Variability in the Ocular Phenotype in Mucopolysaccharidosis.€¦ · Confidential: For Review Only TITLE PAGE Variability in the Ocular Phenotype in Mucopolysaccharidosis. Krishanthy

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Variability in the Ocular Phenotype inMucopolysaccharidosis.DOI:10.1136/bjophthalmol-2017-311749

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Citation for published version (APA):Sornalingam, K., Javed, A., Aslam, T., Sergouniotis, P., Jones, S. A., Ghosh, A., & Ashworth, J. (2018). Variabilityin the Ocular Phenotype in Mucopolysaccharidosis. British Journal Of Ophthalmology.https://doi.org/10.1136/bjophthalmol-2017-311749

Published in:British Journal Of Ophthalmology

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https://doi.org/10.1136/bjophthalmol-2017-311749

Confidential: For Review Only

Variability in the ocular phenotype in Mucopolysaccharidosis

Journal: British Journal of Ophthalmology

Manuscript ID bjophthalmol-2017-311749.R1

Article Type: Clinical science

Date Submitted by the Author: n/a

Complete List of Authors: Sornalingam, Krishanthy; Manchester Royal Eye Hospital; The University of Manchester, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health Javed, Ahmed; Manchester Royal Eye Hospital Aslam, Tariq; Manchester Royal Eye Hospital; The University of Manchester, Centre for Ophthalmology and Vision Sciences, Faculty of Biology, Medicine and Health Sergouniotis, Panagiotis ; Manchester Royal Eye Hospital; The University of Manchester, Centre for Ophthalmology and Vision Sciences, Faculty of Biology, Medicine and Health Jones, Simon ; Manchester Centre for Genomic Medicine, St Mary's

Hospital, Willink Unit Ghosh, Arunabha; Manchester Centre for Genomic Medicine, St Mary's Hospital, Willink Unit Ashworth, Jane; Manchester Royal Eye Hospital; The University of Manchester, Centre for Ophthalmology and Vision Sciences, Faculty of Biology, Medicine and Health

Keywords: Cornea, Genetics, Imaging, Vision, Retina

https://mc.manuscriptcentral.com/bjo

British Journal of Ophthalmology

Confidential: For Review OnlyTITLE PAGE

Variability in the Ocular Phenotype in Mucopolysaccharidosis.

Krishanthy Sornalingam1, Ahmed Javed1, Tariq Aslam1,2, Panagiotis

Sergouniotis1,2, Simon A Jones3, Arunabha Ghosh3, Jane Ashworth1,2

1Manchester Royal Eye Hospital, Manchester Academic Health Science

Centre, Manchester, UK

2Centre for Ophthalmology and Vision Sciences, Faculty of Biology, Medicine

and Health, University of Manchester, Manchester, UK

3Willink Unit, Manchester Centre for Genomic Medicine, St Mary’s Hospital,

Manchester, UK.

Corresponding Author: Jane Ashworth FRCOphth, PhD

Contact email: [email protected]

Contact Number: +44 161 2765579

Address: Manchester Royal Eye Hospital, Oxford Road, Manchester, UK,

M13 9WL

Word count: 2482

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Confidential: For Review OnlySYNOPSIS 1

Prospective observational study, using objective measures of ocular 2

phenotype in Mucopolysaccharidosis and correlating findings with disease 3

type, genotype and treatment efficacy. Ocular phenotype was found to be 4

variable, and ocular imaging useful in detecting complications. 5

6

7

ABSTRACT 8

Purpose: Mucopolysaccharidoses are a heterogeneous group of lysosomal 9

storage disorders. Ocular complications (such as corneal clouding, 10

retinopathy and optic neuropathy) are common. Notably, there is a paucity of 11

data on the effect of genotype, and systemic treatments (enzyme replacement 12

therapy or haematopoietic stem cell transplantation) on the ocular phenotype 13

in mucopolysaccharidosis (MPS). We prospectively studied the ocular 14

features of patients with MPSI (Hurler/Hurler-Scheie/Scheie), MPSIV 15

(Morquio) and MPSVI (Maroteaux-Lamy), to evaluate the effect of different 16

therapeutic interventions and to correlate the findings with genetic and 17

biomarker data. 18

Methods: Prospective observational cohort study. Study participants 19

underwent detailed ocular examination including visual acuity; assessment of 20

corneal clouding (Iris Camera Corneal Opacification Measure (COM) score 21

and Pentacam densitometry); and retinal and optic nerve imaging (optical 22

coherence tomography and wide-field fundus imaging). Data on genotype, 23

biomarkers and delivered therapies (type and length of treatment) were also 24

collected for each patient where available. 25

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123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlyResults: Overall, 21 MPSI, 4 MPSIV and 3 MPSVI patients were recruited. 26

Corneal clouding scores were higher in MPSI compared to MPSIV and 27

MPSVI. Retinopathy was evident in MPSI patients only. Association was 28

observed between corneal clouding and biomarkers in MPSI, MPSIV and 29

MPSVI. However, no clear association was seen between genotype or 30

treatment type and ocular phenotype. 31

Conclusions: The ocular phenotype in MPS is variable, with corneal clouding 32

occurring in MPSI, MPSIV and MPSVI, and retinopathy in MPSI only. There 33

was an association between corneal clouding and efficacy of systemic 34

treatment as measured by biomarkers. 35

36

Keywords: Cornea, genetics, imaging, vision, retina 37

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Confidential: For Review OnlyINTRODUCTION 38

