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Background <p>To report the genotype–phenotype correlations in neuronal intranuclear inclusion disease (NIID)-related retinopathy.</p> Methods <p>13 patients from 12 families (62–81&#xa0;years) clinically diagnosed with late-onset NIID were studied. Best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinography (ERGs) were examined. The number of CGG repeats in <i>NOTCH2NLC</i> was determined. Genotype–phenotype correlations between the number of CGG repeats and the age at onset of ocular symptoms, disease duration, ellipsoid zone (EZ) length of photoreceptors in the peripapillary area, and ERGs amplitudes were determined.</p> Results <p>All patients had expanded CGG repeats (100–177 repeat units) in the <i>NOTCH2NLC</i>, and 11 patients noticed ocular symptoms before cognitive decline and two noticed them in their 20&#xa0;s. FAF decrease and EZ absence in the peripapillary area were observed in all cases. ERGs indicated rod-cone dysfunction. The number of repeats was significantly correlated with an amplitude of all components of scotopic and photopic ERGs except for the b-wave in dark-adapted (DA) 0.01 and DA 10.0 ERGs. The highest coefficient of correlation was found between the amplitudes of the d-wave, a-wave, and the b-wave in light-adapted (LA) ON–OFF ERG (ρ = −0.97, <i>P</i> &lt; 0.001, ρ = −0.92, <i>P</i> &lt; 0.01, ρ = −0.84, <i>P</i> &lt; 0.01 respectively), the b-wave in LA 3.0 (ρ = −0.75, <i>P</i> &lt; 0.01), and 30&#xa0;Hz flicker (ρ = −0.71, <i>P</i> &lt; 0.05).</p> Conclusions <p>Expanded CGG repeats in <i>NOTCH2NLC</i> develop ocular symptoms earlier than reported. The number of repeats can be a biomarker for the severity of retinal dysfunction in NIID-related retinopathy.</p>

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Genotype–phenotype correlations in neuronal intranuclear inclusion disease-related retinopathy with CGG repeat increases in NOTCH2NLC

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • Natsuko Nakamura,
  • Kazushige Tsunoda,
  • Akihiko Mitsutake,
  • Shota Shibata,
  • Miho Kawabe Matsukawa,
  • Hiroya Naruse,
  • Meiko Maeda,
  • Masashi Hamada,
  • Wataru Satake,
  • Hiroyuki Ishiura,
  • Shoji Tsuji,
  • Tatsushi Toda,
  • Hiromasa Sawamura

摘要

Background

To report the genotype–phenotype correlations in neuronal intranuclear inclusion disease (NIID)-related retinopathy.

Methods

13 patients from 12 families (62–81 years) clinically diagnosed with late-onset NIID were studied. Best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinography (ERGs) were examined. The number of CGG repeats in NOTCH2NLC was determined. Genotype–phenotype correlations between the number of CGG repeats and the age at onset of ocular symptoms, disease duration, ellipsoid zone (EZ) length of photoreceptors in the peripapillary area, and ERGs amplitudes were determined.

Results

All patients had expanded CGG repeats (100–177 repeat units) in the NOTCH2NLC, and 11 patients noticed ocular symptoms before cognitive decline and two noticed them in their 20 s. FAF decrease and EZ absence in the peripapillary area were observed in all cases. ERGs indicated rod-cone dysfunction. The number of repeats was significantly correlated with an amplitude of all components of scotopic and photopic ERGs except for the b-wave in dark-adapted (DA) 0.01 and DA 10.0 ERGs. The highest coefficient of correlation was found between the amplitudes of the d-wave, a-wave, and the b-wave in light-adapted (LA) ON–OFF ERG (ρ = −0.97, P < 0.001, ρ = −0.92, P < 0.01, ρ = −0.84, P < 0.01 respectively), the b-wave in LA 3.0 (ρ = −0.75, P < 0.01), and 30 Hz flicker (ρ = −0.71, P < 0.05).

Conclusions

Expanded CGG repeats in NOTCH2NLC develop ocular symptoms earlier than reported. The number of repeats can be a biomarker for the severity of retinal dysfunction in NIID-related retinopathy.