Retinal and optic nerve degeneration in α-mannosidosis

Retinal and optic nerve degeneration in α-mannosidosis Background: α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described. Methods: We report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging. Results: Tapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen. Conclusion: Ocular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time. Keywords: α-mannosidosis, Retinal degeneration, Optic nerve atrophy, Ocular findings, OCT Background based on clinical severity: a severe infantile form (type I) α-mannosidosis is a rare, autosomal-recessive, lysosomal characterized by early death due to rapid progressive cen- storage disease arising from a deficiency in lysosomal tral nervous system involvement and a milder phenotype α-mannosidase caused by mutations in MAN2B1 located with a slower disease progression and survival into adult- on chromosome 19 with an estimated prevalence of 0.5– hood (type II) [1, 2]. Diagnosis of α-mannosidosis is made 1:500.000. Deficiency of α-mannosidase leads to accumu- by measuring acid α-mannosidase activity in leukocytes or lation of mannose-rich oligosaccharides in all tissues other nucleated cells and can be confirmed by genetic resulting in cell dysfunction. Clinical characteristics show testing. Elevated urinary secretion of mannose-rich oligo- different phenotypic variations including cognitive disabil- saccharides is suggestive of the disease, however not diag- ity with gradual impairment of speech and mental func- nostic [1]. Öckerman first described a Hurler-like tions, psychosis, motor function and hearing disturbances, appearance of a four-year-old boy in 1967. In a postmortal facial and skeletal abnormalities, and immune deficiency. examination, a large amount of oligosaccharides, espe- Two α-mannosidosis phenotypes have been described cially mannose-rich oligosaccharides, was found in his or- gans and tissues [3]. He therefore named the disorder * Correspondence: juliane.matlach@unimedizin-mainz.de “mannosidosis” [4]. As it is a deficiency in lysosomal Department of Ophthalmology, University Medical Center, Johannes α-mannosidase, oligosaccharides accumulate in different Gutenberg University Mainz, Mainz, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 2 of 9 tissues and organs. Since these early clinical descriptions of Table 1 Demographics and ocular findings of all patients mannosidosis, many research groups have contributed to n of patients 32 the characterization of the presenting phenotype, enzyme Sex, male/female 19 (59.4%)/13 (40.6%) and corresponding genes in several species including ocular Age, years pathologies in 20 α-mannosidosis patients [5–8]. Early re- 1st presentation 18.4 ± 11.8 (1–53) ports have described strabismus, opacities of the cornea Last presentation 20.8 ± 11.6 (3–53) and lens as typical ocular symptoms and pathologies in BCVA, decimal mannosidosis [5]. However, only recently, retinal abnormal- ities and optic nerve atrophy have been described in a few 1st presentation 0.56 ± 0.28 (0.04–1.00) case reports and confirmed by electrophysiology or optical Last presentation 0.60 ± 0.25 (0.10–1.00) coherence tomography (OCT) as fundus biomicroscopy ERT with velmanase alfa 7 (21.9%) only reveals subtle retinal changes [9, 10]. Currently, there Ocular pathologies are two treatment options for α-mannosidosis: stem cell Lens opacity 3 (9.4%) transplantation and enzyme replacement therapy (ERT). Corneal haze 2 (6.3%) Haematopoietic stem cell transplantation has been reported in less than 20 patients with different outcomes and a high Optic nerve atrophy, also partial 6 (18.8%) risk of morbidity and mortality [11]. The efficacy and safety Tapeto-retinal degeneration (by funduscopy) 3 (9.4%) of ERT with a recombinant human α-mannosidase (velma- Tapeto-retinal degeneration (by OCT) 6/8 nase alfa) has been studied in randomized clinical trials [12] Tapeto-retinal degeneration (by photo) 3/8 and let to approval by the European Medicines Agency Manifest strabismus 6 (18.8%) (EMA) in January 2018. Nystagmus 4 (12.5%) Here, we report ocular findings of 32 patients including a report of two siblings with confirmed α-mannosidosis Saccadic/hypometric eye movements 5 (15.6%) and especially concentrated on retinal degeneration which Data are absolute vales (%), mean ± standard deviation (min-max), as appropriate. we supported by posterior segment examination, fundus ocular pathologies that were noticed at all presentations photography and Spectral-Domain OCT (SD-OCT). b 8 retinal images could be obtained by OCT/fundus photography; of these, 6 showed retinal degeneration on OCT (thinning of the outer layers); in 1 woman, macular edema was seen due to tapeto-retinal degeneration. Abbreviations: n number of patients, BCVA best-corrected visual acuity, ERT Methods enzyme replacement therapy, OCT optical coherence tomography In total, 32 patients with α-mannosidosis were examined; of these 25 participated in a multicenter, multinational pro- All patients or their relatives were asked for ocular spective natural history study of α-mannosidosis (Trial-ID: history and medication, and underwent a standard rhLAMAN-01). Clinical evaluations included physical ophthalmic examination including best-corrected vis- examination, recording of medical history, measurement of ual acuity (BCVA) testing, slit-lamp biomicroscopy for endurance by six-minute walk test and three-minute stair anterior segment and indirect ophthalmoscopy for climb-test, lung function testing, hearing test, echocardiog- fundus examination, and assessment of strabismus, raphy and electrocardiography, and laboratory testing. These ocular motility and nystagmus. Measurement of the results were previously published by Beck et al. [13]. In this optic nerve head, peripapillary retinal nerve fiber layer report, general ophthalmic investigations such as vision, and macular region using SD-OCT (Spectralis OCT, anterior and posterior segment abnormalities were only Heidelberg Engineering GmbH, Heidelberg, Germany) briefly described. These 25 patients were initially examined was introduced later as part of our examinations and between 2007 and 2009 and followed-up over two to three was therefore only performed in eight of 32 patients. years. In addition to this, we examined seven more patients Due to individual patient’s abilities, not all of the with α-mannosidosis between 2008 and 2017. mentioned examinations could be performed. Some of In total, seven patients received ERT with velmanase theseprovedtobedifficult duetothe patients‘ men- alfa; of these, six (Man-1, Man-3, Man-4, Man-21, tal and physical disabilities, especially examinations Man-28, Man-31) began treatment during or before our which need patients’ cooperation (e.g. vision and mo- ophthalmic examinations; only Man-32 received his treat- tility testing, photographs, OCT). No visual acuity ment after examination (Tables 1 and 2). could be obtained from two patients, one with severe optic nerve atrophy and retinal degeneration. Ocular Ophthalmological assessment examinations of four patients were proved to be very Ophthalmic examinations were carried out at the difficult to impossible. Our analyses are mainly de- Department of Ophthalmology, University Medical Center scriptive and report single cases supported by fundus Mainz, Germany. photographs and retinal imaging by SD-OCT. Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 3 of 9 Table 2 Genotype and ocular characteristics of all patients Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility Man-1, male c.418C > T/ p.Arg140X/ yes, from the age 18 0.8/0.7 normal normal normal unremarkable OCT + thinning of c.418C > T p.Arg140X of 14 yrs. ongoing photo outer retinal layers Man-2, male c.1830 + 1G > A/ p.?/ p.Arg750Trp no 17 0.63/0.63 normal normal normal unremarkable no n.a. c.2248C > T Man-3, male c.1358C > T/ p.Ser453Phe/ yes, from the age 21 0.5/0.63 normal normal partial saccadic OCT + thinning of c.1358C > T p.Ser453Phe of 15 yrs. ongoing atrophy motility photo outer retinal layers Man-4, female c.1358C > T/ p.Ser453Phe/ yes, from the age 25 0.25/0.4 normal normal partial saccadic OCT + thinning of c.1358C > T p.Ser453Phe of 22 yrs. ongoing atrophy motility photo outer retina, macular edema Man-5, male c.164G > T/ p.Cys55Phe/ no 25 0.63/0.8 normal normal normal unremarkable no n.a. c.599A > T p.His200Leu Man-6, male c.164G > T/ p.Cys55Phe/ no 19 0.5/0.63 normal normal normal unremarkable no n.a. c.599A > T p.His200Leu Man-7, female c.2248C > T/ p.Arg750Trp/ no 26 0.32/0.5 cerulean normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp cataract Man-8, female c.1830 + 1G > C / p.VAL549_ no 34 0.32/0.32 normal normal normal down-beat nystagmus, no n.a. c.1830 + 1G > C Glu610del/ saccadic motility p.VAL549_ Glu610del Man-9, male c.2248C > T/ p.Arg750Trp/ no 29 n.a. normal tapeto-retinal, atrophy exotropia, photo n.a. c.2248C > T p.Arg750Trp one spicules down-beat nystagmus Man-10, male c.484_487dupGCCA/ p.Thr163Serfsx25/ no, but stem cell 3 0.5/0.25 normal normal normal unremarkable no n.a. c.484_487dupGCCA p.Thr163Serfsx25 transplantation at the age of 3 yrs Man-11, male c.338-348dup11/ p.Ile117profsX44/ no 3 binocular normal normal normal unremarkable no n.a. c.338-348dup11 p.Ile117profsX44 0.8 Man-12, male c.2921_2922delCA/ p.(Thr974ArgfsTer80/ no 14 binocular normal normal normal unremarkable no n.a. c.2921_2922delCA p.(Thr974ArgfsTer80 0.1 Man-13, female c.1830 + 1G > C/ p.VAL549_Glu610del/ no 19 1.0/0.63 normal normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp Man-14, male c.844C > T/ p.Pro282Ser/ no 16 0.2/0.2 normal tapeto-retinal normal unremarkable no n.a. c.844C > T p.Pro282Ser degeneration Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 4 of 9 Table 2 Genotype and ocular characteristics of all patients (Continued) Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility Man-15, female c.2248C > T/ p.Arg750Trp/ no 20 0.5/0.5 normal normal normal unremarkable no n.a. c.2426 T > C p.Leu809Pro Man-16, male c.2248C > T/ p.Arg750Trp/ no 15 0.8/0.63 corneal haze normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp Man-17, male c.2724G > A/ p.TRP908X no 5 0.5/0.5 normal normal normal unremarkable no n.a. c.2724G > A Man-18, male c.1351G > T/ p.Gly451Cys/ no 9 1.0/1.0 normal normal normal unremarkable no n.a. c.[1501 T > A; p.([Cys501Ser; 2849G > C] Arg950Pro]) Man-19, female c.2248C > T/ p.Arg750Trp/ no 33 0.63/0.63 normal myelinated partial unremarkable no n.a. c.2248C > T p.Arg750Trp nerve fibers atrophy Man-20, male c.283G > C/ p.Ala95Pro/ no 13 0.8/0.8 normal normal normal unremarkable no n.a. c.283G > C p.Ala95Pro Man-21, male c.2234C > G/ p.Thr745Arg/ yes, from the 29 1.0/0.9 normal normal normal hypometric OCT + thinning of c.2234C > G p.Thr745Arg age of 25 yrs. motility photo outer retinal ongoing layers Man-22, female c.788C > T/ p.Pro263Leu/ no 18 n.a. normal normal normal esotropia no n.a. c.2355G > A p.Arg757MetfsTer6 Man-23, male c.1816delA/ p.Thr606ProfsTer18/ no 42 0.9/0.5 normal normal normal esotropia, no n.a. c.1830 + 1G > C p. Val549_Glu610del nystagmus on lateral gaze Man-24, female c.1816delA/ p.Thr606ProfsTer18/ no 40 0.32/0.8 normal macular atrophy esotropia no n.a. c.1830 + 1G > C p. Val549_Glu610del changes Man-25, male c.1310-2A > G/ p.?/ p.Arg750Trp no 27 0.25/0.25 normal normal partial unremarkable no n.a. c.2248C > T atrophy Man-26, male c.283G > C/ p.Ala95Pro/ no 16 1.0/0.8 corneal haze normal normal unremarkable no n.a. c.283G > C p.Ala95Pro Man-27, female c.1351G > T/ p.Gly451Cys/ no 27 0.5/0.63 normal normal normal unremarkable no n.a. c.1830 + 1G > C p. Val549_Glu610del Man-28, female c.2248C > T/ p.Arg750Trp/ p.? yes, from the 14 1.0/0.8 normal normal normal unremarkable OCT + normal c.1046insC age of 7 yrs. photo ongoing Man-29, female c.263-2A > c/ p.?/p.Glu402Lys no 53 0.8/0.7 normal normal normal saccadic OCT + thinning of c.1204G > A motility photo outer retinal layers Man-30, female no 24 0.63/1.0 normal normal Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 5 of 9 Table 2 Genotype and ocular characteristics of all patients (Continued) Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility c.215A > T/ p.His72Leu/ anterior polar esotropia, OCT + thinning of c.2471G > A p.Gly824Glu cataract up-beat photo outer retinal nystagmus layers Man-31, female c.2248C > T/ p.Arg750Trp/ yes, from the 3 binocular normal normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp age of 3 yrs. 0.5 ongoing Man-32, male n.a. n.a. yes, from the 10 0.2/0.63 normal normal normal exotropia OCT + normal age of 10 yrs. photo ongoing a b c ERT: weekly treatment with velmanase alfa; age at the last ophthalmic examination; ophthalmic findings at the last presentation Abbreviations: BCVA best-corrected visual acuity, ERT enzyme replacement therapy, n.a. not available/applicable, OCT optical coherence tomography, yrs. years Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 6 of 9 Results A total of 32 patients with α-mannosidosis were in- cluded 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 im- Fig. 1 Tapeto-retinal degeneration in α-mannosidosis. Fundus paired smooth pursuit or hypometric saccades in five pa- photograph of a 33-year-old man with Retinitis Pigmentosa-like changes in both eyes. Peripheral pigment clumping (green arrows), tients (15.6%) at the first presentation or during partial optic nerve atrophy (blue arrow), chorioretinal atrophy around follow-up. the optic disc (black stars), thin retinal vessels (white crosses), and mottled patches in the macula (yellow circle) were seen Fundus abnormalities and OCT findings We have seen retinal changes on funduscopy in some patients during the course of our examinations over intraocular pressure reading of 15 mmHg in both eyes years; however, it was only until later that we performed and an unremarkable anterior segment without corneal SD-OCT and noticed early changes of the outer retinal haze or cataract. Fundus examination revealed a normal layers. We could bring back and examine four patients optic nerve head; the posterior pole was unremarkable from the natural history study again and found thinning with a normal foveal reflex before the start of ERT. of outer retinal layers outside the fovea on OCT in all At the age of 22, weekly treatment of velmanase alfa four patients. Of the seven additional patients that were was initiated. SD-OCT showed retinal thinning, espe- included after the natural history study, an OCT was ob- cially with loss of the outer retinal layers, atrophy of tained in four; of these two had retinal degeneration of theRPE outsidethefovea attheageof24. Within a the outer layers. year at the age of 25 she developed cystic macular edema Overall, optic nerve atrophy was seen in six patients seen on SD-OCT with a reduced vision of 0.25 (20/80); (18.8%); of these four with partial atrophy. Tapeto-retinal the