<p> 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. </p><p> 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 <i>CLN2</i> 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 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.</p><p> 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 increasing intensity in normal and CLN2-affected dogs. We found that CLN2-affected dogs exhibit PLR deficits that progress with age and other symptoms of disease. Deficits are particularly apparent with dim stimuli and likely result from a combination of decline in retinal function and disease related changes in areas of the midbrain involved in modulating the PLR.</p><p> In the Dachshund CLN2 disease model, it was previously shown that administration of recombinant TPP1 via infusion into the cerebrospinal fluid (CSF) results in widespread distribution and uptake of the active enzyme into many structures of the brain and in reduction in the accumulation of neuronal lysosomal storage material that is characteristic of this disease. Studies were undertaken to determine if TPP1 enzyme replacement therapy (ERT) could ameliorate PLR deficits associated with CLN2. One-third of the dogs treated with ERT exhibited a substantial delay in the appearance of PLR deficits compared with untreated, affected dogs. However, no improvements in retinal function could be measured by the ERG. It is unlikely that TPP1 reached the retina, and it is more likely that ERT normalized the PLR by preventing degeneration in areas of the midbrain involved in modulating the PLR. However, further analysis of retinal and midbrain tissues is necessary to fully explain these treatment effects.</p><p> The characterization of disease-related alterations in light induced responses contributes to our understanding of the pathology underlying CLN2. Preventing development of the deficits in the PLR and ERG responses can be used to objectively assess the efficacy of therapeutic interventions for CLN2 that are currently being evaluated. An ideal therapy would prevent the declines in both the PLR and the ERG responses by preventing both retina and brain degeneration.</p><p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:13877175 |
| Date | 16 April 2019 |
| Creators | Whiting, Rebecca E.H. |
| Publisher | University of Missouri - Columbia |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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