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Clinical and molecular characterization of non-syndromic retinal dystrophy due to c.175G>A mutation in ceroid lipofuscinosis neuronal 3 (CLN3)

  • Clinical Case Report
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Abstract

Purpose

Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations.

Methods

A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing.

Results

Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient’s serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected.

Conclusions

Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease.

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References

  1. Consortium TIBD (1995) Isolation of a novel gene underlying Batten disease, CLN3. Cell 82(6):949–957

    Article  Google Scholar 

  2. Munroe PB, Mitchison HM, O’Rawe AM, Anderson JW, Boustany RM, Lerner TJ, Taschner PE, de Vos N, Breuning MH, Gardiner RM, Mole SE (1997) Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet 61(2):310–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jarvela I, Autti T, Lamminranta S, Aberg L, Raininko R, Santavuori P (1997) Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann Neurol 42(5):799–802. https://doi.org/10.1002/ana.410420517

    Article  CAS  PubMed  Google Scholar 

  4. Lauronen L, Munroe PB, Jarvela I, Autti T, Mitchison HM, O’Rawe AM, Gardiner RM, Mole SE, Puranen J, Hakkinen AM, Kirveskari E, Santavuori P (1999) Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis. Neurology 52(2):360–365

    Article  CAS  PubMed  Google Scholar 

  5. Wisniewski KE, Zhong N, Kaczmarski W, Kaczmarski A, Kida E, Brown WT, Schwarz KO, Lazzarini AM, Rubin AJ, Stenroos ES, Johnson WG, Wisniewski TM (1998) Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis. Ann Neurol 43(1):106–110. https://doi.org/10.1002/ana.410430118

    Article  CAS  PubMed  Google Scholar 

  6. Wang F, Wang H, Tuan HF, Nguyen DH, Sun V, Keser V, Bowne SJ, Sullivan LS, Luo H, Zhao L, Wang X, Zaneveld JE, Salvo JS, Siddiqui S, Mao L, Wheaton DK, Birch DG, Branham KE, Heckenlively JR, Wen C, Flagg K, Ferreyra H, Pei J, Khan A, Ren H, Wang K, Lopez I, Qamar R, Zenteno JC, Ayala-Ramirez R, Buentello-Volante B, Fu Q, Simpson DA, Li Y, Sui R, Silvestri G, Daiger SP, Koenekoop RK, Zhang K, Chen R (2014) Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet 133(3):331–345. https://doi.org/10.1007/s00439-013-1381-5

    Article  CAS  PubMed  Google Scholar 

  7. Ku CA, Hull S, Arno G, Vincent A, Carss K, Kayton R, Weeks D, Anderson GW, Geraets R, Parker C, Pearce DA, Michaelides M, MacLaren RE, Robson AG, Holder GE, Heon E, Raymond FL, Moore AT, Webster AR, Pennesi ME (2017) Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration. JAMA Ophthalmol 135(7):749–760. https://doi.org/10.1001/jamaophthalmol.2017.1401

    Article  PubMed  PubMed Central  Google Scholar 

  8. Drack AV, Mullins RF, Pfeifer WL, Augustine EF, Stasheff SF, Hong SD (2015) Immunosuppressive treatment for retinal degeneration in juvenile neuronal ceroid lipofuscinosis (juvenile batten disease). Ophthalmic Genet 36(4):359–364. https://doi.org/10.3109/13816810.2014.886271

    Article  CAS  PubMed  Google Scholar 

  9. Pearce DA, Atkinson M, Tagle DA (2004) Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders. Neurology 63(11):2001–2005

    Article  CAS  PubMed  Google Scholar 

  10. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol Adv Ophthalmol 130(1):1–12. https://doi.org/10.1007/s10633-014-9473-7

    Article  Google Scholar 

  11. Chen FK, Chew AL, Zhang D, Chen SC, Chelva E, Chandrasekera E, Koay EMH, Forrester J, McLenachan S (2017) Acute progressive paravascular placoid neuroretinopathy with negative-type electroretinography in paraneoplastic retinopathy. Doc Ophthalmol Adv Ophthalmol 134(3):227–235. https://doi.org/10.1007/s10633-017-9587-9