The mucopolysaccharidoses (MPSs) are a group of rare metabolic disorders 39

characterized by defects in specific lysosomal enzymes involved in the 40

degradation of glycosaminoglycans (GAGs). Intra- and extra-cellular 41

deposition of GAGs occurs and can result in a wide range of systemic 42

manifestations, including distinctive facial features; visual and hearing 43

impairment; cardiorespiratory, skeletal and neurological problems, and 44

intellectual impairment.[1] Quality of life in patients with MPS may be 45

significantly affected by visual impairment secondary to corneal opacification; 46

other ocular complications such as retinopathy, glaucoma, and optic 47

neuropathy, may also contribute to visual loss.[2] Previous studies have 48

shown that the ocular phenotype varies in different MPS types, with corneal 49

clouding being a prominent feature of MPSI (Hurler, Hurler-Scheie and 50

Scheie), MPSIV (Morquio), MPSVI (Maroteaux-Lamy) and MPSVII (Sly), and 51

retinopathy being a feature in MPSI, MPSII (Hunter), MPSIII (Sanfilippo A-D) 52

and MPSIV.[2-4] 53

54

Systemic interventions available for MPS include Haematopoietic Stem Cell 55

Transplantation (HSCT) and Enzyme Replacement Therapy (ERT). 56

Importantly, these can result in improvement of systemic manifestations and 57

lifespan.[5] Biochemical parameters have previously been validated as 58

markers of efficacy of HSCT and ERT,[6-8] and a correlation between 59

treatment efficacy and systemic and ocular outcomes has been shown in 60

MPSI Hurler treated with HSCT.[9] No such relationship has been shown 61

between ERT and ocular phenotype. This may be related to the fact that ERT 62

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Confidential: For Review Onlyis unable to cross the blood brain barrier.[10] Treatments such as substrate 63

reduction therapy and gene therapy are currently undergoing clinical trails in 64

MPS [5,11]. 65

66

The utility of ocular imaging modalities in MPS has previously been reviewed 67

by our group,[12] and were thought to be useful in objectively assessing the 68

ocular phenotype in MPS. 69

70

This study aims to use objective investigations to document the ocular 71

phenotype in patients with MPS and correlate the findings with MPS type, 72

genotype and efficacy of treatment. 73

74

75

METHODS 76

The study was conducted inline with the tenants of the Declaration of Helsinki. 77

Patients with MPS were recruited from Ophthalmology clinics at Manchester 78

Royal Eye Hospital, UK. Data on genotype and biomarkers were collected 79

from the Willink Unit, Manchester, UK. Any patient with a diagnosis of MPS, 80

over 3 years of age, was eligible to participate in this study. 81

Each patient underwent assessment of visual acuity (VA); clinical examination 82

(subjective evaluation of corneal clouding, intraocular pressure [IOP] 83

measurement, fundoscopy) and corneal clouding assessment using an iris 84

camera (IrisGuard model IG-AD100 ®, Irisguard Ltd, Buckinghamshire, UK; 85

Corneal Opacification Measure [COM] score)[13] and the Pentacam system 86

(Oculus Inc, Germany; densitometry measure).[14] Digital slit lamp 87

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Confidential: For Review Onlyphotographs were also obtained to document the level of corneal clouding. 88

Posterior segment evaluation was performed using optical coherence 89

tomography (OCT; Spectralis HRA+OCT, Heidelberg Engineering, 90

Heidelberg, Germany) and digital wide-field fundus imaging (Optos Vantage, 91

Optos PLC, Dunfermline, Scotland, UK). Some patients did not have all 92

measures due to issues such as time constraints or patient fatigue. 93

Biomarkers have previously been validated as markers of treatment efficacy 94

in MPS.[6-8] Biomarkers evaluated included dermatan sulphate/chondroitin 95

sulphate [DS/CS] ratio (MPSI and MPSVI), keratan sulphate/chondroitin 96

sulphate [KS/CS] ratio (MPSIV) and post-HSCT iduronidase enzyme levels 97

(MPSI treated with HSCT), where available. 98

Corneal clouding was graded clinically as absent, mild (corneal clouding not 99

obstructing view of structures in the anterior chamber or fundus), moderate 100

(details of iris and fundus obscured) or severe (unable to view structures in 101

the anterior chamber or fundus).[4,15] Grades of corneal clouding were 102

expressed numerically as 0=absent, 1=mild, 2=moderate, 3=severe. IOP was 103

measured with either Icare rebound tonometer or Goldman applanation 104

tonometer. 105

International Society for Clinical Electrophysiology of Vision (ISCEV) standard 106

electroretinograms had been performed in a subset of cases. 107

108

109

RESULTS 110

Data was collected for 28 patients; 21 patients had MPSI, 4 had MPSIV and 3 111

had MPSVI. The age range was 4-44 years old; 14 patients were male and 14 112

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Confidential: For Review Onlywere female. In total 14 patients received ERT, 12 received HSCT and 2 113

received no treatment (Table1 and Supplementary Table1). One study 114

participant (subject 22) had a trial of ERT stopped following an adverse 115

reaction. 116

117

MPS Type

Total number of

patients

Age range (in

years)

Treatments Age at start of treatment range

(Mean)

Average length of treatment (completed years)

Gender

I n= 21 4 - 44 ERT (n=9) HSCT (n=12)

5months – 34years (3.1 years)

ERT= 9.45 HSCT= 9.42

Male 12 Female 9

IV n= 4 11 - 19 ERT (n=2) No treatment (n=2)

10-14 years (12 years)

ERT= 1

Male 0 Female 4

VI n= 3 7 - 22 ERT (n=3) 1-5years (2.3 years)

ERT= 12.33

Male 2 Female 1

Table 1. Demographic data summarised by MPS type.

