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

Doc Ophthalmol. 2019 Feb;138(1):55-70. doi: 10.1007/s10633-018-9665-7. Epub 2018 Nov 16.


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.

Keywords: Autoimmune retinopathy; CLN3; Juvenile neuronal ceroid lipofuscinosis; Retina; Retinitis pigmentosa; Splicing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / blood
  • Autoantigens / immunology
  • Blotting, Western
  • Electroretinography
  • Exons
  • Female
  • Humans
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Molecular Chaperones / genetics*
  • Multimodal Imaging
  • Mutation, Missense*
  • Neuronal Ceroid-Lipofuscinoses / diagnosis
  • Neuronal Ceroid-Lipofuscinoses / genetics*
  • Neuronal Ceroid-Lipofuscinoses / immunology
  • Neuronal Ceroid-Lipofuscinoses / physiopathology
  • Pedigree
  • Retina / immunology
  • Retina / physiopathology
  • Retinal Dystrophies / diagnosis
  • Retinal Dystrophies / genetics*
  • Retinal Dystrophies / immunology
  • Retinal Dystrophies / physiopathology
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Visual Acuity / physiology


  • Autoantibodies
  • Autoantigens
  • CLN3 protein, human
  • Membrane Glycoproteins
  • Molecular Chaperones