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Martha Neuringer, Lauren Renner, Trevor J McGill, Jonathan Stoddard, Mark E Pennesi, Lois Colgin, Rebecca Ducore, Robert Zweig, Ian Tagge, Samuel Peterson, Anne Lewis, Betsy Ferguson; Identification of a macaque model of neuronal ceroid lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1852.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize the retinal degeneration associated with neuronal ceroid lipofuscinosis (NCL) in a newly-identified, naturally-occurring model in Japanese macaques (Macaca fuscata).
Cases were identified by neurological observations, structural brain MRI, and histopathology of brain and retina. Exon sequencing of DNA from affected, obligate carriers and unaffected/unrelated individuals was used to identify the underlying genetic mutation. One living case was evaluated by color fundus photography, fluorescein angiography, sdOCT, quantitative fundus autofluorescence and multifocal electroretinography (mfERG). Findings were compared to age-matched controls.
Five affected monkeys presented at 4 - 5 years of age (equivalent to 12-15 human years) with neurological signs including loss of coordination, ataxia, hypermetria, intention tremors and impaired vision. T1-weighted MRI scans showed cerebral atrophy, with most severe loss in cerebellum. Histopathology documented astrocytosis, microgliosis and enlarged hyper-autofluorescent lysosomal storage compartments in both brain and retina, and osmophilic intracytoplasmic deposits were seen by electron microscopy. Retinal sections were hyper-autofluorescent throughout, with highest levels observed in the photoreceptor inner segments. Genetic sequencing confirmed a single base pair deletion in the CLN7/MFSD8 gene. By in vivo OCT imaging, retinal thickness in the macula measured was reduced by 12% at 3 years of age and 18% at 4 years compared to age-matched unaffected controls. Quantitative fundus autofluorescence was increased by 80% and 170% above controls at 3 and 4 years, respectively. The mfERG was severely reduced in amplitude throughout the central 30° but showed foveal sparing.
We identified a naturally-occurring model of NCL in Japanese macaques due to a point mutation in the CLN7/MFSD8 gene. Consistent with human NCL, the syndrome is characterized by neurological and structural brain abnormalities, significant retinal pathology and loss of retinal function. Genetic screening of all colony members is underway to identify additional affected individuals and carriers, and a breeding group is being established. This model provides an opportunity for characterizing disease pathophysiology and for preclinical testing of therapies for this disabling and fatal disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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