118

The median VA was 0.4 logMAR in the MPSI group, 0.16 logMAR in MPSIV 119

and 0.2 logMAR in MPSVI (Supplementary Figure 1a). The median IOP was 120

21.0mmHg in MPSI, 24.0mmHg in MPSIV and 18.5mmHg in MPSVI. The 121

clinical findings from each study participant are summarised in Table 2. 122

Patient number

MPS type

Treatment Clinical Corneal clouding

Slit lamp examination

Visual Acuity

IOP

Other known ocular issues

Disc Retina – evidence of retinopathy

OD OS OD OS

1 I ERT 1 NAD N 0.26 0.2 24 24 Astigmatism

2 I HSCT 2 NAD N 0.22 0.24 30 32

Hypermetropia and astigmatism

3

I

HSCT 2 NAD N 0.1 0.3 19 23

Inferior punctate epithelial erosions bilaterally, myopic astigmatism

4 I 3 NAD N 0.46 0.62 22 25 Nyctalopia, hypermetropia and

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Confidential: For Review OnlyERT

astigmatism, thick corneas

5 I

ERT 1 NAD Y

♯ 0.1 0.3 21 23

ERG evidence of rod/ cone dystrophy

6 I

ERT 2

Hazy view OD/ chorioretinal atrophy OS

♯ 0.56 0.52 21 21

ERG evidence of rod/ cone dystrophy

7

I

ERT 2 NAD

No comment on retina 0.3 0.3 32 30

Ocular hypertension and increased corneal thickness

8 I

ERT 2 NAD

No comment on retina 0.275 1

Left esotropia and amblyopia, hypermetropia

9

I

ERT 1 NAD Y

♯ 0.9 0.84 12 11

ERG evidence of rod/ cone dystrophy, hypermetropia

10 I

HSCT * 2

Full discs N 0.4 0.4 15 13 Hypermetropia

11 I

ERT 2 NAD Hazy view

♯ 0.2 0.2 15 17

Early retinal dystrophy - rods only affected

12

I

HSCT * 2 NAD N 0.4 0.48 22 20

ERG evidence of rod dysfunction, hypermetropic astigmatism

13 I HSCT * 1 NAD NAD 0.2 0.2 22 17 Hypermetropia

14 I

HSCT 2 NAD

RPE change periphery OS

♯ 0.74 0.76 22 22

ERG evidence rod cone dystrophy, thick corneas and previous right inferior oblique myectomy

15

I

HSCT * 1 NAD N 0.575 0.9 24 26

Left amblyopia, fully accommodative esotropia, hypermetropia

16 I

HSCT * 1 NAD N 0.46 0.4 23 15

Myopia and astigmatism

17 I

HSCT * 2 .

NAD though difficult view

♯ 0.72 0.7 19 21

Registered blind, accommodative convergent squint and evidence of retinopathy on ERG

18 I HSCT * 1 NAD N 0.14 0.14 22 17 Hypermetropia

19 I HSCT 1 NAD N 0.2 0.2 19 21

20

I

ERT 2 NAD N 0.8 0.32 18 16

FPS misdirection, surgical PI, lensectomy and vitrectomy

21 I

HSCT 2 NAD

No comment on retina 0.42 0.5 20 20

22

IV

No current treatment 1 NAD N 0.18 0.14 21 27

23 IV

No treatment 2 NAD N 0.2 0.3 30 32

Thick corneas, OHT

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Confidential: For Review Only24

IV ERT 1 NAD N 0.12 0.4 n/a n/a

25

IVA

ERT 1 NAD N 0.06 0.06 12 14

Partially accommodative esotropia, Hypermetropia

26 VI

ERT 1

Small hyperm-etropic

Hypopigmented fundi 0.3 0.2 18 17

Mild hypermetropia

27

VI

ERT 1 NAD N 0.34 0.2 22 19

Low hypermetropia and astigmatism

28 VI

ERT 2 NAD though difficult view

♯ 0.2 0.2

Corneal vascularisation right eye

Table 2. Clinical data by patient. Includes clinical grade of corneal clouding, optic disc appearance, evidence of retinopathy, visual acuity and Intra ocular Pressure (IOP). N= no evidence of retinopathy. Y= evidence of retinopathy. *= short course of ERT prior to HSCT.

♯=evidence of retinopathy on ERG. NAD= no abnormality detected. No comment on

retina= no data on appearance of retina recorded.

123

Anterior segment 124

Clinically all 28 patients showed some degree of corneal clouding. A notable 125

proportion of patients (13/28) showed mild (grade 1) corneal clouding. The 126

MPSI group had a higher proportion of patients with moderate to severe 127

(grades 2 and 3) corneal clouding (13/21 of MPSI patients compared to 1/4 of 128

MPSIV and 1/3 of MPSVI). 129

Corneal clouding was assessed objectively using the Pentacam system 130

(densitometry measure) and an iris camera (COM score). No association 131

between VA and COM score (Figure 1a) or between VA and Pentacam 132

densitometry (Figure 1b) was observed. Also there was no association 133

between VA and clinical corneal clouding grade. 134

Clinically graded mild corneal clouding was associated with COM scores 135

between 0.1164 and 2.859. Moderate corneal clouding was associated with 136

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Confidential: For Review OnlyCOM scores between 0.5587 and 3.9148. Although there is significant 137

overlap in COM scores for mild and moderate clinically graded corneal 138

clouding there is an overall trend toward higher COM scores in higher clinical 139

grades of corneal clouding (Figure 1c). Clinically graded mild corneal 140

clouding was associated with Pentacam densitometry scores between 16.2 141

and 32.8. Moderate corneal clouding was associated with densitometry 142

scores of between 38.1 and 54.9 (Figure 1d). Notably, the Pentacam was 143

unable to take pictures for two study participants with significant corneal 144

clouding (subjects 4 and 28; Supplementary Table2). 145

146

Posterior segment 147

Seven MPSI patients had retinopathy confirmed on full field 148

electroretinograms, all of which revealed predominant rod system dysfunction 149

(Table 2). Retinal pigment epithelial changes were seen in 4 of these patients 150

on fundoscopy. In 2 patients the fundal view was limited due to significant 151

corneal clouding. One patient with no evidence of retinopathy on fundoscopy 152

had electroretinographic evidence of rod system dysfunction (subject 12: 153

MPSI, 7years old). 154

Two study participants were noted to have small, crowded optic nerve heads 155

clinically, in keeping with Optos fundus imaging findings. Small crowded discs 156

were noted on Optos imaging in another patient (subject 9; Figure 3d), though 157

had not been recorded clinically. 158

Twelve patients underwent Optos wide-field imaging. A clear fundal view was 159

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Confidential: For Review Onlyobtained in all participants with mild corneal clouding (4 subjects; Figure 2a & 160

b). A hazy fundal view was obtained in the majority of patients with moderate 161

corneal clouding (6/7) and one patient with severe corneal clouding (Figure 2). 162

