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.

Figure 1.

Results of Goldmann perimetry of four cases of NIID-related retinopathy with CGG repeat expansions in the NOTCH2NLC gene. Concentric contraction of the I-4 isopter is present in all four cases. The physiological blind spot is also enlarged in patients 4 and 7.

Figure 2.

Fundus photographs and FAF images of patients with NIID. (A) Ultra-widefield photographs and FAF images. CRA in the peripapillary regions was observed in all cases. In patient 7, the CRA extended to close to the macula. All patients showed abnormalities of the color of the RPE in the peripheral regions. In patient 7, diffuse CRA in the peripheral region was observed. Fine white dots were detected in all the cases except in patient 4 either in the posterior pole or peripheral regions (white arrowhead). Widefield FAF images show absence of AF around the optic disk in all cases. In the midperiphery, mild-hypo AF was observed along the equator in patients 1, 5, and 6 and diffuse absence of AF in patient 7. (B) Posterior FAF images showed hyper- and hypo-AF spots in the posterior polar region.

Figure 3.

OCT images of six patients. The EZ is absent in the peripapillary regions in all cases. The regions of absent EZ are shown by two yellow arrows, and their size varies among the cases. In patient 7, the EZ is absent in the entire posterior pole region. The foveal EZ was relatively preserved in all the cases. A thinning of the ONL is present in the peripapillary region in all cases except patient 1. A thinning of the RPE and choroid is observed in the peripapillary region in patients 3, 4, and 6 and in the entire posterior pole region in patient 7. The inner retinal structures (i.e., NFL and retinal GCL) are normally preserved, and high-reflectivity fine spots can be seen between the GCL and ONL in all cases (white arrowheads).

Figure 4.

Full-field ERGs recorded under scotopic and photopic conditions. The scotopic ERGs are severely reduced or extinguished in all cases. The amplitudes of the a-wave and b-wave of the dark-adapted 10.0 and light-adapted 3.0 ERGs are reduced with prolonged implicit times. All the responses were nonrecordable in patient 7.