IMPG1 Variant Causing Adult-Onset Foveomacular Vitelliform Dystrophy in Chinese: A Case Report

Abstract

Introduction

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare entity and is mostly reported in French individuals. Here, we report a Chinese patient with AOFVD who had IMPG1 mutation and was misdiagnosed with age-related macular degeneration (AMD).

Case Presentation

A 59-year-old man complaining of vision loss was misdiagnosed with AMD and treated with intravitreal injections of anti-vascular endothelial growth factor, but with no improvement. Visual acuity was 20/50 in the right eye and 20/40 in the left eye. Fundus examinations revealed a bilateral symmetrical vitelliform “egg yolk” lesion. Spectral-domain optical coherence tomography revealed dome-shaped subretinal hyperreflective materials and cuticular drusen at the retinal pigment epithelium-Bruch’s membrane complex in both eyes. No clear neovascularization was observed. Electrooculography revealed a decreased Arden ratio. Based on multimodal imaging analysis and genetic testing, the patient was diagnosed with AOFVD. No therapeutic intervention was administered. One month after the patient’s visit, vitelliform “egg yolk” lesion was absorbed in the right eye, and the patient’s visual acuity decreased to 20/100 in the right eye.

Conclusion

AOFVD is rare and underdiagnosed. It can disguise as AMD or other similar macular diseases. Clinicians should be alert to this condition, pay attention to its identification, and avoid unnecessary treatments.

Introduction

Adult-onset foveomacular dystrophy (AOFVD) was originally proposed by Gass in 1974 as “a peculiar central macular dystrophy” [1]. Battaglia Parodi et al. [2] first coined the term “AOFVD” in 1996. It is characterized by the presence of bilateral, subfoveal vitelliform material [3]. Studies on AOFVD have been reported worldwide, with a prevalence of 1 in 7,400–8,200 individuals [4–6]. AOFVD can lead to visual impairment and even severe vision loss due to the development of choroidal neovascularization (CNV) or retinal pigmented epithelium (RPE) atrophy in the macula area [5].

AOFVD is often misdiagnosed with age-related macular degeneration (AMD) due to similar fundus manifestations. Currently, no consensus has been reached on the treatment of AOFVD. It has been reported that intravitreal injections of anti-vascular endothelial growth factor (VEGF) is beneficial in patients with CNV secondary to AOFVD [7]. However, Berhuni [8]argued that it was not an appropriate treatment option. Previous studies suggested that patients’ visual function in AOFVD could be preserved for a long time [9]. Reported studies rarely included the multimodal imaging information and a complete history of regression. Herein, we report a case of AOFVD misdiagnosed with AMD and treated with anti-VEGF therapy. This report aimed to provide the comprehensive multimodal imaging analysis and clinical course of AOFVD regression, which could help clinicians better diagnose and manage it.

Case Presentation

A 59-year-old man presented to our hospital with a complaint of gradual loss of binocular vision accompanied by metamorphopsia for 1 year. Systemic diseases included diabetes mellitus and hypertension. The visual acuity was 20/50 in the right eye and 20/40 in the left eye. The intraocular pressure in both eyes was within the normal range. Slit-lamp examination revealed mild senile cataract. He was diagnosed with AMD and received binocular intravitreal injection of anti-VEGF therapy, but with no improvement.

Fundus examinations ruled out diabetic retinopathy and revealed a bilateral symmetrical vitelliform “egg yolk” lesion, appearing as an elevated lesion within the fovea (Fig. 1). Drusen surrounding the lesion was observed. Fundus autofluorescence revealed a hyperautofluorescent lesion with a hypoautofluorescent central part in the right eye and a larger hyperautofluorescent lesion with a hypoautofluorescent superior part in the left eye (Fig. 1c, d). Horizontal and vertical spectral-domain optical coherence tomography (OCT) revealed dome-shaped subretinal hyperreflective materials (SHRMs) with widespread loss of photoreceptor layers and RPE atrophy in the right eye (Fig. 1e). In left eye, SHRM was also observed. A shallow central hyporeflective subretinal space was present, along with irregular hyperreflective deposits adjacent to the foveal lesion (Fig. 1f). Both eyes had drusen at the RPE-Bruch’s membrane complex with associated RPE elevation. No clear neovascularization was observed on optical coherence tomography angiography (OCTA) (Fig. 1g, h). Fundus fluorescein angiography was not performed in this patient, which represented a limitation of the present study and precluded further angiographic evaluation of possible macular neovascularization. Electrooculography suggested a decreased Arden ratio (Fig. 1i).

Fig. 1.

Baseline presentation of bilateral AOFVD. a, b Color fundus photography showed vitelliform “egg yolk” lesions at baseline (white arrowheads). c, d Fundus autofluorescence showed bilateral hyperautofluorescent lesions in the fovea (yellow arrows). e, f SD-OCT showed SHRM (yellow arrows) and drusen (red arrowheads) at RPE-Bruch’s membrane. g, h OCTA showed no clear neovascularization (yellow star). i EOG indicated a decrease in Arden ratio. SD-OCT, spectral-domain optical coherence tomography; SHRM, subretinal hyperreflective materials; RPE, retinal pigment epithelium; OCTA, optical coherence tomography angiography; EOG: electrooculography.

