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<p>Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder linked to specific genetic mutations, including those in the CHMP2B gene, which encodes a component of the ESCRT-III complex involved in endosomal trafficking and autophagy. Here, we report a 62-year-old woman presenting with apathy, hyperorality, and language impairment, harbouring a novel heterozygous c.440&#xa0;A &gt; G CHMP2B variant of uncertain significance, causing D147G substitution. Neuropsychological evaluation revealed severe apathy, whereas MRI and 18FDG-PET were consistent with an early left prefrontal impairment. The D147G substitution is located in proximity to the D148Y mutation, previously associated with semantic variant primary progressive aphasia, suggesting it may similarly disrupt protein conformation or stability. Our findings raise the possibility that this variant may be relevant in the context of an FTD-like phenotype. This case highlights the importance of investigating missense variants to further elucidate the pathogenic mechanisms of ESCRT-III dysfunction in neurodegeneration.</p>

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A novel CHMP2B variant of uncertain significance in a patient with apathy, hyperorality, and mild language impairment

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Alessio Rocco Sangiorgio,
  • Carlo Manco,
  • Delia Righi,
  • Silvia Bianchi,
  • Domenico Plantone

摘要

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder linked to specific genetic mutations, including those in the CHMP2B gene, which encodes a component of the ESCRT-III complex involved in endosomal trafficking and autophagy. Here, we report a 62-year-old woman presenting with apathy, hyperorality, and language impairment, harbouring a novel heterozygous c.440 A > G CHMP2B variant of uncertain significance, causing D147G substitution. Neuropsychological evaluation revealed severe apathy, whereas MRI and 18FDG-PET were consistent with an early left prefrontal impairment. The D147G substitution is located in proximity to the D148Y mutation, previously associated with semantic variant primary progressive aphasia, suggesting it may similarly disrupt protein conformation or stability. Our findings raise the possibility that this variant may be relevant in the context of an FTD-like phenotype. This case highlights the importance of investigating missense variants to further elucidate the pathogenic mechanisms of ESCRT-III dysfunction in neurodegeneration.