    Article  Google Scholar 

  12. De Roach JN, McLaren TL, Paterson RL, O’Brien EC, Hoffmann L, Mackey DA, Hewitt AW, Lamey TM (2013) Establishment and evolution of the Australian inherited retinal disease register and DNA bank. Clin Exp Ophthalmol 41(5):476–483. https://doi.org/10.1111/ceo.12020

    Article  PubMed  Google Scholar 

  13. Chiang JP, Lamey T, McLaren T, Thompson JA, Montgomery H, De Roach J (2015) Progress and prospects of next-generation sequencing testing for inherited retinal dystrophy. Expert Rev Mol Diagn 15(10):1269–1275. https://doi.org/10.1586/14737159.2015.1081057

    Article  CAS  PubMed  Google Scholar 

  14. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE (2016) HGVS recommendations for the description of sequence variants: 2016 update. Hum mutat 37(6):564–569. https://doi.org/10.1002/humu.22981

    Article  CAS  Google Scholar 

  15. Thompson JA, De Roach JN, McLaren TL, Montgomery HE, Hoffmann LH, Campbell IR, Chen FK, Mackey DA, Lamey TM (2017) The genetic profile of Leber congenital amaurosis in an Australian cohort. Mol Genet Genomic Med 5(6):652–667. https://doi.org/10.1002/mgg3.321

    Article  PubMed  PubMed Central  Google Scholar 

  16. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for molecular pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  17. Aungaroon G, Hallinan B, Jain P, Horn PS, Spaeth C, Arya R (2016) Correlation among genotype, phenotype, and histology in neuronal ceroid lipofuscinoses: an individual patient data meta-analysis. Pediatr Neurol 60:42–48.e44. https://doi.org/10.1016/j.pediatrneurol.2016.03.018

    Article  PubMed  Google Scholar 

  18. Sarpong A, Schottmann G, Ruther K, Stoltenburg G, Kohlschutter A, Hubner C, Schuelke M (2009) Protracted course of juvenile ceroid lipofuscinosis associated with a novel CLN3 mutation (p.Y199X). Clin Genet 76(1):38–45. https://doi.org/10.1111/j.1399-0004.2009.01179.x

    Article  CAS  PubMed  Google Scholar 

  19. Ouseph MM, Kleinman ME, Wang QJ (2016) Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Ann N Y Acad Sci 1371(1):55–67. https://doi.org/10.1111/nyas.12990

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hainsworth DP, Liu GT, Hamm CW, Katz ML (2009) Funduscopic and angiographic appearance in the neuronal ceroid lipofuscinoses. Retina 29(5):657–668. https://doi.org/10.1097/IAE.0b013e31819b0542

    Article  PubMed  Google Scholar 

  21. Collins J, Holder GE, Herbert H, Adams GG (2006) Batten disease: features to facilitate early diagnosis. Br J Ophthalmol 90(9):1119–1124. https://doi.org/10.1136/bjo.2006.091637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eksandh LB, Ponjavic VB, Munroe PB, Eiberg HE, Uvebrant PE, Ehinger BE, Mole SE, Andreasson S (2000) Full-field ERG in patients with Batten/Spielmeyer-Vogt disease caused by mutations in the CLN3 gene. Ophthalmic Genet 21(2):69–77

    Article  CAS  PubMed  Google Scholar 

  23. Dulz S, Wagenfeld L, Nickel M, Richard G, Schwartz R, Bartsch U, Kohlschutter A, Schulz A (2016) Novel morphological macular findings in juvenile CLN3 disease. Br J Ophthalmol 100(6):824–828. https://doi.org/10.1136/bjophthalmol-2015-307320

    Article  CAS  PubMed  Google Scholar 

  24. Hansen MS, Hove MN, Jensen H, Larsen M (2016) Optical coherence tomography in juvenile neuronal ceroid lipofuscinosis. Retin Cases Brief Rep 10(2):137–139. https://doi.org/10.1097/icb.0000000000000200

    Article  PubMed  PubMed Central  Google Scholar 

  25. Preising MN, Abura M, Jäger M, Wassill K-H, Lorenz B (2017) Ocular morphology and function in juvenile neuronal ceroid lipofuscinosis (CLN3) in the first decade of life. Ophthalmic Genet 38(3):252–259

