variability in the ocular phenotype in mucopolysaccharidosis.€¦ · confidential: for review only...
TRANSCRIPT
The University of Manchester Research
Variability in the Ocular Phenotype inMucopolysaccharidosis.DOI:10.1136/bjophthalmol-2017-311749
Document VersionAccepted author manuscript
Link to publication record in Manchester Research Explorer
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
Citing this paperPlease note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscriptor Proof version this may differ from the final Published version. If citing, it is advised that you check and use thepublisher's definitive version.
General rightsCopyright and moral rights for the publications made accessible in the Research Explorer are retained by theauthors and/or other copyright owners and it is a condition of accessing publications that users recognise andabide by the legal requirements associated with these rights.
Takedown policyIf you believe that this document breaches copyright please refer to the University of Manchester’s TakedownProcedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providingrelevant details, so we can investigate your claim.
Download date:21. Jun. 2020
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
Page 1 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 2 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
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
Page 3 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 4 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 5 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 6 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 7 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 8 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 9 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 10 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 11 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 12 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 13 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 14 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 15 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 16 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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.
Page 17 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 18 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 19 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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.
Page 20 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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)
Page 21 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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)
Page 22 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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)
Page 23 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
Page 24 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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
Page 25 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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
Page 26 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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
Page 27 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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
Page 28 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
*
*
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).
Page 29 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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)
Page 30 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
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)
Page 31 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
209x297mm (300 x 300 DPI)
Page 32 of 32
https://mc.manuscriptcentral.com/bjo
British Journal of Ophthalmology
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960