OPHTHALMOLOGICAL FINDINGS IN A PATIENT WITH MUCOLIPIDOSIS III (PSEUDO- HURLER POLYDYSTROPHY). A CASE REPORT.

POURJAVAN S.*, FRYNS J.P.**, VAN HOVE J.L.K. ***, POORTHUIS B.J.H.M. ****, CASTEELS I.*

SUMMARY: stigmatisme. We stellen een patiëntje voor met de bovenbenoemde oftalmologische afwijkingen. Mucolipidosis III (Pseudo- Hurler Polydystrophy) is a rare autosomal recessively inherited Hurler-like dis- KEY-WORDS: ease. The ophthalmological findings in these pa- tients include a triad of mild retinopathy, corneal Pseudo- Hurler polydystrophy, corneal clouding and hyperopic astigmatism. We present a clouding, retinopathy. patient with these ophthalmological characteristics. MOTS-CLÉS: RÉSUMÉ: Pseudo- Hurler polydystrophie, opacités de la La Mucolipidose III (Pseudo- Hurler Polydystrophie) cornée, rétinopathie. est une maladie héréditaire autosomale récessive très rare. Les caractéristiques ophtalmologiques de cet- te maladie consistent en la triade de rétinopathie lé- gère, opacités de la cornée et astigmatisme hypero- pique. Une patiente avec des symptômes ophtalmo- logiques typiques est présentée. SAMENVATTING: Mucolipidosis III ( Pseudo- Hurler Polydystrophy) is een zeldzame autosomaal recessief erfelijke aandoe- ning. De oftalmologische bevindingen bij deze pa- tiënten omvatten een typische triade van milde reti- nopathie, corneale opaciteiten en hypermetroop a-

zzzzzz * Department of Ophthalmology, UZ. Leuven, Belgium ** Department of Genetics, UZ.Leuven, Belgium *** Department of Pediatrics, UZ.Leuven, Belgium **** Department of Pediatrics, LUMC, Leiden, The Netherlands

received: 08.07.02 accepted: 20.08.02

Bull. Soc. belge Ophtalmol., 286, 19-24, 2002. 19 INTRODUCTION CASE REPORT Mucolipidosis II (I-cell disease, Leroy disease) A thirteen-year-old girl with the clinical char- and III (ML-III or pseudo-Hurler polydystrophy) acteristics of ML-III presented for ophthalmo- are respectively the severe and mild forms of logical evaluation as a part of a multidisci- an autosomal recessive genetic disorder char- plinary investigation. She was the first child acterized by deficient activity of the enzyme born to unrelated and healthy parents after a UDP-N-acetylglucosamine:lysosomal enzyme normal pregnancy and delivery. Retardation of N-acetylglucosaminyl-1-phosphotransferase psychomotor development was noted during (termed phosphotransferase). This enzyme pro- the second year when she started to walk at vides the first step in the biosynthesis of the man- the age of 20 months, but verbal skills were nose-6-phosphate lysosome-targeting marker on normal for her age. Striking hip dysplasia in a nascent lysosomal enzymes. Its deficiency results developing spondylometaphyseal skeletal dys- in defective posttranslational processing and trans- plasia was noted in addition to facial coarse- port of lysosomal enzymes, leading to deficient ac- ness, short neck, short and pronounced pec- tivity of multiple enzymes in the lysosomes, but tus and restricted joint mobility in the knees and increased activity of these enzymes in the extra- hips. At the age of ten she developed a hyper- cellular environment (2, 3, 5). trophic cardiomyopathy with aortic and mitral Patients with mucolipidosis II present a severe valvular insufficiency resulting in pulmonary storage phenotype in the perinatal period. In distress and dyspnoea. Hearing loss due to oti- contrast, patients with the less severe pheno- tis serosa was marked at the age of eleven. At type of mucolipidosis III, or pseudo-Hurler poly- 13 years, the kyphosis was exaggerated by spon- dystrophy, present at the ages of 2 to 4 years taneous vertebral fracture. Pronounced cardio- with stiffness of the hand joints, progressively pathy and restrictive dyspnoea in addition to restricted joint mobility, short stature, and se- skeletal dysplasia limited her mobility, making verely dysplastic hip joints. They develop a Hur- her wheelchair-bound. She weighed 16.8 kg ler-like dysmorphism of the face and dysosto- and measured 103.5 cm (<aortic insufficiency), restrictive pulmonary dis- carpal tunnel syndrome. She was treated with ease, gingival hyperplasia and carpal tunnel beta-blockers, lisinopril and furosemide. syndrome. Some have learning disabilities or The biochemical diagnosis was suggested by a mild mental retardation. Affected children have strikingly elevated arylsulfatase A activity in the normal puberty, and survival into early adult- serum: 9165 mU/l (control 126-540). Fibro- hood is common. In contrast to other muco- blasts showed deficient intracellular activity of polysaccharidoses, such as Hurler syndrome, N-acetyl-β-D-glucosaminidase A: 113 nmol/ mucopolysaccharide excretion in the urine is mg/hour (control 950-1750) and of total (A and not increased. The biochemical diagnosis is B) N-acetyl-β-D-glucosaminidase: 1193 nmol/ made by the demonstration of deficient intra- mg/hour (control 6000-20000), in contrast to cellular activities of some lysosomal enzymes normal activity of β-glucosidase, which has man- and increased activities in serum (2, 3, 5). nose-6-phosphate-independent lysosomal tar- The triad of corneal clouding, mild retinopathy and geting. A deficient activity of the N-acetylglu- hyperopic astigmatism is a consistent ophthal- cosaminylphosphotransferase of 3 pmol/mg/ mological finding in patients with ML-III (7). In hour (control 40-90) completed the diagnostic this study we report the eye findings in a patient studies. with ML-III and contrast these with the corneal Ophthalmological examination at the age of 12 findings in Hurler and Hurler-Scheie syndrome. showed normal pupils and reflexes. Visual acuity Hurler syndrome and its milder variant Hurler- was 1.0 (Sn 1) in both eyes with a hyper- Scheie syndrome, which clinically resemble ML- metropic correction of +2 (+0.5 / 90°) for the III, are diseases caused by a deficiency of a sin- right eye and +3 (+0.5 / 90°) for the left eye. gle lysosomal enzyme, α-L-iduronidase, The axial length was 20 mm and 20.1 mm in

