Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets

Abstract

The neuronal ceroid lipofuscinoses (NCLs), more commonly known as Batten disease, are a group of fatal inherited neurodegenerative lysosomal storage disorders. Each form is caused by mutations in a different gene, resulting in lysosomal dysfunction, which, by largely unknown mechanisms, has a devastating impact on the central nervous system. The NCLs are grouped together owing to their broadly shared clinical presentations and the presence of autofluorescent storage material. Nevertheless, being caused by deficiencies in dissimilar proteins, marked differences are apparent between NCLs in their clinical presentation and pathology. The effects of disease are not confined to neurons and appear unrelated to autofluorescent storage material, with glial cells also affected. The rest of the body is also affected, with life-limiting disease in the bowel and effects on other body systems, which will also require treatment for maximal therapeutic benefit. Since the development of enzyme replacement therapy for CLN2 disease, much has been learnt about the practicalities of its delivery. Considerable progress has also been made in the understanding of NCL cell biology, disease pathogenesis and potential links to other disorders. Here, we highlight these advances and how they inform the ongoing development of therapeutic strategies and their future prospects.