Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms (1). Only a few reports have shown ophthalmic manifestations in patients with DRPLA. Corneal endothelial degeneration (2–4) and optic atrophy (5) have been reported separately; however, there are no reports of corneal endothelial degeneration and optic atrophy simultaneously in these patients. Herein, we present four patients from a single family with DRPLA and corneal endothelial degeneration and/or optic atrophy.

Quantitative ophthalmological examinations are crucial to evaluate the corneal and optic nerve lesions in neurological diseases. Specular micrography can qualitatively describe the cellular morphology and quantify the endothelial cell damage (6). Essentially, specular microscopy automatically measures the corneal endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX). Optical coherence tomography (OCT) (7) can assess the ocular fundus, as well as the circumpapillary retinal nerve fiber layer (RNFL). This is the first study to quantify both corneal ECD and RNFL in patients with DRPLA.

The pedigree of a single Japanese family with DRPLA, including the following four patients, is presented in Figure 1. The proband was a 69-year-old Japanese woman (III-10) whose family history revealed that her mother (II-7) experienced gait disturbances in her 80s and died at 93 years old. In addition, she noticed progressive worsening of vision, even after cataract surgery. Her cousin (III-1) died at 80 years old of an unknown cause and suffered from a psychotic disorder for many years. The proposita and affected relatives (III-5, IV-3, and IV-1) are presented in detail in the following subsections.

In this study, we described four patients with DRPLA: two (Patients 1 and 2 in Table 1) who exhibited both corneal endothelial degeneration and optic atrophy and two (Patients 3 and 4 in Table 1) who exhibited only corneal endothelial degeneration. Our patients had no history of trauma, inflammation, glaucoma, or contact lens use; however, Patients 1, 2, and 4 had a history of ophthalmologic surgery. Patient 4, who is phakic, was first diagnosed with bullous keratopathy due to corneal endothelial degeneration. She then received cataract surgery in her left eye prior to corneal transplantation. Therefore, the effect of ophthalmologic surgery on corneal endothelial cells was not considered. Patients 1, 2, and 3 showed corneal guttata, which may have influenced the reliability of the specular microscopy through swelling of the cornea. However, we could estimate the counts of ECD, CV, and HEX in the specular microscopy, which are valuable enough to evaluate the corneal morphology despite the swollen cornea. Furthermore, comorbidities such as Fuchs' endothelial corneal dystrophy are unlikely in our four patients because specific corneal pigmentation was not observed in the slit-lamp examination. Patient 4 underwent a pathologic examination of her endothelium and did not have the classic excrescences of Fuchs' dystrophy; therefore, this was a different process than Fuchs' dystrophy.

We summarized the clinical characteristics, genetic analysis, MRI findings, and ophthalmological examination in the four patients and those with ophthalmologic lesions previously reported (2–5) in Table 1. These patients showed typical signs similar to those of DRPLA patients without ophthalmological lesions. There was no relationship between corneal endothelial degeneration and/or optic atrophy and the number of CAG repeats at the DRPLA locus in our four patients. Although Patient 4 showed mild ataxia in the lower extremities and obvious corneal endothelial degeneration, the number of CAG repeats was almost the same as that in our other patients. Patients 1 and 2, who had both corneal endothelial degeneration and optic atrophy, as well as white matter changes on MRI, were aged persons. As previously reported (8), white matter changes on MRI are unsurprisingly related to aging and the size of the expanded CAG repeat in patients with DRPLA. Since the patient with optic atrophy (5) was not aged, this ophthalmic manifestation may be influenced by other specific factors, such as the DRPLA gene product atrophin-1 (9, 10).

We recommend that all patients with DRPLA undergo a detailed ophthalmological examination, including OCT and specular micrography, when possible. A specular micrograph can present qualitative cellular morphology and quantitative endothelial cell damage by determining the corneal ECD. Corneal endothelial cell loss is compensated by increased cell size and decreased cell density (6). A Japanese population-based cross-sectional study, enrolling 5,713 participants (62.8 ± 10.3 years old), determined the mean ECD (men: 2,762 ± 241, women: 2,719 ± 234 cells/mm²), CV (men: 41.55 ± 6.70%, women: 43.29 ± 6.63%), and HEX (men: 47.25 ± 7.20%, women: 44.77 ± 7.14%) of the cohort (11). Compared with these normal values, corneal ECD and HEX in our patients were reduced in addition to corneal guttata and rounded dark cells with light borders corresponding to corneal endothelial cell damage. Silver et al. (5) simply described the presence of corneas with 2–3+ guttata in slit-lamp examinations without showing any pictures; however, a slit-lamp examination cannot accurately detect corneal endothelial damage like specular micrography at high magnification can (6).

Optical coherence tomography can analyze specific retina structures and provide high-resolution cross-sectional and volumetric images in the ocular fundi. In particular, RNFL measurements can provide objective evidence of nerve swelling or atrophy. Although one report has presented a patient with DRPLA accompanied by optic atrophy (6), optic atrophy was confirmed only by fundoscopic examination rather than RNFL measurement. Conversely, OCT was performed only in spinocerebellar ataxia type 1, showing prominent RNFL reduction in temporal areas with high statistical significance (12). However, we did not observe selective RNFL reduction in temporal areas in our patients with DRPLA.

The pathophysiological mechanism underlying corneal endothelial cell loss and optic nerve atrophy in patients with DRPLA is unclear. We found no specific pathological abnormality in Descemet's membrane or the corneal endothelial cells in Patient 4. Ito et al. (3) found that corneal endothelial cells, derived from the neuroectoderm, clearly express DRPLA protein, suggesting that mutant DRPLA protein may be directly related to corneal endothelial and neuronal degeneration. Recently, the nuclear receptor TLX, an orphan nuclear receptor, has been identified to modulate the retinal progenitor cell proliferation and cell cycle re-entry by regulating the expression of PTEN and cyclin D1 (13). Since TLX interacts with atrophin-1, a transcriptional corepressor involved in DRPLA (9, 10). it may be implicated in ophthalmic manifestations of DRPLA (13).

In conclusion, in patients with DRPLA, the presence of corneal endothelial degeneration and/or optic atrophy should be examined using specular micrography and OCT. Depending on the situation, corneal transplantation may be considered one of the treatments for avoiding blindness.

The datasets presented in this article are not readily available because of ethical and privacy restrictions. Requests to access the datasets should be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee in Tokai University Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

ST, EN, and WT contributed to the conception and design of the study. ST, KK, YuO, YoO, and HM participated in the clinical management of patients and data collection. ST wrote the first draft of the manuscript. YuO, EN, WT, and HM wrote sections of the manuscript. All authors, especially HM, contributed to manuscript revision, read, and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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