20 Fig 1 and 2. Fundus photographs right and left. Note the mild macular surface wrinkling as horizontal lines, especially at the nasal and temporal side of the fovea. the right and left eyes respectively. There were mild retinal vascular tortuosity, and mild ma- no signs of squint and the ocular motility was cular surface wrinkling (Fig. 1, 2) were visual- not restricted. The visual field examination us- ized. ing Goldmann perimetry showed normal sec- Corneal clouding was evident on biomicrosco- toral limits. On funduscopy normal optic nerves, pic examination (Fig. 3). The opacities were

21 Fig 3. Showing the discrete corneal clouding as fine pinpoint opacities.

Fig 4. Corneal clouding. Fine opacities involve the full corneal thickness, except for the epithelium. fine and discrete, pinpoint dots-like, and in- patient with Hurler-Scheie syndrome. The cor- volved the full corneal thickness (Fig. 4) ex- neas are markedly cloudy and the fundi can no cept for the epithelium. The corneal clouding longer be visualized. was markedly more severe in an age-matched

22 DISCUSSION papiloedema. The origin of surface wrinkling maculopathy and retinal vascular retinopathy Our patient exhibited the typical clinical and en- is unknown.It may reflect underlying retinal zymatic findings of mucolipidosis III. The triad damage secondary to the abnormal storage pro- of corneal clouding, mild retinopathy and hy- cess and the formation of epiretinal mem- peropic astigmatism is a consistent ophthal- branes. The vision could be affected with pro- mological finding in ML-III (7). gressive retinopathy. Our patient showed mild Corneal clouding in ML-III is initially mild. It in- retinal changes. In contrast to other lysosomal creases with age, progressing to full-thickness storage disorders, such as Hurler syndrome, vi- involvement. It usually does not affect vision. sion in ML III remains largely unaffected. ERG The histopathology of the cornea has not yet wasn’t performed in our patient because of the been described in this condition. Electron mi- absence of any visual problems, and when per- croscopical examination of a conjunctival bi- formed in previously published patients showed opsy showed an abnormal accumulation of acid consistently a normal response in ML-III pa- mucopolysaccharides in fibroblasts in an ar- tients (1, 4). In the presence of pronounced cor- ranged membranous lamellar manner (6). Ex- neal clouding an electroretinogram is a useful trapolating from the similarity between con- adjunct in the evaluation of ML-III patients with junctival connective tissue and cornea, the mech- regard to their postoperative prognosis for kerato- anism of corneal clouding in these patients has plasty. been attributed to an abnormal accumulation of storage material in and around stromal kera- CONCLUSION tocytes in the anterior and posterior stroma (6). The epithelial cells are not involved. Therefore In consistency with previous reports, our pa- the interface between the cornea and tear film tient shows the characteristic triad of mild cor- is regular, and good visual acuity preserved. A neal clouding, mild retinopathy and hyperopic penetrating keratoplasty would be a good al- astigmatism. Hyperopia and astigmatism are ternative for the patients with a disturbing cor- mild; the