In 2 patients the quality of images were different between eyes, (subjects 6 163

and 7). 164

Four MPSI patients showed evidence of retinopathy (RPE mottling, bone 165

spicule pigmentation and/or atrophic retinal changes) on Optos imaging, 166

(subjects 1, 6, 7 and 9) (Figure 2c,d & e). One of these patients had no 167

previous clinical evidence of retinopathy (subject 1: MPSI, 12 years old). One 168

MPSI patient with electroretinographic evidence of retinopathy, had 169

unremarkable Optos imaging (patient 5: MPSI, 14 years old). 170

Macular OCT was performed in 12/28 patients. Central foveal thickness 171

(CFT) was found to be between 166µm and 254µm. Mean CFT and central 172

retinal subfield thickness (CRST) were 213.90µm (n=21 images) and 173

259.24µm (n=17 images); (the mean CFT was 227.63+/-11.43µm in healthy 174

young adults,[16] and average CRST was 271.2+/- 2.0µm in healthy 175

children).[17] One MPSI patient (subject 7: MPSI, 17 years old), was found to 176

have abnormal retinal contour in keeping with chorioretinal folds; CFT and 177

CRST measurements were therefore not attempted for this subject. Patient 3 178

(MPSI, 15 years old) and patient 14 (MPS I, 18 years old) had extensive 179

photoreceptor outer segment loss with preserved inner segment ellipsoid line 180

in the fovea (Figure 3a & b). Patient 9 (MPSI, 44years old) had widespread 181

photoreceptor loss bilaterally and a left intraretinal cyst (Figure 3c & d). A 182

central foveal hyper-reflective zone was observed above the inner segment 183

ellipsoid line in 16/20 MPSI eyes (Supplementary Table3). 184

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Confidential: For Review OnlyDisc OCT was obtained in 8 patients. These were generally unremarkable 185

and in keeping with clinical findings. Notably, in one patient (subject 7: MPSI, 186

17years), medial thickening of the optic nerve fiber layer was appreciated on 187

OCT, though not recorded clinically. 188

189

Biomarkers 190

In MPSI patients the median DS/CS ratios were 0.5 for those with mild 191

corneal clouding (n=8), 0.60 for those with moderate corneal clouding (n=12) 192

and 0.70 for those with severe corneal clouding (n=1), (Supplementary Figure 193

1b). In MPSIV patients the median KS/CS ratio was higher in those with 194

moderate corneal clouding (0.49, n=1) compared to those with mild corneal 195

clouding (0.32, n=1), (Supplementary Figure 1c). In MPSVI the median 196

DS/CS ratio was also slightly higher in those with moderate corneal clouding 197

(0.71, n=1) compared to those with mild corneal clouding (0.62, n=2), 198

(Supplementary Figure 1d). Due to the small numbers in some groups 199

statistical analysis was not performed. 200

Iduronidase levels were available for all 12 MPSI patients who underwent 201

HSCT. There was a trend for lower post-HSCT iduronidase levels in 202

participants with more severe corneal clouding: the median value was 203

47.0µmol/g/hr in those with absent to mild corneal clouding (n=5) and 204

31.4µmol/g/hr in those with moderate corneal clouding (n=7) (Supplementary 205

figure 1e). 206

The median DS/CS ratio in MPSI patients with retinopathy was 0.49 (n=7) 207

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Confidential: For Review Onlycompared to 0.59 in those without (n=14) (Supplementary Figure 1f). Three 208

patients with evidence of retinopathy had a HSCT, their median post-HSCT 209

iduronidase level being 31.4 µmol/g/hr. 210

211

Genetics 212

Genetic data was available for 21/28 patients; (Supplementary Table 4). 213

There was no clear association between the severity of corneal clouding and 214

the disease genotype in the present cohort. In the MPSI group, there were 6 215

patients homozygous for the p.(Leu490Pro) variant in the IDUA gene. Four of 216

these displayed clinically moderate corneal clouding and 2 displayed mild 217

corneal clouding; all 6 were being treated with weekly ERT. Genetic data was 218

available for 6/6 MPSI patients with known retinopathy: two had 219

p.(Leu490Pro)(;)(Leu490Pro), two had p.(Trp402*)(;)(Trp402*), one had 220

p.(Gln380Arg)(;)(Thr388Arg) and one had p.(Trp402*)(;)(Ala327Pro). 221

222

DISCUSSION 223

Over the past few decades the development of treatments for MPS has 224

greatly improved systemic outcomes and quality of life in patients with MPS. 225

Given this, it is important that we try to better understand the MPS-associated 226

ocular phenotype. In this study we used objective measures to assess the 227

ocular phenotype in patients with MPS. Correlations between these 228

measures, the MPS type, treatment, biomarkers and genotype were sought. 229

A notable finding of this study is the lack of significant correlation between the 230

level of MPS-associated corneal clouding and visual acuity. VA 231

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Confidential: For Review Onlymeasurements may be influenced by cooperation and understanding, and the 232

presence of other ocular involvement such as optic neuropathy and 233

retinopathy in patients with MPS. It is likely that the lower average VA in the 234

