Ocular Changes in Patients with Mucopolysaccharidosis I Receiving Enzyme Replacement Therapy a 4-Year Experience

CLINICAL SCIENCES Ocular Changes in Patients With Mucopolysaccharidosis I Receiving Enzyme Replacement Therapy A 4-Year Experience

Susanne Pitz, MD, PhD; Olufunmilola Ogun, FWACS; Manal Bajbouj, MD; Laila Arash, MD; Gudrun Schulze-Frenking, MD; Michael Beck, MD, PhD

Objective: To describe the progression of ocular changes edema. All patients had typical corneal stromal opaci- in patients with mucopolysaccharidosis I receiving en- ties, however, to a variable extent. Two patients had zyme replacement therapy. already undergone corneal transplantation before re- cruitment in the study. Their grafts remained clear Methods: Three male and five female patients with mu- throughout follow-up. Of 2 patients with an elevated in- copolysaccharidosis I were followed up for 4 years while traocular pressure, 1 developed intraocular pressure– undergoing enzyme replacement therapy with ␣-L- related optic nerve damage. Vision remained stable in a iduronidase (Aldurazyme). Visual acuity, corneal cloud- patient with bilateral optic atrophy. ing, intraocular pressure, ophthalmoscopy, and optic disc measurements were performed yearly. Conclusions: Ocular findings remain stable in most patients with mucopolysaccharidosis I receiving enzyme re- Results: Vision remained stable in 5 patients and dete- placement therapy. However, enzyme replacement therapy riorated by at least 2 Snellen lines in 3 patients. Deterio- does not seem to prevent progression of corneal or optic ration in 2 of these patients was related to progressive disc changes and, thus, the related worsening of visual corneal clouding. Visual acuities improved in 1 patient function. after bilateral penetrating keratoplasties. In the third patient, deterioration was related to increasing papillo- Arch Ophthalmol. 2007;125(10):1353-1356