posterior pole demonstrated a partial optic nerve atro- degeneration with bone spicule formations in the per- phy and mottled nummular yellow to white deposits at ipheral retina or macular changes were seen in three pa- the level of the RPE, most notable surrounding the optic tients (9.4%) on funduscopy (Fig. 1); of these, two with nerve head (Fig. 2). optic nerve atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on fundus- Case 2 copy. However, the other two patients with partial atro- Her brother was diagnosed with α-mannosidosis just phy only showed thinning of the outer retinal layers on after birth. Hearing impairment and motor development OCT that was not seen on funduscopy. delay were the first recognized symptoms. At the age of Table 2 shows the genotype and ocular characteristics 12 he presented with various abnormalities including of all patients in detail. coarse facial features, intellectual disability, ataxia, thora- columbar kyphosis, aortic valve insufficiency grade I, Report of two siblings and recurrent infections. His BCVA was 0.63 (20/32) in Case 1 both eyes with a normal pupillary reaction on his first Case 1 is a girl who was diagnosed at the age of two and examination at the age of 12. Before the start of ERT, an- a half as having α-mannosidosis due to motor develop- terior and posterior segment appeared unremarkable ment delay and thoracolumbar kyphosis. At the age of without corneal haze or cataract, optic nerve atrophy or 15 she presented with coarse facial features, severe hear- retinal degeneration. Weekly treatment of velmanase alfa ing impairment, intellectual disability, ataxia, mitral was started at the age of 15. During follow-up at the age valve insufficiency grade I, and recurrent infections. Her of 21, SD-OCT demonstrated early outer retinal thin- BCVA at the age of 15 was 0.63 (20/32) in both eyes ning without any evidence of yellow-white or pigmented without evidence of an afferent pupillary defect, an deposits, besides a more visible choroid around the optic Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 7 of 9 Fig. 2 Tapeto-retinal degeneration in α-mannosidosis in two siblings. Fundus photographs (a, b) of the sister revealed progression of retinal pigment epithelium (RPE) atrophy outside the macula with yellow-white deposits around the optic disc and chorioretinal atrophy (black stars, b), and partial optic nerve atrophy (blue arrow, b). Optical coherence tomography (OCT) showed perifoveal thinning of the outer retinal layers and RPE (red arrows, c) with normal retinal layers in the fovea (green bracket, c). A progression of the outer retina thinning was seen and a cystic macula edema has developed within a year’s time at the age of 25 (red arrows, d) nerve head and early partial optic nerve atrophy on fun- Bennet and co-workers reported on ocular pathologies in duscopy and fundus photography (Fig. 3). 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 Discussion was diagnosed with type II mannosidosis in late adulthood We report ocular abnormalities in a large patient popula- and maintained normal vision but deteriorated with pro- tion of 32 patients with α-mannosidosis. In this to date lar- gressive neurologic systems and horizontal nystagmus on gest case series investigating ocular manifestations of lateral gaze [6]. In areport byArbisseretal. threepatients α-mannosidosis patients we detected a high incidence of with α-mannosidosis showed similar lenticular opacities retinal degeneration and optic nerve atrophy. Obvious without any corneal haze. Ophthalmoscopic anomalies tapeto-retinal characteristics of the retina as detected by were noticed in two younger patients despite normal elec- funduscopy were rarely found; however early thinning of trophysiology. [5]. Histological studies of the eye in humans theouter retina seen on SD-OCT maysuggest aprogres- with α-mannosidosis are not available; however Jolly et al. sive nature of this retinal degeneration in α-mannosidosis. studied this in a bovine model and found vacuoles in differ- Optic nerve atrophy can be associated with retinal degener- ent cell types including corneal epithelium, Descemet’s ation but we have also seen it in some of our patients with- membrane, corneal endothelium, corneal fibroblasts, pig- out any retinal abnormalities. Also of importance is our mented cells, lens epithelium, lens fibers, pigment epithe- observation that four of seven patients treated with lium and also all cell types of the neuroretina. Histological velmanase alfa developed retinal degeneration despite ERT. examinations showed that the mannose-rich oligosaccha- Corneal and lenticular opacities as well as strabismus and rides were stored in vacuoles. They hypothesized that this motility disorders were less frequent in our cohort of may be the cause of lens and corneal opacities in humans α-mannosidosis patients and may be a nonspecific finding with α-mannosidosis [7]. Moreover, the retained storage as encountered in other storage diseases. material in the retina can lead to photoreceptor loss and Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 8 of 9 Fig. 3 Tapeto-retinal degeneration in α-mannosidosis in two siblings. Fundus photographs (a, b) of the brother showed early partial optic nerve atrophy (blue arrow, b) but without any yellow-white or pigmented deposits, besides a more visible choroid around the optic nerve head (black stars, b). Optical coherence tomography (OCT) showed a perifoveal thinning of the outer retinal layers and retinal pigment epithelium (RPE, red arrows, c, d) with normal retinal layers in the fovea (green bracket, c, d). However, outer retina thinning progressed over time (smaller green bracket, d) with a larger perifoveal area of outer retinal atrophy (red arrows, d) tapeto-retinal degeneration [10]. This may also be an ex- Interestingly, certain similar ocular abnormalities can planation for the progression of clinical symptoms includ- be found in other storage diseases. In mucopolyasac- ing retinal degeneration and optic nerve atrophy with age charidoses (MPS), glycosaminoglycans accumulate in the as we have seen in the two siblings during follow-up. In retina and induce retinal degeneration, pigmentary retin- contrast to previously published articles on ocular patholo- opathy with bony spicules, or depigmented chorioretino- gies in α-mannosidosis that mainly concentrated on opaci- pathy similar to our findings in α-mannosidosis [14–16]. ties of the cornea or lens, strabismus, nystagmus and other In a recent report by Seok et al. four patients with differ- motility disorders, Springer and co-workers described ent types of MPS showed retinal degeneration with peri- late-onset retinal dystrophy characterized by decreasing vis- foveal thinning of the outer retinal layers on SD-OCT ual acuity and diminished Ganzfeld electroretinograms in often despite normal fundus morphology [15]. This is two brothers with type II α-mannosidosis [9]. Both were in also in line with our findings that SD-OCT displays early their thirties when they were first examined. They had degeneration of the retina with no or subtle retina decreasing vision despite normal findings on fundus changes on funduscopy. examination. Electroretinography showed borderline Another interesting finding of our study is that ERT scotopic and photopic responses; however clinical examin- with velmanase alfa did not protect some of our patients ation was challenging due to the patients’ reduced