MPSI group compared to other groups may be associated with the higher 235

incidence of retinopathy found in MPSI. However, we also found a higher 236

proportion of patients with MPSI have moderate to severe corneal clouding 237

compared to those with MPSIV and MPSVI. In contrast, previous studies have 238

shown corneal clouding to be worse in MPSVI than MPSIV and MPSI.[3,4] 239

This discrepancy may be accounted for by the small numbers of patients in 240

this study, particularly in the MPSIV and MPSVI groups. 241

Anterior Segment imaging with the iris camera and Pentacam have previously 242

been validated to provide an objective measure of corneal clouding in 243

MPS.[13,14] We found an association between Pentacam densitometry 244

values and clinical grades of mild to moderate corneal clouding. However, the 245

Pentacam was unable to take corneal opacification measures when there was 246

severe corneal clouding, which may limit its use in the more severe MPS 247

ocular phenotypes. The iris camera COM score was found to be higher in 248

those with moderate corneal clouding compared to those with mild corneal 249

clouding as assigned by subjective clinical grading. However, there is a 250

significant overlap in the observed scores for these subjective grades. One 251

possible explanation for this is the fact that the clinical grade is based on the 252

overall appearance of the cornea while the iris camera only assesses the 253

central pupillary area of the cornea. Objective measurements such as the iris 254

camera COM score and Pentacam densitometry may be better used for 255

detecting change in the level of corneal clouding over time within an individual 256

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Confidential: For Review Onlypatient (rather than detecting inter-individual severity). 257

This study demonstrated retinopathy in MPSI but not in MPSVI, as found in 258

previous studies. None of our MPSIV patients had evidence of retinopathy, 259

which has been seen also in other studies.[3] We have demonstrated that 260

OCT is useful in detection of retinopathy and cystoid macula edema in MPS. 261

Photoreceptor layer loss was observed in two MPSI patients with fundoscopic 262

findings of retinopathy; OCT evidence of retinopathy was also detected in one 263

patient in whom there had been no clinical suspicion. Seok et al. also reported 264

similar OCT findings in patients with MPS.[18] A hyper-reflective zone was 265

observed above the inner segment ellipsoid line in the central fovea in 16/20 266

MPSI patient eyes. This feature has been previously described in individuals 267

with MPS,[18,19] and is thought to reflect thickening of the External Limiting 268

Membrane (ELM). 269

Despite variable image quality obtained with the Optos imaging system, 270

fundoscopic findings that were not detected by slit-lamp examination were 271

highlighted. In one MPSI patient, evidence of peripheral retinopathy was 272

noted on Optos, which had not been suspected clinically. In a different patient, 273

crowded optic disc clearly seen on Optos imaging had not been appreciated 274

clinically. Wide-field imaging can therefore be useful in detecting and 275

monitoring optic nerve and retinal changes, particularly when the changes are 276

peripheral. Interestingly, one patient with electroretinographic abnormality had 277

normal Optos imaging, suggesting that electrodiagnostic testing maybe better 278

at detecting early retinopathy compared to imaging. 279

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Confidential: For Review OnlyPrevious studies have demonstrated an association between efficacy of 280

treatment (demonstrated by biomarkers) and corneal clouding in patients with 281

MPSI.[9, 20, 21] In this study, median DC/CS or median KS/CS ratios were 282

found to generally increase with increasing grades of corneal clouding in 25 283

patients. Furthermore, median post-HSCT enzyme levels were lower in those 284

with moderate corneal clouding compared to those with mild corneal clouding, 285

also suggesting an association between the ocular phenotype and 286

biomarkers. 287

In this study we have attempted to quantify the degree of corneal clouding 288

and assess the clinical utility of fundus imaging in children and adults with 289

MPS. Limitations of this study include small numbers in MPSIV and MPSVI 290

groups, and the absence of all imaging modalities being obtained for all 291

participants. However, the rare nature of this condition and patient factors 292

such as easy fatigability, skeletal deformity and intellectual difficulties makes 293

addressing these limitations challenging. 294

We found significant variability in the ocular phenotype associated with MPS 295

but the causes of this variability remain poorly understood. It is unclear to 296

what extent the varying effect of genotype or enzyme levels contributes to this 297

variability and future prospective studies of large, well characterised MPS 298

cohorts are expected to provide important insights. 299

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Confidential: For Review OnlyAcknowledgements

The authors would like to acknowledge the contribution of Jean Mercer and

Jane Roberts in helping to identify patients suitable for this study. They also

acknowledge the support of the Manchester Biomedical Research Centre and

the Greater Manchester Comprehensive Local Research Network in helping

to facilitate this work.

Funding

This work was supported by BioMarin Pharmaceutical Inc. Grant

number: Ashworth / Grant G00423. The organization had no role in the design

or conduct of this research..

Competing interests

Dr. Ashworth reports grants from Biomarin Ltd, during the conduct of the

study; personal fees from Biomarin Ltd, personal fees from Inventiva,

personal fees from AbbVie, outside the submitted work.

Dr. Aslam reports grants from Biomarin, during the conduct of the study.

Dr. Jones reports personal fees and non-financial support from Biomarin,

outside the submitted work.

Dr. Ghosh reports personal fees from Alexion Pharmaceuticals, non-financial

support from Biomarin Pharmaceuticals, non-financial support from Shire

Pharmaceuticals, outside the submitted work.

Dr. Sergouniotis has nothing to disclose.

Dr. Javed has nothing to disclose.

Dr. Sornalingam reports grants from Biomarin, during the conduct of the

study, (research grant awarded to Jane Ashworth and paid to institution).

Contributorship Statement

Krishanthy Sornalingam drafted the manuscript, performed analysis and

interpretation of data, and was responsible for making revisions to the

manuscript.

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Confidential: For Review OnlyAhmed Javed was involved in acquisition of data and review of the

manuscript.

Tariq Aslam was involved in the design of this study, analysed data and

critically revised the manuscript.