    Article  CAS  PubMed  Google Scholar 

  26. Castaneda JA, Pearce DA (2008) Identification of alpha-fetoprotein as an autoantigen in juvenile Batten disease. Neurobiol Dis 29(1):92–102. https://doi.org/10.1016/j.nbd.2007.08.007

    Article  CAS  PubMed  Google Scholar 

  27. Chattopadhyay S, Ito M, Cooper JD, Brooks AI, Curran TM, Powers JM, Pearce DA (2002) An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 11(12):1421–1431

    Article  CAS  PubMed  Google Scholar 

  28. Lim MJ, Beake J, Bible E, Curran TM, Ramirez-Montealegre D, Pearce DA, Cooper JD (2006) Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosis. Neuropathol Appl Neurobiol 32(5):469–482. https://doi.org/10.1111/j.1365-2990.2006.00738.x

    Article  CAS  PubMed  Google Scholar 

  29. Ramirez-Montealegre D, Chattopadhyay S, Curran TM, Wasserfall C, Pritchard L, Schatz D, Petitto J, Hopkins D, She JX, Rothberg PG, Atkinson M, Pearce DA (2005) Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Neurology 64(4):743–745. https://doi.org/10.1212/01.wnl.0000151973.08426.7e

    Article  CAS  PubMed  Google Scholar 

  30. Seehafer SS, Ramirez-Montealegre D, Wong AM, Chan CH, Castaneda J, Horak M, Ahmadi SM, Lim MJ, Cooper JD, Pearce DA (2011) Immunosuppression alters disease severity in juvenile Batten disease mice. J Neuroimmunol 230(1–2):169–172. https://doi.org/10.1016/j.jneuroim.2010.08.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Groh J, Berve K, Martini R (2017) Fingolimod and teriflunomide attenuate neurodegeneration in mouse models of neuronal ceroid lipofuscinosis. Mol Ther 25(8):1889–1899. https://doi.org/10.1016/j.ymthe.2017.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Adamus G, Chew EY, Ferris FL, Klein ML (2014) Prevalence of anti-retinal autoantibodies in different stages of age-related macular degeneration. BMC Ophthalmol 14:154. https://doi.org/10.1186/1471-2415-14-154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Adamus G, Ren G, Weleber RG (2004) Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 4:5. https://doi.org/10.1186/1471-2415-4-5

    Article  PubMed  PubMed Central  Google Scholar 

  34. Heckenlively JR, Jordan BL, Aptsiauri N (1999) Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 127(5):565–573

    Article  CAS  PubMed  Google Scholar 

  35. Iannaccone A, Giorgianni F, New DD, Hollingsworth TJ, Umfress A, Alhatem AH, Neeli I, Lenchik NI, Jennings BJ, Calzada JI, Satterfield S, Mathews D, Diaz RI, Harris T, Johnson KC, Charles S, Kritchevsky SB, Gerling IC, Beranova-Giorgianni S, Radic MZ (2015) Circulating autoantibodies in age-related macular degeneration recognize human macular tissue antigens implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. PLoS ONE 10(12):e0145323. https://doi.org/10.1371/journal.pone.0145323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhu L, Shen W, Zhu M, Coorey NJ, Nguyen AP, Barthelmes D, Gillies MC (2013) Anti-retinal antibodies in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci 54(8):5675–5683. https://doi.org/10.1167/iovs.13-12050

    Article  CAS  PubMed  Google Scholar 

  37. Adamus G (2018) Are anti-retinal autoantibodies a cause or a consequence of retinal degeneration in autoimmune retinopathies? Front Immunol 9:765. https://doi.org/10.3389/fimmu.2018.00765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N (2000) Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol 118(11):1525–1533

    Article  CAS  PubMed  Google Scholar 

  39. Boudreault K, Justus S, Sengillo JD, Schuerch K, Lee W, Cabral T, Tsang SH (2017) Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy. Orphanet J Rare Dis 12(1):129. https://doi.org/10.1186/s13023-017-0680-7

    Article  PubMed  PubMed Central  Google Scholar 

  40. Davoudi S, Ebrahimiadib N, Yasa C, Sevgi DD, Roohipoor R, Papavasilieou E, Comander J, Sobrin L (2017) Outcomes in autoimmune retinopathy patients treated with rituximab. Am J Ophthalmol 180:124–132. https://doi.org/10.1016/j.ajo.2017.04.019

