Recurrent Bilateral Macular Edema Linked to NOTCH2NLC GGC Repeat Expansion: A Case Report

Introduction

A pioneering study in 2019 showed that expansion of GGC repeats in the 5′ region of NOTCH2NLC may contribute to the development of neuronal intranuclear inclusion disease (NIID) [1], which presents with a variety of clinical manifestations. Here, we report a case of a young woman carrying this mutation, who presented with refractory bilateral macular edema, and showed good response to anti-VEGF treatment. The patient underwent 26 intravitreal anti-VEGF injections per eye over the course of 5 years.

Case Report

A 35-year-old woman with no history of hypertension, diabetes, or comorbidities presented with bilateral blurred vision. Her uncorrected visual acuity (UCVA) was 10/20 in both eyes, and her best corrected visual acuity (BCVA) was 20/20. The intraocular pressure (IOP) was 16.7 mmHg in the right eye and 15.3 mmHg in the left eye (1 mmHg=0.133 kPa). Although the BCVA was normal, the patient still experienced significant subjective blurring. No obvious abnormalities were found in the anterior segment, lens, or retina (Figure 1A, 1B). Optical coherence tomography (OCT) confirmed the presence of cystoid edema and localized loss of the ellipsoid zone (EZ) (Figure 1C, 1D). Autofluorescence showed cystic mottled fluorescence at the fovea, while fluorescein angiography combined with indocyanine-green angiography (FFA+ICGA) detected multiple cystic hyperfluorescent areas (Figure 1E–1H). Electroretinogram, visual field test, and comprehensive blood tests yielded normal results. Based on these findings, after excluding surgical contraindications, the patient received bilateral intravitreal injections of aflibercept (40 mg/mL, 0.05 mL) to obtain restoration of retinal architecture. One week postoperatively, the edema was significantly resolved (Figure 1I, 1J), and the patient’s UCVA improved to 0.8.

The patient’s father had experienced similar chronic bilateral vision loss (BCVA: right eye, 5/20; left eye, 2/20). Additionally, he was diagnosed with NIID during a prior hospitalization in the neurology department. Genetic testing revealed that 1 allele of NOTCH2NLC had a GGC repeat of 124 times. Pigmentary disruption was observed in the posterior pole (Figure 2A, 2B). OCT revealed a deepened fovea, accompanied by thinning of the outer layers and localized disruption of the EZ (Figure 2C, 2D). FFA showed mottled hyper-and-hypofluorescence staining (Figure 2E–2H). Flash electroretinogram indicated a rod-cone dysfunction. Given the financial burden and unfavorable prognosis, no specific treatment was ever administered to the patient’s father.

During the following medical visit of the patient herself, we tried every method to find the etiology. Laboratory tests including complete blood count, coagulation profile, liver and kidney function, and infectious markers were all within normal limits. Through serological and microbiological testing, prevalent contagious conditions such as HIV infection, syphilis, and active tuberculosis were excluded. Comprehensive immunologic screenings were conducted, including testing for Toxoplasma, other congenital pathogens, Rubella, Cytomegalovirus, and Herpesvirus (TORCH), antinuclear antibody examination, B27 testing, erythrocyte sedimentation rate measurement, rheumatoid factor determination, immunoglobulin and complement assay, anti-O testing, antiphospholipid syndrome antibody profile, anti-β2-glycoprotein 1 antibody measurement, Coombs’ test, anti-glomerular basement membrane antibody assay, anti-phospholipase A2 receptor antibody detection, and vasculitis antibody profile. All these screenings showed no significant abnormalities. Based on the patient’s clinical manifestations and the results above, we excluded common retinal causes including occult uveitis, inherited retinal dystrophies, medication-induced edema and subclinical vascular disease. Due to the inability to identify a clear etiology, we attempted Ozurdex injection for patient convenience and economic relief. However, discontinuation was necessary following post-injection ocular pain and discomfort. Additionally, we attempted micropulse laser therapy to the macula to facilitate edema absorption, but the efficacy was suboptimal. Finally, considering her father’s NIID, we suggested genetic testing. It revealed a GGC repeat expansion to 114 alleles in the NOTCH2NLC gene, identical to that identified in her father. Over 5 years, the patient experienced recurrent bilateral macular edema with anti-VEGF therapy (26 injections/eye; the majority administered as aflibercept, with a few switches to conbercept, ranibizumab, and faricimab), maintaining BCVA of 10/20. Despite the wide range of intravitreal medications, aflibercept was preferentially utilized given its similar therapeutic outcomes and relatively lower cost. The interval between injections has shortened from over 2 months at the initial diagnosis to less than 6 weeks. The patient continues to attend regular follow-up visits.