Panagiotis Sergouniotis was involved in data analysis and critically revising

the manuscript.

Simon Jones was involved with the design of the study and revision of the

manuscript.

Arunabha Ghosh helped with data acquisition and review of the manuscript.

Jane Ashworth designed this study, was involved with data analysis and

interpretation, and drafting and critically revising this work.

All authors have approved this work and agree to be accountable for its content. Reference List

1 Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology 2011;50:v4-v12 2 Fenzl CR, Teramoto K and Moshirfar M. Ocular manifestations and management recommendations of lysosomal storage disorders I: mucopolysaccharidoses. Clinical Ophthalmology 2015;9:1633-1644

3 Ashworth JL, Biswas S, Wraith E et al. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006;51(1):1-17. 4 Ashworth JL, Biswas S, Wraith E et al. The Ocular features of the Mucopolysaccharidoses. Eye. 2006;20:553-563 5 Sawamoto K, Chen H, Almeciga-Diaz CJ et al. Gene Therapy for Mucopolysaccharidoses. Mol Genet Metab. 2018; 123; 59-68 6 Wynn RF, Wraith JE, Mercer J et al. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr. 2009;154(4):609-11 7 Langereis EJ, van Vlies N, Church HJ et al. Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy. Mol Genet Metab. 2015;114(2):129-37. 8 Bigger B, Langford-Smith K, Mercer J et al. Serum HCII-T and urinary DS:CS ratio are both predictive biomarkers of treatment outcome in patients

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Confidential: For Review Onlywith MPS I, II and VI Mol Genet Metab. 2011;102(2):S8-S9 9 Aldenhoven M, Wynn RF, Orchard PJ et al., Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125(13):2164-72.

10 Summers CG, Fahnehjelm KT, Pitz S et al. Systemic therapies for mucopolysaccharidosis: ocular changes following haematopoietic stem cell transplantation or enzyme replacement therapy- a review. Clin Experiment Ophthalmol.2010;38:34-42 11 Poswar F, Baldo G and Guigliani R. Phase I and II clinical trials for the mucopolysaccharidoses. Expert Opin Investig Drugs. 2017;26(12):1331-1340 12 Ahmed J, Aslam T and Ashworth J. Use of new imaging in detecting and monitoring ocular manifestations of the mucopolysaccharidoses. Acta Ophthalmol. 2016; 94(8) 13 Aslam TM, Tan SZ and Dhillon B. Use of iris recognition camera technology for the quantification of corneal opacification in mucopolysaccharidoses. Br J Ophthalmol. 2012;96(12):1466-8. 14 Elflein HM, Hofherr T, Berisha-Ramadani F et al. Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme. Br J Ophthalmol. 2013;97(7):829-33.

15 Fahnehjelm KT, Ashworth JL, Pitz S, et al Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 2012; 90:595–602. 16 Carpineto P, Nubile M, Toto L et al. Correlation in foveal thickness measurements between spectral-domain and time-domain optical coherence tomography in normal individuals. Eye. 2010;24:251-258 17 Yanni SE, Wang J, Cheng CS et al. Normative reference ranges for the retinal nerve fiber layer, macula, and retinal layer thicknesses in children. Am J Opthalmol. 2013;155(2):354-36

18 Seok S, Lyn IJ, Park KA et al., Spectral domain optical coherence tomography imaging of mucopolysaccharidoses I,II and VI A. Graefes Arch Clin Exp Ophthalmol. 2015;253:2111-2119

19 Lee YC. Spectral domain optical coherence tomography imaging of mucopolysaccharidoses I, II, IV A, and VI. Graefes Arch Clin Exp Ophthalmol. 2015; 253:2053

20 Ahmed J, Aslam T, Jones SA et al. The effect of haemopoietic stem cell transplantation on the ocular phenotype in mucopolysaccharidosis type I Hurler. Acta Ophthalmol. 2017; Advanced online publication. DOI: 10.1111/aos.13627

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Confidential: For Review Only 21 Ahmed J, Aslam T, Jones S et al. Objective Quantification of Changes in Corneal Clouding Over Time in Patients with Mucopolysaccharidosis. Invest ophth vis sci. 2017; 58:954-958

Figure Legends

Figure 1. Scatter graphs (a) Visual acuity against Iris camera Corneal Opacification Measure (COM) score (n=20 eyes). (b) Visual acuity against Pentacam densitometry scores (n=17 eyes). Data for patients with known retinopathy was excluded in (a) and (b). (c) Iris camera COM score against clinical corneal clouding grade (n=26 eyes) (d) Pentacam densitometry against clinical corneal clouding grade (n=23 eyes). Figure 2. Optos Vantage Colour images. (a) Optos right eye patient 5 (MPSI, 14years old). (b) Optos left eye patient 5. Clear view of fundus in both eyes and no abnormality detected in a patient with clinically graded mild corneal clouding. (c) Optos right eye patient 1 (MPSI, 4years old). Superior temporal peripheral RPE mottling. (d) Optos right eye patient 9 (MPSI, 44years old). Bone spicule pigmentation, RPE mottling and a small full disc. (e) Optos Left eye patient 7 (MPSI, 17 years old). Peri-macular and posterior pole likely atrophic changes. Mildly hazy view of fundus, in a patient with clinically graded moderate corneal clouding. (f) Optos right eye patient 4 (MPSI, 13 years old). Hazy view of fundus in a patient with clinically graded severe corneal clouding. Figure 3. Heidelberg OCT images. (a) OCT macula of right eye in patient 3 (MPSI, 15 years old). (b) OCT macula of left eye in Patient 3. Both eyes show parafoveal loss of the outer nuclear layer and inner segment ellipsoid corresponding to photoreceptor loss. A central foveal hyper-reflective zone was observed above the inner segment ellipsoid line in both eyes, possibly representing ELM thickening. (c) OCT macula of right eye in patient 9 (MPSI, 44years old). (d) OCT macula of left eye in patient 9. Both eyes show widespread thinning of photoreceptor layers. A hypo-reflective foveal lesion is seen in the left eye, consistent with a intraretinal cyst.

