs 3.6%, 30/822, p < 0.0001), including for (GAA•TTC)200–249 alleles (8.2% vs 2.6%, p = 0.0026). We identified 12 ataxic patients with a phenotype compatible with SCA27B carrying a (GAA•TTC)200–249 expansion supporting the pathogenicity of these alleles in some patients. We further delineated the phenotype of 125 symptomatic individuals from 69 families who carried an FGF14 (GAA•TTC)≥200 repeat expansion. Patients with (GAA•TTC)200–249, (GAA•TTC)250–299, and (GAA•TTC)≥300 had a similar phenotype. We observed that 14% of patients with episodic symptoms (13/92) had severe episodes that were initially misdiagnosed as stroke, vestibular neuritis, Wernicke’s encephalopathy, or seizures.

Discussion and conclusion

This large cohort demonstrates that (GAA•TTC)200–249 alleles are enriched in patients with ataxia compared to controls and can be pathogenic for SCA27B, supporting the need to define a lower pathogenic threshold in the presence of specific clinical criteria.