Pupillary Light Reflex Deficits in a Canine Model of Neuronal Ceroid Lipofuscinosis and the Effects of Enzyme Replacement Therapy
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Pupil size is controlled by the autonomic nervous system, and iris behavior reflects a balance of input from both the sympathetic and parasympathetic nervous systems. The pupillary light reflex (PLR) occurs in response to light entering the eye and requires functional integrity of the retina and specific nuclei of the midbrain. Recently, pupillography or quantitative analysis of the PLR has been developed as a non-invasive, objective technique capable of detecting subtle changes associated with the complex network of neuronal circuitry involved in modulating pupil size. This makes the PLR a useful biomarker that can be used to monitor disease progression in neurological disorders. The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage disorders that are inherited in an autosomal recessive manner. A late-infantile onset form of NCL (CLN2) is caused by a mutation in the CLN2 gene which codes for tripeptidyl peptidase-1 (TPP1), a soluble, lysosomal enzyme that aids degradation of peptides in cells throughout the body. A Dachshund model of CLN2 was developed and is currently being maintained at the University of Missouri. Dogs affected by CLN2 lack functional TPP1 and present with xvi progressive ataxia, cognitive and behavioral changes, and myoclonic seizures starting at approximately 7-8 months of age and progressing to a terminal state requiring euthanasia at 10 to 11 months of age. In addition, affected dogs exhibit vision loss and marked deficits in ERG b-wave amplitude and significant thinning of the inner retina by disease end-stage. The strong resemblance to the human CLN2 makes these dogs an excellent model in which to test possible treatment options prior to beginning human clinical trials. In the effort to make optimal use of the canine model of CLN2, studies were undertaken to develop a reliable protocol for the quantitative assessment of the canine PLR. Using the developed equipment and methodology, we thoroughly evaluated the PLR in response to short flashes of white light of increa
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