Retinal and optic nerve degeneration in α-mannosidosis

α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease arising from a deficiency in lysosomal α-mannosidase caused by mutations in MAN2B1 located on chromosome 19 with an estimated prevalence of 0.5–1:500.000. Deficiency of α-mannosidase leads to accumulation of mannose-rich oligosaccharides in all tissues resulting in cell dysfunction. Clinical characteristics show different phenotypic variations including cognitive disability with gradual impairment of speech and mental functions, psychosis, motor function and hearing disturbances, facial and skeletal abnormalities, and immune deficiency. Two α-mannosidosis phenotypes have been described based on clinical severity: a severe infantile form (type I) characterized by early death due to rapid progressive central nervous system involvement and a milder phenotype with a slower disease progression and survival into adulthood (type II) [1, 2]. Diagnosis of α-mannosidosis is made by measuring acid α-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive of the disease, however not diagnostic [1]. Öckerman first described a Hurler-like appearance of a four-year-old boy in 1967. In a postmortal examination, a large amount of oligosaccharides, especially mannose-rich oligosaccharides, was found in his organs and tissues [3]. He therefore named the disorder “mannosidosis” [4]. As it is a deficiency in lysosomal α-mannosidase, oligosaccharides accumulate in different tissues and organs. Since these early clinical descriptions of mannosidosis, many research groups have contributed to the characterization of the presenting phenotype, enzyme and corresponding genes in several species including ocular pathologies in 20 α-mannosidosis patients [5‐8]. Early reports have described strabismus, opacities of the cornea and lens as typical ocular symptoms and pathologies in mannosidosis [5]. However, only recently, retinal abnormalities and optic nerve atrophy have been described in a few case reports and confirmed by electrophysiology or optical coherence tomography (OCT) as fundus biomicroscopy only reveals subtle retinal changes [9, 10]. Currently, there are two treatment options for α-mannosidosis: stem cell transplantation and enzyme replacement therapy (ERT). Haematopoietic stem cell transplantation has been reported in less than 20 patients with different outcomes and a high risk of morbidity and mortality [11]. The efficacy and safety of ERT with a recombinant human α-mannosidase (velmanase alfa) has been studied in randomized clinical trials [12] and let to approval by the European Medicines Agency (EMA) in January 2018.

Here, we report ocular findings of 32 patients including a report of two siblings with confirmed α-mannosidosis and especially concentrated on retinal degeneration which we supported by posterior segment examination, fundus photography and Spectral-Domain OCT (SD-OCT).

In total, 32 patients with α-mannosidosis were examined; of these 25 participated in a multicenter, multinational prospective natural history study of α-mannosidosis (Trial-ID: rhLAMAN-01). Clinical evaluations included physical examination, recording of medical history, measurement of endurance by six-minute walk test and three-minute stair climb-test, lung function testing, hearing test, echocardiography and electrocardiography, and laboratory testing. These results were previously published by Beck et al. [13]. In this report, general ophthalmic investigations such as vision, anterior and posterior segment abnormalities were only briefly described. These 25 patients were initially examined between 2007 and 2009 and followed-up over two to three years. In addition to this, we examined seven more patients with α-mannosidosis between 2008 and 2017.

In total, seven patients received ERT with velmanase alfa; of these, six (Man-1, Man-3, Man-4, Man-21, Man-28, Man-31) began treatment during or before our ophthalmic examinations; only Man-32 received his treatment after examination (Tables 1 and 2).

A total of 32 patients with α-mannosidosis were included and ophthalmlogically examined. All patients were assigned to the attenuated form of α-mannosidosis (type II). Table 1 summarizes the patients’ demographics and ocular abnormalities. Some patients were only seen once whereas others were followed-up over many years.

Mean BCVA at first presentation was 20/40 (decimal 0.56 ± 0.28) with a range between 20/500 (decimal 0.04) and 20/20 (decimal 1.00); BCVA at the last (available) presentation was 20/32 (decimal 0.60 ± 0.25) with a range between 20/200 (decimal 0.10) and 20/20 (decimal 1.00). Cataract was seen in two (6.3%) and corneal haze also in two patients (6.3%). Manifest strabismus was seen in six (18.8%), nystagmus in four (12.5%) and impaired smooth pursuit or hypometric saccades in five patients (15.6%) at the first presentation or during follow-up.

We report ocular abnormalities in a large patient population of 32 patients with α-mannosidosis. In this to date largest case series investigating ocular manifestations of α-mannosidosis patients we detected a high incidence of retinal degeneration and optic nerve atrophy. Obvious tapeto-retinal characteristics of the retina as detected by funduscopy were rarely found; however early thinning of the outer retina seen on SD-OCT may suggest a progressive nature of this retinal degeneration in α-mannosidosis. Optic nerve atrophy can be associated with retinal degeneration but we have also seen it in some of our patients without any retinal abnormalities. Also of importance is our observation that four of seven patients treated with velmanase alfa developed retinal degeneration despite ERT. Corneal and lenticular opacities as well as strabismus and motility disorders were less frequent in our cohort of α-mannosidosis patients and may be a nonspecific finding as encountered in other storage diseases.

