Documenta Ophthalmologica

, Volume 138, Issue 1, pp 55–70 | Cite as

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

  • Fred K. Chen
  • Xiao Zhang
  • Jonathan Eintracht
  • Dan Zhang
  • Sukanya Arunachalam
  • Jennifer A. Thompson
  • Enid Chelva
  • Dominic Mallon
  • Shang-Chih Chen
  • Terri McLaren
  • Tina Lamey
  • John De Roach
  • Samuel McLenachanEmail author
Clinical Case Report



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.


Juvenile 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 availability

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

Informed consent

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.

Supplementary material

10633_2018_9665_MOESM1_ESM.pdf (3 mb)
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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Ophthalmology and Visual ScienceThe University of Western AustraliaPerthAustralia
  2. 2.Ocular Tissue Engineering LaboratoryLions Eye InstitutePerth, NedlandsAustralia
  3. 3.Department of OphthalmologyRoyal Perth HospitalPerthAustralia
  4. 4.Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and PhysicsSir Charles Gairdner HospitalPerthAustralia
  5. 5.Department of ImmunologyFiona Stanley HospitalPerthAustralia

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