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Figure 1. Scatter graphs (a) Visual acuity against Iris camera Corneal Opacification Measure (COM) score (n=20 eyes). (b) Visual acuity against Pentacam densitometry scores (n=17 eyes). Data for patients with

known retinopathy was excluded in (a) and (b).

(c) Iris camera COM score against clinical corneal clouding grade (n=26 eyes) (d) Pentacam densitometry against clinical corneal clouding grade (n=23 eyes).

209x297mm (300 x 300 DPI)

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Figure 2. Optos Vantage Colour images. (a) Optos right eye patient 5 (MPSI, 14years old). (b) Optos left eye patient 5. Clear view of fundus in both eyes and no abnormality detected in a patient with clinically

graded mild corneal clouding. (c) Optos right eye patient 1 (MPSI, 4years old). Superior temporal peripheral

RPE mottling. (d) Optos right eye patient 9 (MPSI, 44years old). Bone spicule pigmentation, RPE mottling and a small full disc. (e) Optos Left eye patient 7 (MPSI, 17 years old). Peri-macular and posterior pole likely atrophic changes. Mildly hazy view of fundus, in a patient with clinically graded moderate corneal

clouding. (f) Optos right eye patient 4 (MPSI, 13 years old). Hazy view of fundus in a patient with clinically graded severe corneal clouding.

209x297mm (300 x 300 DPI)

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Figure 3. Heidelberg OCT images. (a) OCT macula of right eye in patient 3 (MPSI, 15 years old). (b) OCT macula of left eye in Patient 3. Both eyes show parafoveal loss of the outer nuclear layer and inner segment ellipsoid corresponding to photoreceptor loss. A central foveal hyper-reflective zone was observed above

the inner segment ellipsoid line in both eyes, possibly representing ELM thickening. (c) OCT macula of right eye in patient 9 (MPSI, 44years old). (d) OCT macula of left eye in patient 9. Both eyes show widespread thinning of photoreceptor layers. A hypo-reflective foveal lesion is seen in the left eye, consistent with a

intraretinal cyst.

209x297mm (300 x 300 DPI)

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Confidential: For Review OnlyPatient number

MPS Type

(Subtype)

Age (years)

Treatment Age at treatment

start

Length of treatment (complete

years)

Gender

1 I (H-S) 12 ERT 4years 8 M 2 I (H) 13 HSCT 1 year 12 F 3 I (H) 15 HSCT 1 year 14 F 4 I (H-S) 13 ERT 7 months 12 M 5 I (H-S) 14 ERT 2 years 12 M 6 I (H-S) 10 ERT 4 months 9 F 7 I (H) 17 ERT 6 years 11 F 8 I (H-S) 6 ERT 5 years 1 M 9 I 44 ERT 34 years 9 M 10 I (H) 7 HSCT * 10 months 6 F 11 I (H-S) 15 ERT 2 years 13 M 12 I (H) 7 HSCT * 7 months 6 M 13 I (H) 4 HSCT * 5 months 3 M 14 I (H) 18 HSCT 1 year 17 M 15 I (H) 4 HSCT * 6 months 3 F 16 I (H) 8 HSCT * 5 months 7 M 17 I (H) 12 HSCT * 1 year 11 F 18 I (H) 12 HSCT * 1 year 11 M 19 I (H) 11 HSCT 1 year 10 F 20 I (H-S) 12 ERT 2 years 10 F 21 I (H) 14 HSCT 1 year 13 M 22 IV 19 No current

treatment F

23 IV 13 No treatment

F

24 IV 11 ERT 10 years 1 F 25 IV(A) 15 ERT 14 years 1 F 26 VI 7 ERT 1 year 6 M 27 VI 15 ERT 5 years 10 F 28 VI 22 ERT 11 year 21 M Supplementary Table 1. Patient demographic and treatment data. H= Hurler, H-S= Hurler- Scheie ERT= Enzyme Replacement Therapy – in all subtypes given weekly MPS I (Laronidase), MPS IV (Elosulfate alfa) and MPS VI (Galsulfase). HSCT = Haematopoietic Stem Cell Transplant HSCT* = Indicates patients that had a short course of ERT prior to HSCT M= male, F= female

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Patient number

Clinical Corneal

Clouding Grade

Pentacam Densitometry scores IRIS Camera COM

scores

Digital slit lamp

colour images

OD OS OD OS GRADE

1 1 30.1 0.2844 0.3208 1

2 2 43.9 45.1 0.6784 ex 2

3 2 38.1 ex ex 2

4 3 No value given No value given ex ex 3

5 1 29.9 29.9 0.5081 1.0924

6 2 ex ex

7 2 0.5587 ex

8 2 3.9148 ex

9 1 17.7 16.2 1.5536 0.5349 1

10 2 42.7 40.6 ex ex

11 2 46.3 44.1 ex 1.1204 2

12 2

0.6959 ex 13 1 ex

14 2 52.1 54.9 ex ex

15 1 ND 0.126

16 1 30.4 32.1 0.838 0.3164

17 2 2.4686 ex 2

18 1 ex 2.859

19 1 29 ex ex

20 2 ex ex ex

21 2

22 1 1.1108 ex

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23 2 49.2 50.4 ex 4.2748 2

24 1 28.8 0.6824 ex 1

25 1 30 26.9 0.1164 0.1835 1

26 1 22.3 23.6 0.2196 0.2883 1

27 1 32.8 0.7669 1.2485 1

28 2 No value given No value given ex 4.0862 !