mental receiving ERT during the observational period from de- capacity and inability to cooperate [9]. More recently, veloping retinal degeneration. A phase I-II study evalu- Courtney and Pennesi publisheda shortreportoftwocases ated the efficacy and safety of the recombinant human of retinal dystrophy in α-mannosidosis [10]. This case re- α-mannosidase (velmanase alfa) in 10 patients with port is the first to describe, in addition to corneal and len- weekly therapy over 12 months. Borgwardt et al. showed ticular opacity, chorioretinal atrophy with retinal thinning, promising results with improved motor and cognitive loss of the outer retina and RPE as well as granular areas of function and reduced oligosaccharide concentrations in hyper- and hypoautofluorescence in the macula and sur- the serum, urine and cerebrospinal fluid [12]. Ocular rounding the optic nerve using OCT, fundus autofluores- changes were not evaluated in this study. In our patients cence and fundus photography [10]. on long-term ERT, only those starting treatment after Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 9 of 9 the age of 14 years developed progressive retinal degener- Competing interests The authors declare that they have no competing interests. ation. One patient starting treatment at the age of 7 years did not yet develop retinal or optic nerve degeneration. Publisher’sNote Theoretically, the efficacy of ERT might be better the youn- Springer Nature remains neutral with regard to jurisdictional claims in ger the patients are when starting treatment. However, we published maps and institutional affiliations. cannot conclude yet that ERT might prevent ophthalmo- Author details logical changes in patients with α-mannosidosis even on Department of Ophthalmology, University Medical Center, Johannes long-term ERT. 2 Gutenberg University Mainz, Mainz, Germany. Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. Orbital Center, Ophthalmic Clinic, Bürgerhospital, Frankfurt, Conclusions Germany. In conclusion, ocular pathologies in α-mannosidosis do not confine to corneal or lenticular opacities. Our investi- Received: 23 March 2018 Accepted: 21 May 2018 gations revealed retinal and optic nerve degeneration as common eye pathologies in α-mannosidosis. This is in References contrast to some of the earlier reports of ophthalmological 1. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis. 2008;3:21. 2. Borgwardt L, Lund AM, Dali CI. Alpha-mannosidosis - a review of genetic, findings in α-mannosidosis with no clinical significance to clinical findings and options of treatment. Pediatr Endocrinol Rev. 2014; the patients. OCT provides early diagnosis of retinal de- 12(Suppl 1):185–91. generation by showing thinning of the outer retinal layers 3. Öckerman PA, Generalised Storage A. Disorder Resembling Hurler's Syndrome. Lancet. 1967;290(7509):239–41. when conventional funduscopy or photography fails to de- 4. Ockerman PA. Mannosidosis: isolation of oligosaccharide storage material tect it. Also optic nerve atrophy may be a new feature of from brain. J Pediatr. 1969;75(3):360–5. α-mannosidosis. Future larger prospective studies with 5. Arbisser AI, Murphree AL, Garcia CA, Howell RR. Ocular findings in mannosidosis. Am J Ophthalmol. 1976;82(3):465–71. retinal imaging such as OCT are required to evaluate inci- 6. Bennet JK, Dembure PP, Elsas LJ. Clinical and biochemical analysis of two families dence of retinal degeneration in α-mannosidosis as it may with type I and type II mannosidosis. Am J Med Genet. 1995;55(1):21–6. be commonly seen when systematically examined with 7. Jolly RD, Shimada A, Dalefield RR, Slack PM. Mannosidosis: ocular lesions in the bovine model. Curr Eye Res. 1987;6(9):1073–8. OCT. Furthermore it has to be investigated whether and 8. Wong LT, Vallance H, Savage A, Davidson AG, Applegarth D. Oral zinc therapy when retinal degeneration progresses in α-mannosidosis in the treatment of alpha-mannosidosis. Am J Med Genet. 1993;46(4):410–4. to a potentially vision-threatening ocular disease and how 9. Springer C, Gutschalk A, Meinck HM, Rohrschneider K. Late-onset retinal dystrophy in alpha-mannosidosis. Graefes Arch Clin Exp Ophthalmol. 2005; therapeutic principles such as ERT may influence retinal 243(12):1277–9. degeneration. 10. Courtney RJ, Pennesi ME. Retinal dystrophy in 2 brothers with alpha- Mannosidosis. Arch Ophthalmol. 2011;129(6):799–802. Abbreviations 11. Mynarek M, Tolar J, Albert MH, Escolar ML, Boelens JJ, Cowan MJ, Finnegan N, BCVA: Best-corrected visual acuity; EMA: European Medicines Agency; Glomstein A, Jacobsohn DA, Kuhl JS, et al. Allogeneic hematopoietic SCT for ERT: Enzyme replacement therapy; MPS: Mucopolyasaccharidoses; alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. 2012; OCT: Optical coherence tomography; RPE: Retinal pigment epithelium; SD- 47(3):352–9. OCT: Spectral-Domain optical coherence tomography 12. Borgwardt L, Dali CI, Fogh J, Mansson JE, Olsen KJ, Beck HC, Nielsen KG, Nielsen LH, Olsen SO, Riise Stensland HM, et al. Enzyme replacement Acknowledgements therapy for alpha-mannosidosis: 12 months follow-up of a single Centre, Lilian Sophie Norsch aided in compiling some of the clinical data. randomised multiple dose study. J Inherit Metab Dis. 2013;36(6):1015–24. 13. Beck M, Olsen KJ, Wraith JE, Zeman J, Michalski JC, Saftig P, Fogh J, Malm D. Availability of data and materials Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare The datasets used and/or analyzed during the current study are available Dis. 2013;8:88. from the corresponding author on reasonable request. 14. Liang F, Audo I, Sahel JA, Paques M. Retinal degeneration in mucopolysaccharidose type II. Graefes Arch Clin Exp Ophthalmol. 2013; Authors’ contributions 251(7):1871–2. JM performed the ophthalmological examinations of some of the patients 15. Seok S, Lyu IJ, Park KA, Oh SY. Spectral domain optical coherence including the imaging, analyzed and interpreted the data, was the major tomography imaging of mucopolysaccharidoses I, II, and VI a. Graefes Arch contributor in writing the manuscript and critically reviewed the comments by Clin Exp Ophthalmol. 2015;253(12):2111–9. the co-authors. TZ performed the majority of the ophthalmological examinations 16. Huang CT, Chu SY, Lee YC. Optical coherence tomography of Chorioretinopathy of the patients, designed and wrote the ethical proposal. YA performed all clinical caused by Mucopolysaccharidoses. Ophthalmology. 2015;122(7):1535–7. evaluations and was the major contributor to designing the study. LA-K and JBH interpreted the data and critically reviewed comments and questions from all authors. SP had major contributions to the ophthalmic tests being carried out, interpretation of the results and literature review. All authors contributed to the idea and concept of the study, participated in drafting the manuscript, read and approved the final version of the manuscript. Ethics approval and consent to participate The natural history study of α-mannosidosis (study ID: rhLAMAN-01) and the study of ocular characteristics in α-mannosidosis patients (study ID: 9976) were approved by the local ethics committee of the Landesärztekammer Rheinland-Pfalz in Mainz, Germany. The research followed the tenets of the Declaration of Helsinki. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Orphanet Journal of Rare Diseases Springer Journals
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Abstract

