RESUMEN
The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive lysosomal storage diseases characterized by progressive neurodegeneration and by accumulation of autofluorescent storage material in the central nervous system and other tissues. One of the most prominent clinical signs of NCL is progressive decline in cognitive function. We previously described a frame shift mutation of TPP1 in miniature long-haired Dachshunds which causes an early-onset form of NCL analogous to classical late-infantile onset NCL (CLN2) in children. Dogs homozygous for the TPP1 mutation exhibit progressive neurological signs similar to those exhibited by human patients. In order to establish biomarkers for evaluating the efficacy of ongoing therapeutic studies in this canine model, we characterized phenotypic changes in 13 dogs through 9 months of age. Cognitive function was assessed using a T-maze reversal learning (RL) task. Cognitive dysfunction was detected in affected dogs as early as 6 months of age and worsened as the disease progressed. Physical and neurological examination, funduscopy and electroretinography (ERG) were performed at regular intervals. Only the changes in ERG responses showed signs of disease progression earlier than the RL task. In the later stages of the disease clinical signs of visual and motor deficits became evident. The visual and motor deficits were not severe enough to affect the performance of dogs in the T-maze. Declining performance on the RL task is a sensitive measure of higher-order cognitive dysfunction which can serve as a useful biomarker of disease progression.