macular wrinkling is discrete. Corne- neal clouding. al clouding does not affect the visual acuity and Corneal clouding is also seen in mucopolysac- there are no signs of papiloedema. These find- charidoses caused by deficiencies in a single ings are consistent with other observations (7) lysosomal enzyme, such as Hurler syndrome on the slow progression of the ophthalmologi- (MPS-I), Morquio syndrome (MPS-IV), Maro- cal symptoms in patients with ML-III. The oph- teaux-Lamy syndrome (MPS-VI), and variably thalmological findings are mild and only very in Sly syndrome (MPS-VII). In contrast corneal slowly progressing, with preserved good visual clouding is absent in Hunter syndrome (MPS- acuity with optimal correction. A follow-up ex- II) and Sanfilippo syndrome (MPS-III). Patients amination of our patient in July 2002 showed with ML-III clinically resemble patients with no progression in ophthalmological findings. Hurler-Scheie syndrome. The corneal clouding This contrasts to the severe corneal involve- in these patients is more severe and early in ment in Hurler and Hurler-Scheie syndrome. presentation, and in some severe cases neovas- cularization and chronic corneal ulceration have REFERENCES: been reported (4). Optic nerve head swelling of various degree can (1) GILLS J.P., HOBSON R., HANLEY W. B., Mc- occur in ML-III and, if severe, can be associa- KUSICK V.A. − Electroretinography and fundus ted with progressive loss of visual acuity. There oculi findings in Hurler’s disease and allied mu- are different hypotheses on the pathogenesis of copolysaccharidoses. Arch. Ophthal. (Chic.) 1965, 74: 596-603 the optic nerve head swelling (7). The poste- (2) KELLY T.E., THOMAS G.H., TAYLOR H.A., Mc- rior sclera is thickened because of the abnor- KUSICK V.A., SLY W.S., GLASER J.H., ROBI- mal storage of acid mucopolysaccharides, there- NOW M., LUZZATTI L., ESPIRITU C., FEIN- fore the pressure increases within the optic nerve GOLD M., BULL M.J., ASHENHURST E.M., IVES sheath and hinders the axoplasmic reflux. Hy- E.J. − Mucolipidosis III (Pseudo-Hurler Poly- peropia may also explain the apparent pseudo- dystrophy): Clinical and laboratory studies in a

23 series of 12 patients. The John Hopkins Med. Hurler Polydystrophy). Invest. Ophthalmol. 1971, J. 1975, 137: 156-175 10: 568-580 (3) KORNFELD S., SLY W.S. − The metabolic & mo- (7) TRABOULSI E.I., MAUMENEE I.H. − Ophthal- lecular bases of inherited disease. New York; Mc mological findings in Mucolipidosis III (Pseudo- Graw Hill. 8° Ed, 2001, 3469-3482 Hurler polydystrophy). Am. J. Ophthalmol. 1986, (4) LEUNG L.E., WEINSTEIN G.W., HOBSON R.R. 102: 592-597 − Further electroretinographic studies of patients with mucopolysaccharidoses. Birth Defects: Ori- ginal Article series. Vol. VII, 1971, 3: 32-40 zzzzzz (5) MUELLER T., HONEY N.K., LITTLE L., MILLER A., SHOWS T. − Mucolipidosis II and III. The Ge- Address for correspondence: Dr. S. Pourjavan netic relationship between two disorders of lyso- University Hospital St. Rafaël somal enzyme biosynthesis. J. Clin. Invest. 1983, Department of Ophthalmology 72: 1016-1023 Kapucijnenvoer 33 (6) QUIGLEY H.A., GOLDBERG M.F. − Conjuncti- B- 3000 Leuven val ultrastructure in mucolipidosis III (Pseudo- [email protected]

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