Clinical and molecular characterization of non-syndromic retinal dystrophy due to c.175G>A mutation in ceroid lipofuscinosis neuronal 3 (CLN3)
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.
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.
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.
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.
KeywordsJuvenile neuronal ceroid lipofuscinosis Retinitis pigmentosa Autoimmune retinopathy Retina CLN3 Splicing
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).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Data generated during the course of the current study are available from the corresponding author on reasonable request.
Informed consent was obtained from all individual participants included in the study.
Statement of human rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Statement on the welfare of animals
No animals were used in this study.
- 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):360–365CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 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 CrossRefGoogle 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 CrossRefGoogle Scholar