    Article  CAS  PubMed  Google Scholar 

  41. Fox A, Jeffrey B, Hasni S, Nussenblatt R, Sen HN (2015) Rituximab treatment for nonparaneoplastic autoimmune retinopathy. Can J Ophthalmol 50(6):e101–e104. https://doi.org/10.1016/j.jcjo.2015.08.009

    Article  PubMed  Google Scholar 

  42. Cotman SL, Staropoli JF (2012) The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking. Clin Lipidol 7(1):79–91. https://doi.org/10.2217/clp.11.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Golabek AA, Kida E, Walus M, Kaczmarski W, Michalewski M, Wisniewski KE (2000) CLN3 protein regulates lysosomal pH and alters intracellular processing of Alzheimer’s amyloid-beta protein precursor and cathepsin D in human cells. Mol Genet Metab 70(3):203–213. https://doi.org/10.1006/mgme.2000.3006

    Article  CAS  PubMed  Google Scholar 

  44. Lojewski X, Staropoli JF, Biswas-Legrand S, Simas AM, Haliw L, Selig MK, Coppel SH, Goss KA, Petcherski A, Chandrachud U, Sheridan SD, Lucente D, Sims KB, Gusella JF, Sondhi D, Crystal RG, Reinhardt P, Sterneckert J, Scholer H, Haggarty SJ, Storch A, Hermann A, Cotman SL (2014) Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway. Hum Mol Genet 23(8):2005–2022. https://doi.org/10.1093/hmg/ddt596

    Article  CAS  PubMed  Google Scholar 

  45. Rakheja D, Narayan SB, Bennett MJ (2008) The function of CLN3P, the Batten disease protein. Mol Genet Metab 93(3):269–274

    Article  CAS  PubMed  Google Scholar 

  46. Sinha S, Satishchandra P, Santosh V, Gayatri N, Shankar SK (2004) Neuronal ceroid lipofuscinosis: a clinicopathological study. Seizure 13(4):235–240. https://doi.org/10.1016/s1059-1311(03)00163-8

    Article  PubMed  Google Scholar 

  47. Carpenter S, Karpati G, Andermann F, Jacob J, Andermann E (1977) The ultrastructural characteristics of the abnormal cytosomes in Batten-Kufs’ disease. Brain J Neurol 100:137–156

    Article  Google Scholar 

  48. Casper J, Zweig AS, Villarreal C, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, Lee CM, Lee BT, Karolchik D, Hinrichs AS, Haeussler M, Guruvadoo L, Navarro Gonzalez J, Gibson D, Fiddes IT, Eisenhart C, Diekhans M, Clawson H, Barber GP, Armstrong J, Haussler D, Kuhn RM, Kent WJ (2018) The UCSC genome browser database: 2018 update. Nucleic Acids Res 46(D1):D762–d769. https://doi.org/10.1093/nar/gkx1020

    Article  CAS  PubMed  Google Scholar 

  49. Jarvela I, Lehtovirta M, Tikkanen R, Kyttala A, Jalanko A (1999) Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Hum Mol Genet 8(6):1091–1098

    Article  CAS  PubMed  Google Scholar 

  50. Mole SE, Cotman SL (2015) Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochimica et biophysica acta. https://doi.org/10.1016/j.bbadis.2015.05.011

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mole SE, Mitchison HM, Munroe PB (1999) Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Hum Mutat 14(3):199–215. https://doi.org/10.1002/(SICI)1098-1004(1999)14:3%3c199:AID-HUMU3%3e3.0.CO;2-A

    Article  CAS  PubMed  Google Scholar 

  52. Kitzmuller C, Haines RL, Codlin S, Cutler DF, Mole SE (2008) A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis. Hum Mol Genet 17(2):303–312. https://doi.org/10.1093/hmg/ddm306

    Article  CAS  PubMed  Google Scholar 

  53. Chan CH, Mitchison HM, Pearce DA (2008) Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models. Hum Mol Genet 17(21):3332–3339. https://doi.org/10.1093/hmg/ddn228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Miller JN, Chan CH, Pearce DA (2013) The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis. Hum Mol Genet 22(13):2723–2734. https://doi.org/10.1093/hmg/ddt120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bergholz R, Kohlschutter A, Schulz A, Hubert W, Ruther K (2015) Phenotyping heterozygous carriers of juvenile neuronal ceroid lipofuscinosis with CLN3 mutations. Graefe’s Arch Clin Exp Ophthalmol 253(8):1245–1250. https://doi.org/10.1007/s00417-014-2814-0

