PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/624955 |
| Date | 06 June 2017 |
| Creators | Khan, Kamron N., El-Asrag, Mohammed E., Ku, Cristy A., Holder, Graham E., McKibbin, Martin, Arno, Gavin, Poulter, James A., Carss, Keren, Bommireddy, Tejaswi, Bagheri, Saghar, Bakall, Benjamin, Scholl, Hendrik P., Raymond, F. Lucy, Toomes, Carmel, Inglehearn, Chris F., Pennesi, Mark E., Moore, Anthony T., Michaelides, Michel, Webster, Andrew R., Ali, Manir |
| Contributors | Univ Arizona, Coll Med, University College London Institute of Ophthalmology, London, United Kingdom 2Inherited Eye Disease Service, Moorfields Eye Hospital, London, United Kingdom 3Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom 4Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom 5Department of Zoology, Faculty of Science, Benha University, Benha, Egypt, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States, University College London Institute of Ophthalmology, London, United Kingdom 2Inherited Eye Disease Service, Moorfields Eye Hospital, London, United Kingdom 7Department of Electrophysiology, Moorfields Eye Hospital, London, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom 4Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom, University College London Institute of Ophthalmology, London, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom, National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom 9Department of Haematology, University of Cambridge, Cambridge, United Kingdom, Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States, Associated Retina Consultants, Phoenix, Arizona, United States 12University of Arizona, College of Medicine, Phoenix, Arizona, United States, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States, National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom 13Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States, University College London Institute of Ophthalmology, London, United Kingdom 2Inherited Eye Disease Service, Moorfields Eye Hospital, London, United Kingdom 14Department of Ophthalmology, University of California–San Francisco School of Medicine, San Francisco, California, United States, University College London Institute of Ophthalmology, London, United Kingdom 2Inherited Eye Disease Service, Moorfields Eye Hospital, London, United Kingdom, University College London Institute of Ophthalmology, London, United Kingdom 2Inherited Eye Disease Service, Moorfields Eye Hospital, London, United Kingdom, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds, United Kingdom |
| Publisher | ASSOC RESEARCH VISION OPHTHALMOLOGY INC |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | Copyright © 2017 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License. |
| Relation | http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.16-20608 |
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