Background: α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described. Methods: We report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging. Results: Tapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen. Conclusion: Ocular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time. Keywords: α-mannosidosis, Retinal degeneration, Optic nerve atrophy, Ocular findings, OCT Background based on clinical severity: a severe infantile form (type I) α-mannosidosis is a rare, autosomal-recessive, lysosomal characterized by early death due to rapid progressive cen- storage disease arising from a deficiency in lysosomal tral nervous system involvement and a milder phenotype α-mannosidase caused by mutations in MAN2B1 located with a slower disease progression and survival into adult- on chromosome 19 with an estimated prevalence of 0.5– hood (type II) [1, 2]. Diagnosis of α-mannosidosis is made 1:500.000. Deficiency of α-mannosidase leads to accumu- by measuring acid α-mannosidase activity in leukocytes or lation of mannose-rich oligosaccharides in all tissues other nucleated cells and can be confirmed by genetic resulting in cell dysfunction. Clinical characteristics show testing. Elevated urinary secretion of mannose-rich oligo- different phenotypic variations including cognitive disabil- saccharides is suggestive of the disease, however not diag- ity with gradual impairment of speech and mental func- nostic [1]. Öckerman first described a Hurler-like tions, psychosis, motor function and hearing disturbances, appearance of a four-year-old boy in 1967. In a postmortal facial and skeletal abnormalities, and immune deficiency. examination, a large amount of oligosaccharides, espe- Two α-mannosidosis phenotypes have been described cially mannose-rich oligosaccharides, was found in his or- gans and tissues [3]. He therefore named the disorder * Correspondence: juliane.matlach@unimedizin-mainz.de “mannosidosis” [4]. As it is a deficiency in lysosomal Department of Ophthalmology, University Medical Center, Johannes α-mannosidase, oligosaccharides accumulate in different Gutenberg University Mainz, Mainz, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 2 of 9 tissues and organs. Since these early clinical descriptions of Table 1 Demographics and ocular findings of all patients mannosidosis, many research groups have contributed to n of patients 32 the characterization of the presenting phenotype, enzyme Sex, male/female 19 (59.4%)/13 (40.6%) and corresponding genes in several species including ocular Age, years pathologies in 20 α-mannosidosis patients [5–8]. Early re- 1st presentation 18.4 ± 11.8 (1–53) ports have described strabismus, opacities of the cornea Last presentation 20.8 ± 11.6 (3–53) and lens as typical ocular symptoms and pathologies in BCVA, decimal mannosidosis [5]. However, only recently, retinal abnormal- ities and optic nerve atrophy have been described in a few 1st presentation 0.56 ± 0.28 (0.04–1.00) case reports and confirmed by electrophysiology or optical Last presentation 0.60 ± 0.25 (0.10–1.00) coherence tomography (OCT) as fundus biomicroscopy ERT with velmanase alfa 7 (21.9%) only reveals subtle retinal changes [9, 10]. Currently, there Ocular pathologies are two treatment options for α-mannosidosis: stem cell Lens opacity 3 (9.4%) transplantation and enzyme replacement therapy (ERT). Corneal haze 2 (6.3%) Haematopoietic stem cell transplantation has been reported in less than 20 patients with different outcomes and a high Optic nerve atrophy, also partial 6 (18.8%) risk of morbidity and mortality [11]. The efficacy and safety Tapeto-retinal degeneration (by funduscopy) 3 (9.4%) of ERT with a recombinant human α-mannosidase (velma- Tapeto-retinal degeneration (by OCT) 6/8 nase alfa) has been studied in randomized clinical trials [12] Tapeto-retinal degeneration (by photo) 3/8 and let to approval by the European Medicines Agency Manifest strabismus 6 (18.8%) (EMA) in January 2018. Nystagmus 4 (12.5%) Here, we report ocular findings of 32 patients including a report of two siblings with confirmed α-mannosidosis Saccadic/hypometric eye movements 5 (15.6%) and especially concentrated on retinal degeneration which Data are absolute vales (%), mean ± standard deviation (min-max), as appropriate. we supported by posterior segment examination, fundus ocular pathologies that were noticed at all presentations photography and Spectral-Domain OCT (SD-OCT). b 8 retinal images could be obtained by OCT/fundus photography; of these, 6 showed retinal degeneration on OCT (thinning of the outer layers); in 1 woman, macular edema was seen due to tapeto-retinal degeneration. Abbreviations: n number of patients, BCVA best-corrected visual acuity, ERT Methods enzyme replacement therapy, OCT optical coherence tomography In total, 32 patients with α-mannosidosis were examined; of these 25 participated in a multicenter, multinational pro- All patients or their relatives were asked for ocular spective natural history study of α-mannosidosis (Trial-ID: history and medication, and underwent a standard rhLAMAN-01). Clinical evaluations included physical ophthalmic examination including best-corrected vis- examination, recording of medical history, measurement of ual acuity (BCVA) testing, slit-lamp biomicroscopy for endurance by six-minute walk test and three-minute stair anterior segment and indirect ophthalmoscopy for climb-test, lung function testing, hearing test, echocardiog- fundus examination, and assessment of strabismus, raphy and electrocardiography, and laboratory testing. These ocular motility and nystagmus. Measurement of the results were previously published by Beck et al. [13]. In this optic nerve head, peripapillary retinal nerve fiber layer report, general ophthalmic investigations such as vision, and macular region using SD-OCT (Spectralis OCT, anterior and posterior segment abnormalities were only Heidelberg Engineering GmbH, Heidelberg, Germany) briefly described. These 25 patients were initially examined was introduced later as part of our examinations and between 2007 and 2009 and followed-up over two to three was therefore only performed in eight of 32 patients. years. In addition to this, we examined seven more patients Due to individual patient’s abilities, not all of the with α-mannosidosis between 2008 and 2017. mentioned examinations could be performed. Some of In total, seven patients received ERT with velmanase theseprovedtobedifficult duetothe patients‘ men- alfa; of these, six (Man-1, Man-3, Man-4, Man-21, tal and physical disabilities, especially examinations Man-28, Man-31) began treatment during or before our which need patients’ cooperation (e.g. vision and mo- ophthalmic examinations; only Man-32 received his treat- tility testing, photographs, OCT). No visual acuity ment after examination (Tables 1 and 2). could be obtained from two patients, one with severe optic nerve atrophy and retinal degeneration. Ocular Ophthalmological assessment examinations of four patients were proved to be very Ophthalmic examinations were carried out at the difficult to impossible. Our analyses are mainly de- Department of Ophthalmology, University Medical Center scriptive and report single cases supported by fundus Mainz, Germany. photographs and retinal imaging by SD-OCT. Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 3 of 9 Table 2 Genotype and ocular characteristics of all patients Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility Man-1, male c.418C > T/ p.Arg140X/ yes, from the age 18 0.8/0.7 normal normal normal unremarkable OCT + thinning of c.418C > T p.Arg140X of 14 yrs. ongoing photo outer retinal layers Man-2, male c.1830 + 1G > A/ p.?