UCOPOLYSACCHARIDO- with increasing disability and debilita- ses (MPSs) are a hetero- tion.1-5 Without treatment in severe cases, geneous group of death often results within the first decade. inherited lysosomal Mucopolysaccharidosis I is seen as a storage diseases char- clinical spectrum composed of 3 disease en- acterizedM by intracellular accumulation of tities that differ mainly in the severity of glycosaminoglycans (mucopolysacchari- clinical manifestations. Hurler syndrome is des) within various tissues and excretion of the most severe form, and Scheie syn- undegraded or partially degraded gly- drome is at the mild end of the spectrum; cosaminoglycans in the urine.1-4 patients with the Hurler-Scheie syndrome About 11 distinct subtypes of MPSs have are in between these 2 extremes. Mucopoly- been identified based on the specific en- saccharidosis I is characterized by a defi- zyme deficiency and the glycosaminogly- ciency of ␣-L-iduronidase, the enzyme can substrate(s) affected.1 Clinically, the responsible for hydrolyzing the terminal MPSs are characterized by varying de- ␣-L-iduronic acid residues of dermatan grees of skeletal dysmorphism, joint stiff- and heparan sulfate.1 It is inherited as an au- 1-3 Author Affiliations: ness, mental retardation, and respiratory, tosomal recessive trait. According to Department of Ophthalmology cardiac, and ocular abnormalities. The ocu- McKusick, the 2 extremes of the disease (Dr Pitz) and Division of lar features include corneal clouding, op- spectrum are believed to represent allelic Metabolic Disorders, Children’s tic nerve swelling, optic atrophy, glau- forms of a mutation at the p16.3 locus on Hospital (Drs Bajbouj, Arash, coma, and retinal pigment epithelium chromosome 4.1,3 As holds true for sever- Schulze-Frenking, and Beck), degeneration.5,6 Electroretinographic ab- ity of systemic disease manifestation, Johannes Gutenberg University, Mainz, Germany; and normalities have been reported and may be corneal clouding and retinal pigment Department of Ophthalmology, significant even when the retina does not epithelium degeneration are more fre- University College Hospital, show a striking morphologic abnormal- quent and occur at an earlier age in pa- Ibadan, Nigeria (Ms Ogun). ity.7 The disease runs a progressive course, tients with Hurler syndrome or with Hurler-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Scheie syndrome than in those with Scheie syndrome.5,6 those who did not receive ERT. Best-corrected VA re- To our knowledge, only 1 patient with Scheie syndrome mained stable in 5 patients (patients 2, 4, and 6-8). In featuring optic nerve pathological features has been de- patient 6, best-corrected VA seemed to improve in the scribed in the literature,8 whereas optic nerve involve- right eye, from 0.4 to 0.8. However, this most probably ment is a typical finding in patients with the other sub- was related to inadequate refraction initially, because the types of MPS I.5,6,9 better acuity at the end of follow-up was obtained by con- The enzyme ␣-L-iduronidase has been purified and char- tact lens correction. acterized. With the aid of recombinant DNA technology, Best-corrected VA deteriorated by at least 2 Snellen recombinant ␣-L-iduronidase has been synthesized and en- lines in 3 patients (patients 1, 3, and 5). In patients 1 and zyme replacement therapy (ERT) has been approved for 3, visual decline was because of increasing corneal cloud- patients with MPS I. Treatment of patients with MPS is ing. Penetrating keratoplasty was performed in May 2002 mainly symptomatic. However, specific treatments, such and May 2003 in the right and left eyes of patient 3, re- as hematopoietic stem cell transplantation and bone mar- spectively. Despite 2 episodes of endothelial graft rejec- 1-3,10 11 row transplantation (BMT) and, more recently, ERT, tion reactions in her right eye, keratoplasty led to a sus- are targeted at prolonging and improving the quality of life. tained improvement of vision. Mild elevation of 5,6,10,12,13 Published literature exists regarding ocular changes intraocular pressures following topical corticosteroid treat- in patients following BMT. Two separate reports found an ment (administered for graft rejection) resolved with dis- improvement of visual acuity (VA) in 3 of 10 patients af- continuation of the corticosteroids. There was no evi- ter 1 year11 and in 3 patients after 5 years14 of ERT. There 11,14 dence of optic nerve or retinal pathological features. In was no effect on corneal clouding. patient 1, keratoplasty was not considered because of poor general health. As ophthalmoscopy was impossible be- METHODS cause of corneal clouding throughout the study period, we cannot rule out the possibility that impaired visual In December 2000, a phase 3 double-masked, placebo- function might also have been because of additional op- controlled, multicenter trial was initiated to assess the safety and tic nerve and/or retinal pathological features. efficacy of treatment with recombinant ␣-L-iduronidase (Aldu- Two patients (patients 6 and 7) had undergone kera- razyme [BioMarin Pharmaceutical Inc, Novato, California; and toplasty outside the study location and before the study pe- Genzyme Corporation, Cambridge, Massachusetts]) in those with riod. In patient 7, keratoplasty had been performed in 1992 MPS I.15 In this trial, 45 patients were enrolled at 5 sites in the United States, Europe, and Canada. At each study site, institu- and 1995 in the left and right eyes, respectively. Both cor- tional ethic committee approval was obtained. The enzyme (␣- neal grafts remained clear during the study period. The same L-iduronidase) or placebo was administered intravenously once held true for patient 6, who had undergone penetrating kera- each week for 26 weeks at a dosage of 0.58 mg/kg body weight. toplasty in her right eye in 1997 and lamellar keratoplasty At the end of the double-masked phase, all 45 patients entered in her left eye in 1999. In this eye, the macula exhibited a an open-label extension study. Patients enrolled in the study had subtle epiretinal membrane, although the patient did not MPS I with less than 10% iduronidase activity and were at least experience any metamorphopsia. aged 5 years and able to perform the primary efficacy assess- Patient 2 had already been diagnosed as having glau- ments. To be included, forced vital capacity had to be less than coma and had begun taking antiglaucoma medication be- 80% of the predicted normal value and patients had to be able to perform a 6-minute walk test. At the study site in Mainz, 9 pa- fore enlisting in the study. He was poorly compliant with tients were included. Assignment of the patients to the MPS I sub- his eyedrops at the outset. His optic disc exhibited glau- types (Scheie, Hurler-Scheie, or Hurler) was based on clinical find- comatous cupping at the end of follow-up, while his vi- ings. An 8-year-old patient died during the study period because sual fields remained stable. of myocarditis unrelated to ERT. His data are not included in the Optic disc abnormalities were present in 2 additional present report. The remaining 3 male and 5 female patients (mean patients. One (patient 4) had early optic atrophy, evi- age, 25 years at study enrollment; age range, 7-43 years) were fol- denced by bilateral temporal disc pallor and depression lowed up with ERT for 4 years. Ophthalmological assessments of sensitivity on central visual field testing, while the other were performed annually. However, patients with visual com- plaints were seen as required. The examination included mon- (patient 5) had chronic bilateral papilloedema but no per- ocular assessment of best-corrected and uncorrected VA using sistent gross field defects. In the latter patient, VA de- Snellen charts, measurement of intraocular pressure by either Gold- creased by 2 Snellen lines during follow-up, although this mann applanation tonometry or digital palpation, slitlamp ex- patient did not subjectively complain of deterioration. amination of the anterior segment (model BQ 900; Haag Streit, Retinal pigment epithelium dysfunction was strongly Ko¨niz, Switzerland), and direct and indirect ophthalmoscopy. Cor- suspected in patients 2, 7, and 8, because we noted se- neal clouding, if present, was graded as mild, moderate, or severe concentric narrowing of visual fields. Only in pa- vere. In a few patients, static 30° perimetry was performed (Oc- tient 7 did this correlate with the typical pigmentary fun- topus G2 perimeter; Interzeag AG, Schlieren, Switzerland). dus changes. Objective refraction with an autorefractor (Retino- RESULTS max K-plus; Nikon Co Ltd, Tokyo, Japan) revealed moderate degrees of hyperopia and astigmatism in most pa- The Table summarizes the ophthalmological data of all tients examined (7 of 8 patients). The mean spherical the patients. We did not detect any difference in out- equivalent was 5.75 and 6.00 diopters in the right and come between those patients who received ERT during left eyes, respectively. All 8 patients completed 4 years the 26 weeks before entering the open-label study and of evaluation.