Supplementary Table 2. Anterior segment imaging data. Includes Pentacam Densitometry scores, Iris Camera Corneal Opacification Measure (COM) scores and Digital slit lamp colour photograph based clinical corneal clouding grades. No value given = Pentacam unable to give a reading for this patient. Blank boxes = No imaging taken. ex= excluded

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Patient Number

OPTOS Vantage OD

OPTOS Vantage OS

OCT macula OD

OCT macula OS

OCT DISC DONE

Quality Description

of findings Quality Description

of findings Description of findings

Central foveal

thickness

Description of findings

Central foveal

thickness

1 Clear view

Peripheral RPE mottling supra temporally

Clear view

NAD * 215 * 219

2 Clear view

NAD Clear view

NAD * 207

* 201

3 Hazy view

NAD Hazy view

NAD a Loss of inner segment ellipsoid and outer nuclear layer in parafoveal area *

198 Loss of inner segment ellipsoid and outer nuclear layer in parafoveal area *

199

4 Very hazy view

* 207 * 206

5 Clear view

NAD Clear view

NAD * 235 * 235 Y

6 Hazy view

NAD Clear view

Para-macula depigmented

* 209 * 192 Y

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changes 7 Hazy

view Peri-macular and posterior pole changes

Slightly hazy view

Peri-macular and posterior pole changes

Abnormal contour consistent with chorioretinal folds

Excluded Abnormal contour consistent with chorioretinal folds

Excluded Y

8 X X 9 Clear

view Bone spicule pigmentation, RPE mottling, small full disc

Clear view

Bone spicule pigmentation, RPE mottling, small full disc

Widespread thinning of photoreceptor layers

166 Widespread thinning of photoreceptor layers and hyporeflective foveal lesion (likely intraretinal cyst)

Excluded Y

10 Slightly hazy view

Pink full disc Slight haze

Full disc

11 * 218 * 205 Y 12 X X 13 X X 14 X X Disruption of/

loss of parafoveal inner segment ellipsoid

251 Disruption of/ loss of parafoveal inner segment ellipsoid

254 Y

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*

*

15 X X 16 X X 17 X X 18 X X 19 X X 20 X X 21 X X 22 X X 23 Hazy

view NAD a Hazy

view NAD a

24 X X 25 X X NAD 231 NAD 226 Y 26 Clear

view Small grey discs

Clear view

Small grey discs

NAD 209 NAD 209 Y

27 X X 28 Hazy

view NAD Hazy

view NAD

Supplementary Table 3. Posterior segment imaging findings. Includes Optos Vantage widefield imaging and Heidelberg Spectralis OCT findings. X = imaging not performed. NAD= No abnormality detected. a = artefact. *= central foveal hyper-reflective zone observed above the inner segment ellipsoid (possibly represents thickening of ELM).

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Patient number

Genetic defect

Biomarker data

Gene Allele 1 Allele 2 DS/CS ratio KS/CS ratio Iduronidase levels MPS I post-HSCT

(µmol/g/hr) 1 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.59 NA (MPS I) NA (ERT) 2 IDUA p.(Trp402Ter) c.64_65delC 0.84 NA (MPS I) 31 3 IDUA c.783delC c.783delC 0.6 NA (MPS I) 16.6 4 IDUA Not in database 0.7 NA (MPS I) NA (ERT) 5 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.49 NA (MPS I) NA (ERT) 6 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.47 NA (MPS I) NA (ERT) 7 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.66 NA (MPS I) NA (ERT) 8 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.88 NA (MPS I) NA (ERT) 9 IDUA Not in database 1.27 NA (MPS I) NA (ERT)

10 IDUA p.(Gln70Ter) c.1277_1283dup7 0.36 NA (MPS I) 62 11 IDUA p.(Gln380Arg) p.(Thr388Arg) 1.17 NA (MPS I) NA (ERT) 12 IDUA p.(Trp402Ter) p.(Trp402Ter) 0.42 NA (MPS I) 75.59 13 IDUA p.(Asp349Tyr) p.(Asp349Tyr) 0.51 NA (MPS I) 45 14 IDUA p.(Trp402Ter) p.(Ala327Pro) 0.6 NA (MPS I) 31.4 15 IDUA c.(?_- 88)_(299+1_300-1)del c.(?_-88?)_(*136?)del 0.46 NA (MPS I) 21 16 IDUA p.(Trp402Ter) p.(Gln70Ter) 0.34 NA (MPS I) 47 17 IDUA p.(Trp402Ter) p.(Trp402Ter) 0.49 NA (MPS I) 28 18 IDUA c.386-2a->g p.(Leu14Arg) 0.22 NA (MPS I) 61.15 19 IDUA p.(Trp402Ter) c.386-2a->g 0.59 NA (MPS I) 62.57 20 IDUA p.(Leu490Pro) p.(Leu490Pro) 0.73 NA (MPS I) NA (ERT) 21 IDUA p.(Trp402Ter) p.(Thr388Arg) 0.53 NA (MPS I) 43 22 GALNS Not in database NA (MPS IV) No result on NA (not MPS I)

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Supplementary Table 4. Genetic and Biomarker data for individual patients.

file 23 GALNS p.(Gly116Val) p.(Gly116Val) NA (MPS IV) 0.49 NA (not MPS I) 24 GALNS Not in database NA (MPS IV) Not tested NA (not MPS I) 25 GALNS p.(His166Arg) p.(His166Arg) NA (MPS IV) 0.32 NA (not MPS I)

26 ARSB DNA apparently sent but no report in database 0.38 NA (MPS VI) NA (not MPS I)

27 ARSB Not in database 0.85 NA (MPS VI) NA (not MPS I) 28 ARSB Not in database 0.71 NA (MPS VI) NA (not MPS I)

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Documents

Variability in the Ocular Phenotype in Mucopolysaccharidosis.€¦ · Confidential: For Review Only TITLE PAGE Variability in the Ocular Phenotype in Mucopolysaccharidosis. Krishanthy