/ p.Arg750Trp no 17 0.63/0.63 normal normal normal unremarkable no n.a. c.2248C > T Man-3, male c.1358C > T/ p.Ser453Phe/ yes, from the age 21 0.5/0.63 normal normal partial saccadic OCT + thinning of c.1358C > T p.Ser453Phe of 15 yrs. ongoing atrophy motility photo outer retinal layers Man-4, female c.1358C > T/ p.Ser453Phe/ yes, from the age 25 0.25/0.4 normal normal partial saccadic OCT + thinning of c.1358C > T p.Ser453Phe of 22 yrs. ongoing atrophy motility photo outer retina, macular edema Man-5, male c.164G > T/ p.Cys55Phe/ no 25 0.63/0.8 normal normal normal unremarkable no n.a. c.599A > T p.His200Leu Man-6, male c.164G > T/ p.Cys55Phe/ no 19 0.5/0.63 normal normal normal unremarkable no n.a. c.599A > T p.His200Leu Man-7, female c.2248C > T/ p.Arg750Trp/ no 26 0.32/0.5 cerulean normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp cataract Man-8, female c.1830 + 1G > C / p.VAL549_ no 34 0.32/0.32 normal normal normal down-beat nystagmus, no n.a. c.1830 + 1G > C Glu610del/ saccadic motility p.VAL549_ Glu610del Man-9, male c.2248C > T/ p.Arg750Trp/ no 29 n.a. normal tapeto-retinal, atrophy exotropia, photo n.a. c.2248C > T p.Arg750Trp one spicules down-beat nystagmus Man-10, male c.484_487dupGCCA/ p.Thr163Serfsx25/ no, but stem cell 3 0.5/0.25 normal normal normal unremarkable no n.a. c.484_487dupGCCA p.Thr163Serfsx25 transplantation at the age of 3 yrs Man-11, male c.338-348dup11/ p.Ile117profsX44/ no 3 binocular normal normal normal unremarkable no n.a. c.338-348dup11 p.Ile117profsX44 0.8 Man-12, male c.2921_2922delCA/ p.(Thr974ArgfsTer80/ no 14 binocular normal normal normal unremarkable no n.a. c.2921_2922delCA p.(Thr974ArgfsTer80 0.1 Man-13, female c.1830 + 1G > C/ p.VAL549_Glu610del/ no 19 1.0/0.63 normal normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp Man-14, male c.844C > T/ p.Pro282Ser/ no 16 0.2/0.2 normal tapeto-retinal normal unremarkable no n.a. c.844C > T p.Pro282Ser degeneration Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 4 of 9 Table 2 Genotype and ocular characteristics of all patients (Continued) Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility Man-15, female c.2248C > T/ p.Arg750Trp/ no 20 0.5/0.5 normal normal normal unremarkable no n.a. c.2426 T > C p.Leu809Pro Man-16, male c.2248C > T/ p.Arg750Trp/ no 15 0.8/0.63 corneal haze normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp Man-17, male c.2724G > A/ p.TRP908X no 5 0.5/0.5 normal normal normal unremarkable no n.a. c.2724G > A Man-18, male c.1351G > T/ p.Gly451Cys/ no 9 1.0/1.0 normal normal normal unremarkable no n.a. c.[1501 T > A; p.([Cys501Ser; 2849G > C] Arg950Pro]) Man-19, female c.2248C > T/ p.Arg750Trp/ no 33 0.63/0.63 normal myelinated partial unremarkable no n.a. c.2248C > T p.Arg750Trp nerve fibers atrophy Man-20, male c.283G > C/ p.Ala95Pro/ no 13 0.8/0.8 normal normal normal unremarkable no n.a. c.283G > C p.Ala95Pro Man-21, male c.2234C > G/ p.Thr745Arg/ yes, from the 29 1.0/0.9 normal normal normal hypometric OCT + thinning of c.2234C > G p.Thr745Arg age of 25 yrs. motility photo outer retinal ongoing layers Man-22, female c.788C > T/ p.Pro263Leu/ no 18 n.a. normal normal normal esotropia no n.a. c.2355G > A p.Arg757MetfsTer6 Man-23, male c.1816delA/ p.Thr606ProfsTer18/ no 42 0.9/0.5 normal normal normal esotropia, no n.a. c.1830 + 1G > C p. Val549_Glu610del nystagmus on lateral gaze Man-24, female c.1816delA/ p.Thr606ProfsTer18/ no 40 0.32/0.8 normal macular atrophy esotropia no n.a. c.1830 + 1G > C p. Val549_Glu610del changes Man-25, male c.1310-2A > G/ p.?/ p.Arg750Trp no 27 0.25/0.25 normal normal partial unremarkable no n.a. c.2248C > T atrophy Man-26, male c.283G > C/ p.Ala95Pro/ no 16 1.0/0.8 corneal haze normal normal unremarkable no n.a. c.283G > C p.Ala95Pro Man-27, female c.1351G > T/ p.Gly451Cys/ no 27 0.5/0.63 normal normal normal unremarkable no n.a. c.1830 + 1G > C p. Val549_Glu610del Man-28, female c.2248C > T/ p.Arg750Trp/ p.? yes, from the 14 1.0/0.8 normal normal normal unremarkable OCT + normal c.1046insC age of 7 yrs. photo ongoing Man-29, female c.263-2A > c/ p.?/p.Glu402Lys no 53 0.8/0.7 normal normal normal saccadic OCT + thinning of c.1204G > A motility photo outer retinal layers Man-30, female no 24 0.63/1.0 normal normal Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 5 of 9 Table 2 Genotype and ocular characteristics of all patients (Continued) Ophthalmic examination a b pat.no., gender label cDNA label protein ERT age BCVA anterior posterior optic strabismus/ imaging macular OCT (allele 1/ allele 2) (allele 1/ allele 2) [yrs] right/left segment segment nerve nystagmus/ motility c.215A > T/ p.His72Leu/ anterior polar esotropia, OCT + thinning of c.2471G > A p.Gly824Glu cataract up-beat photo outer retinal nystagmus layers Man-31, female c.2248C > T/ p.Arg750Trp/ yes, from the 3 binocular normal normal normal unremarkable no n.a. c.2248C > T p.Arg750Trp age of 3 yrs. 0.5 ongoing Man-32, male n.a. n.a. yes, from the 10 0.2/0.63 normal normal normal exotropia OCT + normal age of 10 yrs. photo ongoing a b c ERT: weekly treatment with velmanase alfa; age at the last ophthalmic examination; ophthalmic findings at the last presentation Abbreviations: BCVA best-corrected visual acuity, ERT enzyme replacement therapy, n.a. not available/applicable, OCT optical coherence tomography, yrs. years Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 6 of 9 Results A total of 32 patients with α-mannosidosis were in- cluded 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 im- Fig. 1 Tapeto-retinal degeneration in α-mannosidosis. Fundus paired smooth pursuit or hypometric saccades in five pa- photograph of a 33-year-old man with Retinitis Pigmentosa-like changes in both eyes. Peripheral pigment clumping (green arrows), tients (15.6%) at the first presentation or during partial optic nerve atrophy (blue arrow), chorioretinal atrophy around follow-up. the optic disc (black stars), thin retinal vessels (white crosses), and mottled patches in the macula (yellow circle) were seen Fundus abnormalities and OCT findings We have seen retinal changes on funduscopy in some patients during the course of our examinations over intraocular pressure reading of 15 mmHg in both eyes years; however, it was only until later that we performed and an unremarkable anterior segment without corneal SD-OCT and noticed early changes of the outer retinal haze or cataract. Fundus examination revealed a normal layers. We could bring back and examine four patients optic nerve head; the posterior pole was unremarkable from the natural history study again and found thinning with a normal foveal reflex before the start of ERT. of outer retinal layers outside the fovea on OCT in all At the age of 22, weekly treatment of velmanase alfa four patients. Of the seven additional patients that were was initiated. SD-OCT showed retinal thinning, espe- included after the natural history study, an OCT was ob- cially with loss of the outer retinal layers, atrophy of tained in four; of these two had retinal degeneration of theRPE outsidethefovea attheageof24. Within a the outer layers. year at the age of 25 she developed cystic macular edema Overall, optic nerve atrophy was seen in six patients seen on SD-OCT with a reduced vision of 0.25 (20/80); (18.8%); of these four with