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Patient Visual Acuityb No./Sex/ MPS I Objective Indirect Visual Age, ya Type Eye Initial Final Refractionc Cornead Optic Nerve Ophthalmoscopy Fielde IOPf 1/F/10 H Right 0.1 (20/200) 0.005 (20/4000) 5.50 ϩϩϩ No view No view ND Increased Left 0.2 (20/100) 0.02 (20/1000) 6.50 − 1.50 ϫ 165° ϩϩϩ No view No view ND N 2/M/17 H-S Right 0.32 (20/63) 0.4 (20/50) 6.75 − 4.00 ϫ 170° ϩϩg Glaucomatous N 10° Concentric Increased cupping: C/D constriction ratio, 0.8 Left 0.63 (20/32) 0.5 (20/40) 8.75 − 4.75 ϫ 177° ϩϩg Glaucomatous N 10° Concentric Increased cupping: C/D constriction ratio, 0.8 3/F/30 S Right 0.3 (20/60) 1.0 (20/20) 4.50 − 0.50 ϫ 92° ϩϩh NN NN Left 0.3 (20/60) 0.8 (20/25) 5.00 − 0.50 ϫ 82° ϩϩh NN NN 4/F/7 S Right 0.05 (20/400)i 0.05 (20/400)i 4.50 − 2.00 ϫ 25° ϩ Diffuse atrophy N ND N Left 0.2 (20/100) 0.25 (20/80) 4.50 − 2.50 ϫ 10° ϩ Diffuse atrophy N Loss of N temporal visual field (Ͼ20° of eccentricity) 5/F/24 S Right 1.0 (20/20) 0.63 (20/32) 6.75 − 1.00 ϫ 93° ϩ Papilloedema N Diffuse loss of N sensitivity Left 1.0 (20/20) 0.63 (20/32) 7.50 − 1.25 ϫ 102° ϩ Papilloedema N Diffuse loss of N sensitivity 6/F/28 S Right 0.4 (20/50) 0.8 (20/25) ND pTx N N ND N Left 0.6 (20/30) 0.8 (20/25) ND lTx N Epiretinal gliosis ND N (macular epiretinal membrane) 7/M/44 S Right 0.5 (20/40) 0.5 (20/40) 9.25 − 2.75 ϫ 37° pTx N Ret deg 10° Concentric N constriction Left 0.5 (20/40) 0.4 (20/50) 8.25 − 3.00 ϫ 165° pTx N Ret deg 10° Concentric N constriction 8/M/40 S Right 1.0 (20/20) 0.8 (20/25) 7.75 − 1.75 ϫ 14° ϩ N N 10° Concentric N constriction Left 1.0 (20/20) 0.8 (20/25) 8.75 − 2.00 ϫ 164° ϩ N N 10° Concentric N constriction

