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<p>Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder caused by abnormal GGC repeat expansions in the <i>NOTCH2NLC</i> gene, leading to multisystem involvement. Electrophysiological abnormalities in NIID have gained increasing attention in recent years. However, subclinical peripheral neuropathy preceding the onset of typical NIID manifestations has not been reported. In this study, we systematically evaluated the clinical characteristics of a family carrying pathogenic <i>NOTCH2NLC</i> expansions. Electrophysiological assessments revealed demyelinating changes in some family members, with or without the classic clinical features of NIID. Notably, one individual with biallelic <i>NOTCH2NLC</i> GGC repeat expansions exhibited subclinical peripheral neuropathy in the absence of overt NIID symptoms. As NIID is typically inherited in an autosomal dominant manner, cases with biallelic GGC repeat expansions are exceedingly rare. To explore the genotype–phenotype relationship, we employed long-read whole-genome sequencing using Oxford Nanopore and Pacific Biosciences (PacBio) technologies. Our results suggest that biallelic repeat expansions do not necessarily exacerbate the severity or progression of NIID. Although larger studies are warranted to confirm these findings, this investigation broadens the clinical and genetic spectrum of NIID and provides new insights into its underlying pathogenesis.</p>

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Subclinical peripheral nerve demyelination without overt symptoms in a family with neuronal intranuclear inclusion disease harboring biallelic repeat expansions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Hang Zhang,
  • Taiqi Zhao,
  • Honglin Zheng,
  • Suying Duan,
  • Chenyang Liu,
  • Yaochong Zhang,
  • Qiang Li,
  • Han Liu,
  • Haiyang Luo,
  • Yuming Xu

摘要

Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder caused by abnormal GGC repeat expansions in the NOTCH2NLC gene, leading to multisystem involvement. Electrophysiological abnormalities in NIID have gained increasing attention in recent years. However, subclinical peripheral neuropathy preceding the onset of typical NIID manifestations has not been reported. In this study, we systematically evaluated the clinical characteristics of a family carrying pathogenic NOTCH2NLC expansions. Electrophysiological assessments revealed demyelinating changes in some family members, with or without the classic clinical features of NIID. Notably, one individual with biallelic NOTCH2NLC GGC repeat expansions exhibited subclinical peripheral neuropathy in the absence of overt NIID symptoms. As NIID is typically inherited in an autosomal dominant manner, cases with biallelic GGC repeat expansions are exceedingly rare. To explore the genotype–phenotype relationship, we employed long-read whole-genome sequencing using Oxford Nanopore and Pacific Biosciences (PacBio) technologies. Our results suggest that biallelic repeat expansions do not necessarily exacerbate the severity or progression of NIID. Although larger studies are warranted to confirm these findings, this investigation broadens the clinical and genetic spectrum of NIID and provides new insights into its underlying pathogenesis.