partial atrophy. Tapeto-retinal the posterior pole demonstrated a partial optic nerve atro- degeneration with bone spicule formations in the per- phy and mottled nummular yellow to white deposits at ipheral retina or macular changes were seen in three pa- the level of the RPE, most notable surrounding the optic tients (9.4%) on funduscopy (Fig. 1); of these, two with nerve head (Fig. 2). optic nerve atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on fundus- Case 2 copy. However, the other two patients with partial atro- Her brother was diagnosed with α-mannosidosis just phy only showed thinning of the outer retinal layers on after birth. Hearing impairment and motor development OCT that was not seen on funduscopy. delay were the first recognized symptoms. At the age of Table 2 shows the genotype and ocular characteristics 12 he presented with various abnormalities including of all patients in detail. coarse facial features, intellectual disability, ataxia, thora- columbar kyphosis, aortic valve insufficiency grade I, Report of two siblings and recurrent infections. His BCVA was 0.63 (20/32) in Case 1 both eyes with a normal pupillary reaction on his first Case 1 is a girl who was diagnosed at the age of two and examination at the age of 12. Before the start of ERT, an- a half as having α-mannosidosis due to motor develop- terior and posterior segment appeared unremarkable ment delay and thoracolumbar kyphosis. At the age of without corneal haze or cataract, optic nerve atrophy or 15 she presented with coarse facial features, severe hear- retinal degeneration. Weekly treatment of velmanase alfa ing impairment, intellectual disability, ataxia, mitral was started at the age of 15. During follow-up at the age valve insufficiency grade I, and recurrent infections. Her of 21, SD-OCT demonstrated early outer retinal thin- BCVA at the age of 15 was 0.63 (20/32) in both eyes ning without any evidence of yellow-white or pigmented without evidence of an afferent pupillary defect, an deposits, besides a more visible choroid around the optic Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 7 of 9 Fig. 2 Tapeto-retinal degeneration in α-mannosidosis in two siblings. Fundus photographs (a, b) of the sister revealed progression of retinal pigment epithelium (RPE) atrophy outside the macula with yellow-white deposits around the optic disc and chorioretinal atrophy (black stars, b), and partial optic nerve atrophy (blue arrow, b). Optical coherence tomography (OCT) showed perifoveal thinning of the outer retinal layers and RPE (red arrows, c) with normal retinal layers in the fovea (green bracket, c). A progression of the outer retina thinning was seen and a cystic macula edema has developed within a year’s time at the age of 25 (red arrows, d) nerve head and early partial optic nerve atrophy on fun- Bennet and co-workers reported on ocular pathologies in duscopy and fundus photography (Fig. 3). 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 Discussion was diagnosed with type II mannosidosis in late adulthood We report ocular abnormalities in a large patient popula- and maintained normal vision but deteriorated with pro- tion of 32 patients with α-mannosidosis. In this to date lar- gressive neurologic systems and horizontal nystagmus on gest case series investigating ocular manifestations of lateral gaze [6]. In areport byArbisseretal. threepatients α-mannosidosis patients we detected a high incidence of with α-mannosidosis showed similar lenticular opacities retinal degeneration and optic nerve atrophy. Obvious without any corneal haze. Ophthalmoscopic anomalies tapeto-retinal characteristics of the retina as detected by were noticed in two younger patients despite normal elec- funduscopy were rarely found; however early thinning of trophysiology. [5]. Histological studies of the eye in humans theouter retina seen on SD-OCT maysuggest aprogres- with α-mannosidosis are not available; however Jolly et al. sive nature of this retinal degeneration in α-mannosidosis. studied this in a bovine model and found vacuoles in differ- Optic nerve atrophy can be associated with retinal degener- ent cell types including corneal epithelium, Descemet’s ation but we have also seen it in some of our patients with- membrane, corneal endothelium, corneal fibroblasts, pig- out any retinal abnormalities. Also of importance is our mented cells, lens epithelium, lens fibers, pigment epithe- observation that four of seven patients treated with lium and also all cell types of the neuroretina. Histological velmanase alfa developed retinal degeneration despite ERT. examinations showed that the mannose-rich oligosaccha- Corneal and lenticular opacities as well as strabismus and rides were stored in vacuoles. They hypothesized that this motility disorders were less frequent in our cohort of may be the cause of lens and corneal opacities in humans α-mannosidosis patients and may be a nonspecific finding with α-mannosidosis [7]. Moreover, the retained storage as encountered in other storage diseases. material in the retina can lead to photoreceptor loss and Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 8 of 9 Fig. 3 Tapeto-retinal degeneration in α-mannosidosis in two siblings. Fundus photographs (a, b) of the brother showed early partial optic nerve atrophy (blue arrow, b) but without any yellow-white or pigmented deposits, besides a more visible choroid around the optic nerve head (black stars, b). Optical coherence tomography (OCT) showed a perifoveal thinning of the outer retinal layers and retinal pigment epithelium (RPE, red arrows, c, d) with normal retinal layers in the fovea (green bracket, c, d). However, outer retina thinning progressed over time (smaller green bracket, d) with a larger perifoveal area of outer retinal atrophy (red arrows, d) tapeto-retinal degeneration [10]. This may also be an ex- Interestingly, certain similar ocular abnormalities can planation for the progression of clinical symptoms includ- be found in other storage diseases. In mucopolyasac- ing retinal degeneration and optic nerve atrophy with age charidoses (MPS), glycosaminoglycans accumulate in the as we have seen in the two siblings during follow-up. In retina and induce retinal degeneration, pigmentary retin- contrast to previously published articles on ocular patholo- opathy with bony spicules, or depigmented chorioretino- gies in α-mannosidosis that mainly concentrated on opaci- pathy similar to our findings in α-mannosidosis [14–16]. ties of the cornea or lens, strabismus, nystagmus and other In a recent report by Seok et al. four patients with differ- motility disorders, Springer and co-workers described ent types of MPS showed retinal degeneration with peri- late-onset retinal dystrophy characterized by decreasing vis- foveal thinning of the outer retinal layers on SD-OCT ual acuity and diminished Ganzfeld electroretinograms in often despite normal fundus morphology [15]. This is two brothers with type II α-mannosidosis [9]. Both were in also in line with our findings that SD-OCT displays early their thirties when they were first examined. They had degeneration of the retina with no or subtle retina decreasing vision despite normal findings on fundus changes on funduscopy. examination. Electroretinography showed borderline Another interesting finding of our study is that ERT scotopic and photopic responses; however clinical examin- with velmanase alfa did not protect some of our patients ation