The University of Manchester Research Variability in the Ocular Phenotype in Mucopolysaccharidosis. DOI: 10.1136/bjophthalmol-2017-311749 Document Version Accepted 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). Variability in 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 paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. General rights Copyright and moral rights for the publications made accessible in the Research Explorer are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Takedown policy If you believe that this document breaches copyright please refer to the University of Manchester’s Takedown Procedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providing relevant details, so we can investigate your claim. Download date:21. Jun. 2020
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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.
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
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
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
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
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.
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
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
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
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).
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)
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)