Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4

Abstract

Purpose: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD).

Methods: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.R45W, and group B, missense variants located between amino acids (aa) 1196 and 1201. The clinical parameters of the two genotypes were compared, and deep learning based on spectral-domain optical coherence tomographic (SD-OCT) images was used to distinguish the morphologic differences.

Results: Groups A and B included 29 and 22 patients, respectively. The median age of onset in groups A and B was 14.0 and 40.0 years, respectively. The median logMAR visual acuity of groups A and B was 0.70 and 0.51, respectively, and the survival curve analysis revealed a 15-year difference in vision loss (logMAR 0.22). A statistically significant difference was observed in the visual field classification, but no significant difference was found in the multifocal electroretinographic classification. High accuracy (75.4%) was achieved in classifying genotype groups based on SD-OCT images using machine learning.

Conclusions: Distinct clinical severities and morphologic phenotypes supported by artificial intelligence-based classification were derived from the two investigated RP1L1 hotspots: a more severe phenotype (p.R45W) and a milder phenotype (1196-1201 aa). This newly identified genotype-phenotype association will be valuable for medical care and the design of therapeutic trials.

Figure 1.

A schematic diagram of the genetic and protein structures of RP1L1, illustrating the location of the two hotspots. The positions of previously reported RP1L1 variants, encompassing both monoallelic and biallelic diseases, are displayed based on previous reports^, and protein information (ID:Q8IWN7; Uniprot; https://www.uniprot.org/; accessed January 2023). The two hotspots included amino acids 45 and 1196 to 1201.

Figure 2.

Clinical findings of two representative cases from genotype groups A and B. Fundus photographs, FAF, SD-OCT images, static VF (30 degrees), ffERG, and mfERG of two cases are presented: genotype A (19-year-old woman, onset at 16 years, LogMAR BCVA 1.00, classical SD-OCT classification, central scotoma VF pattern, group 2 mfERG classification) and genotype B (52-year-old man, onset at 47 years, LogMAR BCVA 0.30, classical SD-OCT classification, no detected scotoma VF pattern, group 2 mfERG classification).

Figure 3.

Survival curves analysis of BCVA for genotype groups A and B. Survival curves of BCVA for age are generated for genotype groups A and B in terms of two BCVA levels: (A) logMAR BCVA 0.22 and (B) logMAR BCVA 1.00. Half of the patients in genotype group A reached a BCVA level of 0.22 at age 42 years, while half of the patients in genotype group B reached that level at age 57 years. Thus, there is a 15-year difference in VA reduction between genotype groups A and B. The diagram for logMAR 1.00 shows that half of patients in genetic group A reached the VA level of 1.00 at age 57 years, while most patients (>80%) in genotype group B did not reach that severe VA level. A statistically significant difference was revealed between genotype groups A and B in terms of survival curves of BCVA.