Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration

Cristy A. Ku, Sarah Hull, Gavin Arno, Ajoy Vincent, Keren Carss, Robert Kayton, Douglas Weeks, Glenn W. Anderson, Ryan Geraets, Camille Parker, David A. Pearce, Michel Michaelides, Robert E. MacLaren, Anthony G. Robson, Graham E. Holder, Elise Heon, F. Lucy Raymond, Anthony T. Moore, Andrew R. Webster, Mark Pennesi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

IMPORTANCE: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. OBJECTIVE: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURES: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. RESULTS: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. CONCLUSIONS AND RELEVANCE: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

Original languageEnglish (US)
Pages (from-to)749-760
Number of pages12
JournalJAMA Ophthalmology
Volume135
Issue number7
DOIs
StatePublished - Jul 1 2017

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Retinal Degeneration
Molecular Biology
Phenotype
Retinal Diseases
Age of Onset
Mutation
Retinitis Pigmentosa
Multimodal Imaging
Neuronal Ceroid-Lipofuscinoses
Exome
Electroretinography
Vertebrate Photoreceptor Cells
Visual Field Tests
Macular Edema
Electrophysiology
Optical Coherence Tomography
Rare Diseases
Neurodegenerative Diseases
Nervous System
Atrophy

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration. / Ku, Cristy A.; Hull, Sarah; Arno, Gavin; Vincent, Ajoy; Carss, Keren; Kayton, Robert; Weeks, Douglas; Anderson, Glenn W.; Geraets, Ryan; Parker, Camille; Pearce, David A.; Michaelides, Michel; MacLaren, Robert E.; Robson, Anthony G.; Holder, Graham E.; Heon, Elise; Raymond, F. Lucy; Moore, Anthony T.; Webster, Andrew R.; Pennesi, Mark.

In: JAMA Ophthalmology, Vol. 135, No. 7, 01.07.2017, p. 749-760.

Research output: Contribution to journalArticle

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, M 2017, 'Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration', JAMA Ophthalmology, vol. 135, no. 7, pp. 749-760. https://doi.org/10.1001/jamaophthalmol.2017.1401
Ku, Cristy A. ; Hull, Sarah ; Arno, Gavin ; Vincent, Ajoy ; Carss, Keren ; Kayton, Robert ; Weeks, Douglas ; Anderson, Glenn W. ; Geraets, Ryan ; Parker, Camille ; Pearce, David A. ; Michaelides, Michel ; MacLaren, Robert E. ; Robson, Anthony G. ; Holder, Graham E. ; Heon, Elise ; Raymond, F. Lucy ; Moore, Anthony T. ; Webster, Andrew R. ; Pennesi, Mark. / Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration. In: JAMA Ophthalmology. 2017 ; Vol. 135, No. 7. pp. 749-760.
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AU - Ku, Cristy A.

AU - Hull, Sarah

AU - Arno, Gavin

AU - Vincent, Ajoy

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AU - Kayton, Robert

AU - Weeks, Douglas

AU - Anderson, Glenn W.

AU - Geraets, Ryan

AU - Parker, Camille

AU - Pearce, David A.

AU - Michaelides, Michel

AU - MacLaren, Robert E.

AU - Robson, Anthony G.

AU - Holder, Graham E.

AU - Heon, Elise

AU - Raymond, F. Lucy

AU - Moore, Anthony T.

AU - Webster, Andrew R.

AU - Pennesi, Mark

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N2 - IMPORTANCE: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. OBJECTIVE: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURES: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. RESULTS: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. CONCLUSIONS AND RELEVANCE: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

AB - IMPORTANCE: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. OBJECTIVE: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURES: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. RESULTS: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. CONCLUSIONS AND RELEVANCE: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

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