Abbreviations: C/D, cup-disc; ERT, enzyme replacement therapy; H, Hunter syndrome; H-S, Hunter-Scheie syndrome; IOP, intraocular pressure; lTx, lamellar keratoplasty (performed before the study); MPS, mucopolysaccharidosis; N, normal; ND, not done; pTx, penetrating keratoplasty (performed before the study); Ret deg, retinal pigmentary degeneration; S, Scheie syndrome; ϩ, mild; ϩϩ, moderate; ϩϩϩ, severe. aAge at study enrollment is given. bBest-corrected visual acuity at study enrollment (initial) and after 4 years of ERT (final). Data are expressed using the decimal notation (or decimal scale), with corresponding values on the traditional Snellen scale in parentheses. cCycloplegic refraction obtained by use of tropicamide. dThe degree of corneal opacity is given. eAnalysis performed by static perimetry (described in the “Methods” section). fNormal IOP is an IOP of 21 mm Hg or lower; increased IOP is an IOP of 22 to 30 mm Hg. gThis patient had additional fine subepithelial punctuate opacifications. hThis patient underwent penetrating keratoplasty during follow-up because of progressive visual decline. iThis eye had amblyopia due to divergent squint.

COMMENT from the adjuvant therapy accompanying BMT, includ- ing irradiation and corticosteroids,13 while retinal function seemed to decline. No changes in corneal opacity were This study examined the progression of ocular changes 11 during ERT in patients during a 4-year period. Our find- observed by Kakkis and coworkers in 10 patients un- ings suggest that, in most patients, ocular abnormalities dergoing ERT for 1 year, although 3 of their patients ex- 14 remain stable or progress slowly during ERT. hibited some improvement of VA. Similarly, Wraith was It is controversial whether the treatment of the sys- unable to demonstrate any effect of 5 years of ERT on cor- temic disease alters the course of ocular changes in pa- neal clouding, as documented by photographs. Some im- tients with MPS.5-14 Bone marrow transplantation was as- provement in photophobia was noted in 3 patients who sociated with a reduction in corneal clouding and had reduced visual function at baseline.14 conjunctival cytoplasmic inclusions, resolution of optic While most of our patients had stable ocular signs, pro- nerve swelling, and improved or stabilized retinal func- gression of corneal clouding and optic nerve pathological tion.10,12 Longer follow-up data confirmed improvement features was seen during follow-up in individual patients. of VA and reduction of corneal clouding in about one- Remarkably, optic nerve pathological features, which have third of patients, while electroretinography showed a de- not been regarded as typical features of the so-called attenu- cline after the first year after BMT.13 Indeed, some pa- ated variant of MPS I, Scheie syndrome,5,6,9 were seen in 2 tients developed new ocular complications (eg, cataracts) patients. One patient with disc swelling had a slow decline

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 in VA, although the patient did not notice any difference genbeckstrasse 1, D 55101 Mainz, Germany (pitz@augen in her sight. The reduced acuity probably signals the on- .klinik.uni-mainz.de). set of secondary atrophy, which is attributed to the accu- Author Contributions: Dr Pitz had full access to all the mulation of acid mucopolysaccharides (glycosaminogly- data in the study and takes responsibility for the integ- cans) within the dura, sclera, or ganglion cells, resulting in rity of the data and the accuracy of the data analysis. optic nerve compression.9 The other patient had optic at- Financial Disclosure: None reported. rophy with temporal disc pallor. Vision was poor but re- Funding/Support: This study was supported by BioMa- mained stable. In both patients with optic nerve involve- rin Pharmaceutical Inc and Genzyme Corporation; and ment, there was no evidence of increased intracranial pres- by unrestricted scientific grants from Genzyme Corpo- sure as detected by clinical investigation and imaging. ration, Shire Company, and BioMarin Pharmaceutical Inc. In patient 3, worsening of VA was related to increasing Role of the Sponsor: The funding bodies had no role in corneal opacity and prompted corneal transplantation. De- the design and conduct of the study; in the collection, spite repeated immunogenic graft rejections, this patient analysis, and interpretation of the data; or in the prepa- showed significantly improved VA, from 0.3 to 0.8, in both ration, review, or approval of the manuscript. eyes. Two of our patients underwent keratoplasty before ERT. In these patients, no change in the corneal transplan- tations was seen during the study period. 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