Bennet and co-workers reported on ocular pathologies in two unrelated patients diagnosed with mannosidosis. One had type I mannosidosis affected from early childhood with poor vision, esotropia and cataracts in both eyes. The other was diagnosed with type II mannosidosis in late adulthood and maintained normal vision but deteriorated with progressive neurologic systems and horizontal nystagmus on lateral gaze [6]. In a report by Arbisser et al. three patients with α-mannosidosis showed similar lenticular opacities without any corneal haze. Ophthalmoscopic anomalies were noticed in two younger patients despite normal electrophysiology. [5]. Histological studies of the eye in humans with α-mannosidosis are not available; however Jolly et al. studied this in a bovine model and found vacuoles in different cell types including corneal epithelium, Descemet’s membrane, corneal endothelium, corneal fibroblasts, pigmented cells, lens epithelium, lens fibers, pigment epithelium and also all cell types of the neuroretina. Histological examinations showed that the mannose-rich oligosaccharides were stored in vacuoles. They hypothesized that this may be the cause of lens and corneal opacities in humans with α-mannosidosis [7]. Moreover, the retained storage material in the retina can lead to photoreceptor loss and tapeto-retinal degeneration [10]. This may also be an explanation for the progression of clinical symptoms including retinal degeneration and optic nerve atrophy with age as we have seen in the two siblings during follow-up. In contrast to previously published articles on ocular pathologies in α-mannosidosis that mainly concentrated on opacities of the cornea or lens, strabismus, nystagmus and other motility disorders, Springer and co-workers described late-onset retinal dystrophy characterized by decreasing visual acuity and diminished Ganzfeld electroretinograms in two brothers with type II α-mannosidosis [9]. Both were in their thirties when they were first examined. They had decreasing vision despite normal findings on fundus examination. Electroretinography showed borderline scotopic and photopic responses; however clinical examination was challenging due to the patients’ reduced mental capacity and inability to cooperate [9]. More recently, Courtney and Pennesi published a short report of two cases of retinal dystrophy in α-mannosidosis [10]. This case report is the first to describe, in addition to corneal and lenticular opacity, chorioretinal atrophy with retinal thinning, loss of the outer retina and RPE as well as granular areas of hyper- and hypoautofluorescence in the macula and surrounding the optic nerve using OCT, fundus autofluorescence and fundus photography [10].

Interestingly, certain similar ocular abnormalities can be found in other storage diseases. In mucopolyasaccharidoses (MPS), glycosaminoglycans accumulate in the retina and induce retinal degeneration, pigmentary retinopathy with bony spicules, or depigmented chorioretinopathy similar to our findings in α-mannosidosis [14‐16]. In a recent report by Seok et al. four patients with different types of MPS showed retinal degeneration with perifoveal thinning of the outer retinal layers on SD-OCT often despite normal fundus morphology [15]. This is also in line with our findings that SD-OCT displays early degeneration of the retina with no or subtle retina changes on funduscopy.

Another interesting finding of our study is that ERT with velmanase alfa did not protect some of our patients receiving ERT during the observational period from developing retinal degeneration. A phase I-II study evaluated the efficacy and safety of the recombinant human α-mannosidase (velmanase alfa) in 10 patients with weekly therapy over 12 months. Borgwardt et al. showed promising results with improved motor and cognitive function and reduced oligosaccharide concentrations in the serum, urine and cerebrospinal fluid [12]. Ocular changes were not evaluated in this study. In our patients on long-term ERT, only those starting treatment after the age of 14 years developed progressive retinal degeneration. One patient starting treatment at the age of 7 years did not yet develop retinal or optic nerve degeneration. Theoretically, the efficacy of ERT might be better the younger the patients are when starting treatment. However, we cannot conclude yet that ERT might prevent ophthalmological changes in patients with α-mannosidosis even on long-term ERT.

In conclusion, ocular pathologies in α-mannosidosis do not confine to corneal or lenticular opacities. Our investigations revealed retinal and optic nerve degeneration as common eye pathologies in α-mannosidosis. This is in contrast to some of the earlier reports of ophthalmological findings in α-mannosidosis with no clinical significance to the patients. OCT provides early diagnosis of retinal degeneration by showing thinning of the outer retinal layers when conventional funduscopy or photography fails to detect it. Also optic nerve atrophy may be a new feature of α-mannosidosis. Future larger prospective studies with retinal imaging such as OCT are required to evaluate incidence of retinal degeneration in α-mannosidosis as it may be commonly seen when systematically examined with OCT. Furthermore it has to be investigated whether and when retinal degeneration progresses in α-mannosidosis to a potentially vision-threatening ocular disease and how therapeutic principles such as ERT may influence retinal degeneration.