    Article  Google Scholar 

  56. Farkas MH, Grant GR, White JA, Sousa ME, Consugar MB, Pierce EA (2013) Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes. BMC Genom 14:486. https://doi.org/10.1186/1471-2164-14-486

    Article  Google Scholar 

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Funding

This work was supported by funding from the Ophthalmic Research Institute of Australia (FKC, SM), Global Ophthalmology Award Program Bayer (FKC), Retina Australia (FKC, TM, JDR, JAT, TL), National Health and Medical Research Council Centre of Research Excellence and Career Development Fellowship (APP1116360, APP1142962, FKC), Department of Health Western Australia New Independent Researcher Infrastructure Support Award (FKC), Australian Foundation for the Prevention of Blindness (FKC) and the Miocevich Retina Fellowship (FKC, SA).

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Authors and Affiliations

  1. Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia

    Fred K. Chen, Xiao Zhang, Jonathan Eintracht, Dan Zhang, Tina Lamey, John De Roach & Samuel McLenachan

  2. Ocular Tissue Engineering Laboratory, Lions Eye Institute, 2 Verdun Street, Perth, Nedlands, WA, Australia

    Fred K. Chen, Xiao Zhang, Jonathan Eintracht, Dan Zhang, Sukanya Arunachalam, Shang-Chih Chen & Samuel McLenachan

  3. Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia

    Fred K. Chen

  4. Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia

    Jennifer A. Thompson, Enid Chelva, Terri McLaren, Tina Lamey & John De Roach

  5. Department of Immunology, Fiona Stanley Hospital, Perth, WA, Australia

    Dominic Mallon

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  1. Fred K. Chen
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Correspondence to Samuel McLenachan.

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Data generated during the course of the current study are available from the corresponding author on reasonable request.

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Online Resource 1:

Greytone output of serial 24-2 Humphrey field test over an 18 year period showing progressive peripheral sensitivity loss and development of a macular scotoma leaving a rim of vision spanning 5-10 degrees eccentricity. The central scotoma appeared first in the left eye and then started to develop in the right eye at around the time the patient noted accelerated vision loss. Online Resource 2: Visual field index trend analysis (24-2) between 37 and 55 years of age (upper panels. Pointwise threshold deviation (24-2) between 37 and 55 years of age (middle panels). Visual acuity change between 37 to 55 years of age (lower panels). Online Resource 3: Right and left eye Optos widefield colour (A, B) and green autofluorescence (C, D) images at the age 54 years (4 years after presentation, see figure 1) showing small circular regions of hypoautofluoresence. Some of these were associated with hyperpigmentation in the right eye (arrows). Online Resource 4: Visual acuity (ETDRS) score change over time (upper panel). Visual field index change over time (middle panel). Total macular volume change over time (lower panel). Online Resource 5: MAIA microperimetry showed central scotoma in both eyes at initial presentation at the age of 50 years old. The size of scotoma enlarged slightly in the left eye by May 2016 and then right scotoma enlarged by November 2016 (2 years following rituximab). By August 2018, dense scotoma size had increased in both eyes and surrounding sensitivity declined further. Insert shows distribution of fixation locus and the bivariate contour ellipsoid area increased significantly in both eyes over a period of 4 years despite improvement in visual acuity in the left eye. Online Resource 6: Serial fundus auto-fluorescence imaging showing the oval ring of hyper-autofluorescence in the foveal region gradually evolving into a stippled hypo-fluorescent ring sparing the foveal centre over a 4 year period. Online Resource 7: Candidate heterozygous variants (pathogenic or of uncertain significance) excluded as a primary cause of disease. (PDF 3039 kb)

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Chen, F.K., Zhang, X., Eintracht, J. et al. Clinical and molecular characterization of non-syndromic retinal dystrophy due to c.175G>A mutation in ceroid lipofuscinosis neuronal 3 (CLN3). Doc Ophthalmol 138, 55–70 (2019). https://doi.org/10.1007/s10633-018-9665-7

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