Clinical Characteristics of Neuronal Intranuclear Inclusion Disease-Related Retinopathy With CGG Repeat Expansions in the NOTCH2NLC Gene

Abstract

Purpose To report the ocular characteristics of neuronal intranuclear inclusion disease (NIID)–related retinopathy with expansion of the CGG repeats in the NOTCH2NLC gene. Methods Seven patients from six families (aged 66–81 years) diagnosed with adult-onset NIID were studied. Ophthalmologic examinations, including the best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and full-field electroretinography (ERGs), were performed. The expansion of the CGG repeats in the NOTCH2NLC gene was determined. Results All patients had an expansion of the CGG repeats (length approximately from 330–520 bp) in the NOTCH2NLC gene. The most common symptoms of the five symptomatic cases were reduced BCVA and night blindness. The other two cases did not have any ocular symptoms. The decimal BCVA varied from 0.15 to 1.2. Goldmann perimetry was constricted in all four cases tested; physiological blind spot was enlarged in two of the cases. The FAF images showed an absence of autofluorescence (AF) around the optic disc in all cases and also showed mild hypo-AF or extinguished AF in the midperiphery. In all cases, the OCT images showed an absence of the ellipsoid zone of the photoreceptors in the peripapillary region, and hyperreflective dots were also present between the retinal ganglion cell layer and outer nuclear layer. The macular region was involved in the late stage of the retinopathy. The full-field ERGs showed rod-cone dysfunction. Conclusions Patients with adult-onset NIID with CGG repeats expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. The primary site is most likely the photoreceptors. Because the ocular symptoms are often overlooked due to dementia and occasionally precede the onset of dementia, detailed ophthalmological examinations are important for the early diagnosis of NIID-related retinopathy.

NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

“…This study is of great significance, as it might reveal a new candidate genetic risk factor that underly ~6% familial patients with ET 14 . NOTCH2NLC GGC repeat expansion was later screened in Chinese,22 23 Singaporean21 and European10 12 24 patients affected by ET and found to account for 0%–6.67% ET pedigrees/patients.…”

“…NOTCH2NLC GGC repeat expansion accounts for 5.6% (11/197 pedigrees) familial ET in the cohort of Sun et al , the 27 patients with familial NOTCH2NLC -ET from the 11 genetically positive pedigrees harboured 60–250 GGC repeats, whereas their unaffected familial members and over 1300 healthy controls harboured 4–41 GGC repeats. In NOTCH2NLC -ET, the tremor phenotype was more severe, the activities of daily living ability were worse and voice was more frequently involved 14. The repeat size was shorter and the frequency of GGA interruptions was lower in NOTCH2NLC -ET than those in NIID 20 21.…”

“…The repeat size was shorter and the frequency of GGA interruptions was lower in NOTCH2NLC -ET than those in NIID 20 21. Additionally, skin biopsies showed deposition of ubiquitin-positve and p62-positve intranuclear inclusions in three genetically positive ET probands but not in a non- NOTCH2NLC -ET proband 14. However, Sone and co-workers3 have verified the deposition of intranuclear inclusions in dermal cells as a useful tool for diagnosis and differential diagnosis of NIID.…”

“…Within the broad range of clinical phenotype, visual abnormalities (miosis, night blindness, reduced electroretinographic responses and degenerative retinal changes) are more frequent in patients with NOTCH2NLC -NIID as 34.1% (29/85) of patients with NOTCH2NLC -NIID reported visual abnormalities, but none in non- NOTCH2NLC -NIID patients, suggesting that the visual abnormalities may be NOTCH2NLC -specific. Patients with NOTCH2NLC -NIID presented with similar ophthalmologic features as rod-cone dysfunction and progressive retinal degeneration in peripapillary and mid-peripheral regions 14. Given the low incidence of NOTCH2NLC -NIID, retinal dystrophy or other ophthalmologic abnormalities, these rare disorders are unlikely to appear simultaneously in an individual 15.…”

Characteristics of ocular findings of patients with neuronal intranuclear inclusion disease

“…NIID shows several ocular manifestations, including rod-cone dysfunction, retinal degeneration, night blindness, mitosis, and reduced best-corrected visual acuity (BCVA) at different ages, especially in adult-onset NIID [8][9][10][11].…”