No intervention was recommended. Gene detection was performed to identify diagnosis. Retinal disease gene panel V5 testing identified a heterozygous variant in IMPG1 on chromosome 6 (chr6:76715249–76715250). The variant was annotated as NM_001563.4: c.888-4_889dup in exon 10, with a predicted protein change of p.Gly296_Ser297insTyrSer. The patient was diagnosed with AOFVD finally.

One month later, the patient’s visual acuity remained the same in the left eye but decreased to 20/100 in the right eye. Color fundus photography showed resolution of “egg yolk” materials in the right eye (Fig. 2a). Correspondingly, OCT revealed complete resolution of SHRM (Fig. 2c). In addition, OCT revealed thinning of outer retina, encompassing the outer nuclear layer, photoreceptor layer, and RPE. Little change was observed in lesions in the left eye (Fig. 2b, d).

Fig. 2.

Color fundus photography and OCT follow-up of both eyes. a Color fundus photography showing resolution of “egg yolk” materials in the right eye (white arrowheads). b Color fundus photography had few changes in the left eye. c, d SD-OCT confirmed resolution of SHRM and atrophy of outer retinal layer in the right eye (red arrowheads) and few changes happened in the left eye.

Discussion

This case report was reported in accordance with the CARE Guidelines. The completed CARE Checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000551709).

AOFVD is a rare entity, and most cases of AOFVD are sporadic and do not adhere to a distinct hereditary scheme. PRPH2, BEST1, IMPG1, and IMPG2 genes have been reported that are associated with AOFVD [10–12]. IMPG1 gene mutation has previously been reported in French individuals, and this case report a Chinese patient with an IMPG1 gene mutation. IMPG1 is secreted by photoreceptors. Proteoglycans were found in the interphotoreceptor matrix and strongly expressed around the outer segments of the photoreceptors in adults [13]. IMPG1 plays an important role during the early stages of photoreceptor development. The IMPG1 mutation impairs macular photoreceptors metabolism, leading to loss of the interphotoreceptor matrix, vitelliform deposits and RPE, photoreceptor dysfunction, which could be a possible mechanism of AOFVD [12].

AOFVD is frequently misdiagnosed. AMD with vitelliform lesions is often difficult to differentiate from AOFVD. Both entities can exhibit drusen and vitelliform material depositions in the macula. According to the Beckman Initiative Classification, drusen are categorized by size into small (≤63 μm), medium (>63 to ≤125 μm), and large (>125 μm), and early AMD is defined by the presence of medium drusen without AMD pigmentary abnormalities [14]. Based on morphology and pathophysiology, drusen can be divided into five main types: soft drusen, hard drusen, calcified drusen, reticular pseudodrusen (also referred to as subretinal drusenoid deposits [SDDs]), and pachydrusen [14–17]. Soft drusen are more appropriately defined by their morphologic appearance, typically as deposits with indistinct or blurred borders, whereas hard drusen are smaller, more discrete deposits [14]. Calcified drusen represent another subtype characterized by glistening whitish calcific change [15]. Pachydrusen are usually larger, more discrete yellow-white deposits with well-defined margins and are considered part of the pachychoroid disease spectrum [16]. SDDs are distinct from conventional drusen because they are located above the retinal pigment epithelium (RPE), whereas soft drusen and pachydrusen are sub-RPE deposits [17]. Our case developed a thinner outer retina with SDD, which could be differentiated from AMD. In addition, AMD has an older onset, a higher incidence of CNV and decreased superficial and deep vessel densities compared to AOFVD [18, 19].

AOFVD was suggested to be classified into four stages based on OCT, including vitelliform phase, pseudohypopyon phase, vitelliruptive phase, and atrophic phase, progressively [20]. This case demonstrated a consecutive progress from vitelliform phase to atrophic phase in the right eye. It is difficult to determine the specific time of vitelliform material absorption and clarify the mechanism. The diffuse loss of the inner segment and outer segment interface is the dominate reason to visual acuity impairment [20].

Conclusion

This case demonstrates a unique and complete chain of evidence of AOFVD. It supplements the mutation spectrum of AOFVD in Chinese. We further clarified and summarized the key points for differentiation between AOFVD and AMD based on multimodal imaging. These findings enhance our understanding of AOFVD and help us manage it better.

Statement of Ethics

This study complied with the tenets of the Declaration of Helsinki. This retrospective study was exempt from formal ethical review according to national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors declare that they possess no competing interests.

Funding Sources

This study was supported by the National Natural Science Foundation of China (82101146) and the Beijing Nova Program (Z211100002121052). The funder had no role in the design, data collection, data analysis, and reporting of this study.

Author Contributions

Juexue Wang: data collection and writing of the manuscript; Qian Wang: supervision and critical revision of the manuscript. All authors read and approved the final manuscript.

Funding Statement

This study was supported by the National Natural Science Foundation of China (82101146) and the Beijing Nova Program (Z211100002121052). The funder had no role in the design, data collection, data analysis, and reporting of this study.

Data Availability Statement

All relevant data of this study have been fully presented in this article. Further inquiries can be directed to the corresponding author.