was challenging due to the patients’ reduced mental receiving ERT during the observational period from de- capacity and inability to cooperate [9]. More recently, veloping retinal degeneration. A phase I-II study evalu- Courtney and Pennesi publisheda shortreportoftwocases ated the efficacy and safety of the recombinant human of retinal dystrophy in α-mannosidosis [10]. This case re- α-mannosidase (velmanase alfa) in 10 patients with port is the first to describe, in addition to corneal and len- weekly therapy over 12 months. Borgwardt et al. showed ticular opacity, chorioretinal atrophy with retinal thinning, promising results with improved motor and cognitive loss of the outer retina and RPE as well as granular areas of function and reduced oligosaccharide concentrations in hyper- and hypoautofluorescence in the macula and sur- the serum, urine and cerebrospinal fluid [12]. Ocular rounding the optic nerve using OCT, fundus autofluores- changes were not evaluated in this study. In our patients cence and fundus photography [10]. on long-term ERT, only those starting treatment after Matlach et al. Orphanet Journal of Rare Diseases (2018) 13:88 Page 9 of 9 the age of 14 years developed progressive retinal degener- Competing interests The authors declare that they have no competing interests. ation. One patient starting treatment at the age of 7 years did not yet develop retinal or optic nerve degeneration. Publisher’sNote Theoretically, the efficacy of ERT might be better the youn- Springer Nature remains neutral with regard to jurisdictional claims in ger the patients are when starting treatment. However, we published maps and institutional affiliations. cannot conclude yet that ERT might prevent ophthalmo- Author details logical changes in patients with α-mannosidosis even on Department of Ophthalmology, University Medical Center, Johannes long-term ERT. 2 Gutenberg University Mainz, Mainz, Germany. Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. Orbital Center, Ophthalmic Clinic, Bürgerhospital, Frankfurt, Conclusions Germany. In conclusion, ocular pathologies in α-mannosidosis do not confine to corneal or lenticular opacities. Our investi- Received: 23 March 2018 Accepted: 21 May 2018 gations revealed retinal and optic nerve degeneration as common eye pathologies in α-mannosidosis. This is in References contrast to some of the earlier reports of ophthalmological 1. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis. 2008;3:21. 2. Borgwardt L, Lund AM, Dali CI. Alpha-mannosidosis - a review of genetic, findings in α-mannosidosis with no clinical significance to clinical findings and options of treatment. Pediatr Endocrinol Rev. 2014; the patients. OCT provides early diagnosis of retinal de- 12(Suppl 1):185–91. generation by showing thinning of the outer retinal layers 3. Öckerman PA, Generalised Storage A. Disorder Resembling Hurler's Syndrome. Lancet. 1967;290(7509):239–41. when conventional funduscopy or photography fails to de- 4. Ockerman PA. Mannosidosis: isolation of oligosaccharide storage material tect it. Also optic nerve atrophy may be a new feature of from brain. J Pediatr. 1969;75(3):360–5. α-mannosidosis. Future larger prospective studies with 5. Arbisser AI, Murphree AL, Garcia CA, Howell RR. Ocular findings in mannosidosis. Am J Ophthalmol. 1976;82(3):465–71. retinal imaging such as OCT are required to evaluate inci- 6. Bennet JK, Dembure PP, Elsas LJ. Clinical and biochemical analysis of two families dence of retinal degeneration in α-mannosidosis as it may with type I and type II mannosidosis. Am J Med Genet. 1995;55(1):21–6. be commonly seen when systematically examined with 7. Jolly RD, Shimada A, Dalefield RR, Slack PM. Mannosidosis: ocular lesions in the bovine model. Curr Eye Res. 1987;6(9):1073–8. OCT. Furthermore it has to be investigated whether and 8. Wong LT, Vallance H, Savage A, Davidson AG, Applegarth D. Oral zinc therapy when retinal degeneration progresses in α-mannosidosis in the treatment of alpha-mannosidosis. Am J Med Genet. 1993;46(4):410–4. to a potentially vision-threatening ocular disease and how 9. Springer C, Gutschalk A, Meinck HM, Rohrschneider K. Late-onset retinal dystrophy in alpha-mannosidosis. Graefes Arch Clin Exp Ophthalmol. 2005; therapeutic principles such as ERT may influence retinal 243(12):1277–9. degeneration. 10. Courtney RJ, Pennesi ME. Retinal dystrophy in 2 brothers with alpha- Mannosidosis. Arch Ophthalmol. 2011;129(6):799–802. Abbreviations 11. Mynarek M, Tolar J, Albert MH, Escolar ML, Boelens JJ, Cowan MJ, Finnegan N, BCVA: Best-corrected visual acuity; EMA: European Medicines Agency; Glomstein A, Jacobsohn DA, Kuhl JS, et al. Allogeneic hematopoietic SCT for ERT: Enzyme replacement therapy; MPS: Mucopolyasaccharidoses; alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. 2012; OCT: Optical coherence tomography; RPE: Retinal pigment epithelium; SD- 47(3):352–9. OCT: Spectral-Domain optical coherence tomography 12. Borgwardt L, Dali CI, Fogh J, Mansson JE, Olsen KJ, Beck HC, Nielsen KG, Nielsen LH, Olsen SO, Riise Stensland HM, et al. Enzyme replacement Acknowledgements therapy for alpha-mannosidosis: 12 months follow-up of a single Centre, Lilian Sophie Norsch aided in compiling some of the clinical data. randomised multiple dose study. J Inherit Metab Dis. 2013;36(6):1015–24. 13. Beck M, Olsen KJ, Wraith JE, Zeman J, Michalski JC, Saftig P, Fogh J, Malm D. Availability of data and materials Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare The datasets used and/or analyzed during the current study are available Dis. 2013;8:88. from the corresponding author on reasonable request. 14. Liang F, Audo I, Sahel JA, Paques M. Retinal degeneration in mucopolysaccharidose type II. Graefes Arch Clin Exp Ophthalmol. 2013; Authors’ contributions 251(7):1871–2. JM performed the ophthalmological examinations of some of the patients 15. Seok S, Lyu IJ, Park KA, Oh SY. Spectral domain optical coherence including the imaging, analyzed and interpreted the data, was the major tomography imaging of mucopolysaccharidoses I, II, and VI a. Graefes Arch contributor in writing the manuscript and critically reviewed the comments by Clin Exp Ophthalmol. 2015;253(12):2111–9. the co-authors. TZ performed the majority of the ophthalmological examinations 16. Huang CT, Chu SY, Lee YC. Optical coherence tomography of Chorioretinopathy of the patients, designed and wrote the ethical proposal. YA performed all clinical caused by Mucopolysaccharidoses. Ophthalmology. 2015;122(7):1535–7. evaluations and was the major contributor to designing the study. LA-K and JBH interpreted the data and critically reviewed comments and questions from all authors. SP had major contributions to the ophthalmic tests being carried out, interpretation of the results and literature review. All authors contributed to the idea and concept of the study, participated in drafting the manuscript, read and approved the final version of the manuscript. Ethics approval and consent to participate The natural history study of α-mannosidosis (study ID: rhLAMAN-01) and the study of ocular characteristics in α-mannosidosis patients (study ID: 9976) were approved by the local ethics committee of the Landesärztekammer Rheinland-Pfalz in Mainz, Germany. The research followed the tenets of the Declaration of Helsinki.

Journal

Orphanet Journal of Rare DiseasesSpringer Journals

Published: Jun 1, 2018

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