NCL pathology outside the central nervous system (CNS) tends to be overlooked due to the profound impact of neurodegeneration and the resulting symptomology. However, the absence of functional NCL protein in peripheral cells is likely to have physiological and pathological consequences for other organs. Sheep with naturally occurring CLN5 and CLN6 disease show neurological symptoms and neuropathology reminiscent of the human disease. Brain directed gene therapy can halt or slow the emergence of neurological disease with some animals surviving up to triple the expected lifespan of an untreated affected sheep. The aim of the current study was to understand if peripheral pathology manifests in CLN5 and CLN6 affected sheep within their normal lifespan, and also determine if peripheral pathologies may be unmasked in treated sheep that survive beyond the typical lifespan of affected sheep. Peripheral organ tissues including heart, lungs, liver, kidney, spleen, and gastrointestinal (GI) tract, were collected from healthy and affected sheep at 6, 12, and 18 months of age, and from affected treated sheep at various ages beyond 18 months. Tissues underwent histological analysis, and quantification of autofluorescent storage material (AFSM). Bloods collected from healthy, affected, and treated sheep between 18 and 36 months underwent haematological, biochemical, and morphological analyses. Additional analyses of the GI tract were performed to assess enteric nervous system pathology. Few changes in peripheral pathology were seen before 18 months of age in affected untreated sheep. However, treated animals displayed variable peripheral pathology, with differences in tissue histology, storage burden, and systemic markers associated with treatment type and age at death. Overall, these results suggest that peripheral pathology in CLN5 and CLN6 sheep models may appear in animals that have been successfully treated with CNS-directed therapies and therefore are living beyond their normal lifespan.