α-Mannosidosis is a rare, autosomal, recessive, lysosomal storage disease that arises from a deficiency in lysosomal α-mannosidase. It occurs in approximately 1 in 500 000 births and can be caused by 40 different mutations in the gene, MAN2B1, which is located on chromosome 19. Clinical characteristics include cognitive, motor, and hearing impairment, facial and skeletal abnormalities, psychosis, and immunodeficiency. Elevated levels of mannose-rich oligosaccharides in urine are suggestive of the disease but diagnosis is made by measuring enzymatic function in leukocytes or other cells; genetic testing can confirm the diagnosis.1
Since its first description in 1967, most reports of ocular manifestations have centered on corneal or lenticular opacities and strabismus.2,3 More recently, Springer et al4 described late-onset retinal dystrophy characterized by decreasing visual acuity and diminished full-field electroretinograms. To the best of our knowledge, abnormal fundus changes have yet to be documented in this disease. Herein we describe 2 further cases of retinal dystrophy supported by fundus photography, autofluorescence, and spectral-domain optical coherence tomography.
A 53-year-old man was referred for evaluation of decreased visual acuity over the past 2 years. He had a diagnosis of α-mannosidosis since childhood, which was confirmed by a repeated enzyme assay in his forties. He had associated cognitive impairment, musculoskeletal dystrophy, and hearing loss and was nonverbal. According to his caregiver, he previously had normal vision including normal findings on eye examinations, but during the past 2 years he had increasing difficulty with near tasks. On examination, the patient had coarse facies and evidence of prior craniosynostosis surgery and was unable to ambulate. Visual acuity was central, steady, and maintained in both eyes; pupils were equally round and reactive without an afferent pupillary defect. Confrontational visual fields were full, and intraocular pressure was 14 mm Hg in the right eye and 16 mm Hg in the left. Anterior segment examination was notable for a slight corneal haze in the right eye only but was otherwise unremarkable. Lenses showed minimal nuclear sclerosis. Fundus examination revealed slightly pale discs with a cup-disc ratio of 0.1. There was attenuation of the retinal vasculature. The posterior pole demonstrated mottled patches of the retinal pigment epithelium (RPE), most notable in the macula and surrounding the fovea. Additionally, there were numerous nummular yellow-white deposits evident at the level of the RPE (Figure 1). There was no foveal light reflex or peripapillary sparing, and there were no bone spicule pigmentary changes in either eye. Spectral-domain optical coherence tomography revealed retinal thinning, with loss of the outer retina and inner segment–outer segment junction, RPE atrophy with a corresponding highly visible choroid, and a slight epiretinal membrane (Figure 2). Fundus autofluorescence showed granular areas of hypoautofluorescence in the macula as well as in the posterior pole surrounding the optic nerve where speckled hyperautofluorescence was intermixed with hypoautofluorescent areas (Figure 3).
A, Fundus photographs of case 1 showing retinal pigment epithelium (RPE) atrophy and pigment mottling with numerous yellow-white deposits at the level of the RPE. B, Fundus photograph collages of case 2 showing more severe RPE atrophy with pigment clumping.
A, Spectral-domain optical coherence tomography of case 1 shows retinal thinning, loss of outer retina, retinal pigment epithelium atrophy, and loss of IS-OS junction. B, Spectral-domain optical coherence tomography of case 2 demonstrates grossly thinned retina, disruption of retinal layers, retinal pigment epithelium atrophy, and loss of inner segment outer segment junction.
Fundus autofluorescence images of case 1 show granular areas of hypoautofluorescence in the macula as well as surrounding the optic nerve with speckled areas of hyperautofluorescence intermixed with the hypoautofluorescence.
The brother of the patient described in case 1 was also examined. He was a 51-year-old man who also had a diagnosis of α-mannosidosis characterized by more severe cognitive impairment, hearing loss, and wheelchair dependence and was nonverbal. Findings of physical examination were similar, with coarse facies and macroglossia. Visual acuity was central, steady, and maintained in both eyes. Anterior segment was unremarkable with the exception of minimally nuclear sclerotic lenses. Fundus examination disclosed more severe retinal degeneration with symmetrical waxy pallor of the optic discs and extensive chorioretinal atrophy of the peripapillary RPE and macula with pigment clumping (Figure 1). Spectral-domain optical coherence tomography demonstrated a grossly thinned retina with disruption of retinal layers, atrophy of the RPE, a prominently visible choroid, and loss of inner segment–outer segment junction (Figure 2).
This case series provides the first clinical description of the retinal appearance in human patients with α-mannosidosis and retinal dystrophy in the sixth decade of life, which appears to be typified by dysfunction and subsequent atrophy of the RPE with resulting chorioretinal atrophy. Unfortunately, owing to the patients' inability to cooperate, it was not possible to obtain electroretinograms. Nevertheless, the degree of retinal dystrophy is consistent with the severely depressed or extinguished responses presented by Springer et al.4 Furthermore, the patients we describe and those reported by Springer et al suggest a progressive nature of the degeneration. The fundus autofluorescence of the less severely affected brother (case 1) shows an area of RPE loss involving the macula and a surrounding area of speckled hyperautofluorescence and hypoautofluorescence, suggesting evolving RPE dysfunction. The fundus of the more severely affected brother demonstrates widespread severe RPE atrophy. The patients described by Springer et al reportedly had normal findings on fundus examination; however, these patients were younger and, considering their ability to provide subjective visual acuity, had presumably less progressed disease.
The progression with age may correlate with progressive changes demonstrated on histopathology, namely the accumulation of lysosomal storage material. As a result of defective or deficient α-mannosidase, insufficient breakdown and subsequent accumulation of mannose-rich oligosaccharides in tissue occurs throughout the body.1 The accumulated material appears as vacuoles on histopathology. While human studies are limited, pathologic examination of bovine ocular specimens shows vacuolation of cells from the cornea, lens, and all cell types of the retina as well as the pigment epithelium; electron microscopy of these vacuoles suggests secondary lysosomes.5 It is unknown exactly how the impaired lysosomal function results in the clinical features, but it is likely that retained storage material in the retina along with other, yet-to-be–elucidated mechanisms results in widespread RPE dysfunction and photoreceptor death.
In conclusion, the 2 patients presented herein and those described by Springer et al demonstrate that, in addition to corneal and lenticular opacity, retinal dystrophy may develop in patients with α-mannosidosis. Consideration of retinal function, either through ERG or detailed fundus examination, is warranted prior to planning any surgical correction of corneal or lenticular opacity. Further study is required to determine the frequency with which it occurs and the rate of progression.
Correspondence: Dr Pennesi, Casey Eye Institute, Oregon Health and Science University, 3375 Terwilliger Blvd, Portland, OR 97239 (email@example.com).
Financial Disclosure: None reported.
Funding/Support: This study was supported by grants C-GE-0706-0365-OHSU01 and from Foundation Fighting Blindness; Collins Medical Trust; and Research to Prevent Blindness.
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