Discussion

NIID was first reported by Haltia et al in 1984 [2] and is currently recognized as a rare, autosomal-dominant, chronic, progressive neurodegenerative disease characterized by the formation of eosinophilic inclusions within neurons. In 2019, a noncoding GGC repeat expansion in NOTCH2NLC was identified as the pathogenic mutation underlying NIID [3]. Currently, tissue or skin biopsy and characteristic changes on diffusion-weighted imaging MRI at the cortical-medullary junction are helpful for diagnosing NIID, while genetic testing for the GGC repeat sequence in the NOTCH2NLC gene has become the gold standard for NIID diagnosis [1,3]. Katayama et al systematically reviewed NOTCH2NLC repeat expansions in NIID patients with retinopathy, reporting allele sizes ranging from 84 to 180 repeats [4]. In contrast, Sone et al reported repeat copy-number ranges of 6 to 30 (controls) and 71 to 183 (subjects with NIID) [1]. The clinical manifestations of NIID are diverse, involving multiple systems such as the central nervous, respiratory, urinary, digestive, and movement systems. Thus, NIID manifests as cognitive impairment and dementia, Parkinsonism, personality changes, ataxia, muscle weakness, coughing, vomiting, and bladder dysfunction [2,5–8]. Several global studies have reported that common ocular symptoms in NIID patients include blurred vision, night blindness, color vision deficits, and photophobia. Most patients present with EZ loss on OCT and photoreceptor dysfunction on electroretinogram [4,6,7,9]. Ophthalmologic findings range from reduced electroretinogram signals in the absence of subjective symptoms to severe retinal degeneration resulting in legal blindness. Nakamura et al [6] noted that NIID patients with CGG repeat expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. Sone et al [9] confirmed the presence of diffusely distributed intranuclear inclusions in retinal cells, gliosis of the retina and optic nerve, and diverse retinal abnormalities in NIID patients with NOTCH2NLC GGC expansion. Visual dysfunction could be the first sign of NIID. Chen et al [10] observed ocular abnormalities in 5 Chinese patients with NIID, confirming the above- mentioned features of retinal degeneration and photoreceptor involvement. However, there are no reports in the existing literature about macular cystic edema in patients with NOTCH2NLC gene mutations. This could imply an age-dependent onset, where edema precedes retinal atrophy. Additionally, it may reflect phenotypic heterogeneity or a lack of recognition of this specific feature. Furthermore, treatment bias is possible, as undiagnosed cases may have responded to empirical therapy, masking the association.

In the present case, the patient presented with refractory, recurrent bilateral macular edema with localized EZ defects. Genetic testing revealed expansion of the GGC repeat in the NOTCH2NLC allele. Due to personal reasons, the patient did not undergo neurology consultation for a definitive diagnosis of NIID. However, based on the diagnostic criteria mentioned earlier (particularly the NOTCH2NLC gene variant), we strongly suspect she shares the same NIID diagnosis as her father. Additionally, imaging showed that the patient’s lesion was localized to the papillomacular bundle, matching retinal findings in previous NIID reports [4,6,7,9]. The father’s ocular manifestations and age at onset were consistent with established NIID characteristics. Therefore, we propose that refractory macular edema may be an early ocular manifestation of the NOTCH2NLC GGC repeat expansion in young patients, whereas the previously reported EZ loss and retinal thinning may reflect late-stage manifestations of this genetic mutation. However, the exact temporal progression and causality have not been definitively established and warrant further investigation.

Neuronal intranuclear inclusions (NIIs) in skin or other tissue biopsy samples are characteristic histopathological features of NIID. Their presence and resulting dysfunction of the ubiquitin-proteasome system are common pathological features of NIID and other neurodegenerative diseases [5]. Studies have confirmed the presence of NIIs in neurons and astrocytes in NIID patients [8,11,12]. The human retina contains 3 main types of glial cells: microglia, astrocytes, and Müller cells. The functions of Müller cells include participating in the establishment and maintenance of the blood-retinal barrier (BRB), regulating electrolyte balance through a large number of ion channels, maintaining retinal homeostasis through the AQP-4 water channel, secreting neurotrophic factors, growth factors, and cytokines, and other supportive functions [13–16]. Therefore, we speculate that NIIs in the Müller cells of patients with NOTCH2NLC GGC repeat expansion affect Müller cell structure and function at an early stage. This would be expected to result in: (1) BRB damage, impaired barrier function, and a large amount of extracellular fluid entering the inner layer of the retina, causing macular edema; and (2) excessive secretion of VEGF by Müller cells, causing abnormal leakage from retinal blood vessels, and then leading to macular edema. Furthermore, frequent macular edema in the early stages is primarily attributed to these effects, and this leads to photoreceptor apoptosis and finally manifests as macular dysfunction in the late stages. It is important to distinguish these clinical findings from the proposed mechanism; direct evidence for Müller cell participation is lacking.

In terms of treatment, the patient demonstrated active engagement in her care, reflecting a shared decision-making model. Intravitreal dexamethasone implants were discontinued due to intolerable ocular pain and progression of cataracts observed after injection. Conversely, despite relatively preserved BCVA, the patient reported severe visual blurring due to macular edema that significantly affected her quality of life. Given the favorable response to anti-VEGF therapy, this regimen was maintained long-term, though it cannot yet be recommended as a standard treatment. This will serve as a reference for clinical treatment strategies and may also promote the development of gene-engineered drugs targeting NOTCH2NLC. In addition, this patient requires long-term, repeated anti-VEGF treatment, so intravitreal injection of long-acting steroid drugs can be considered later to reduce the burden on the patient.

Conclusions

Although limited by the lack of retinal histopathology, our findings suggest that bilateral refractory macular edema of undetermined etiology may be an early ophthalmic manifestation of the NOTCH2NLC GGC repeat expansion. Although anti-VEGF therapy is effective, its mechanism requires further investigation. These findings offer novel insights into diagnosing cystoid macular edema and advance research on the NOTCH2NLC gene.