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Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets

Nature Reviews Neurology (2025)Cite this article

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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.

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Fig. 1: Nature and subcellular location of proteins that, when deficient, cause individual forms of NCL.
Fig. 2: Different routes by which experimental therapies for neuronal ceroid lipofuscinoses can be delivered.
Fig. 3: Presence of disease outside the brain and spinal cord in neuronal ceroid lipofuscinoses.

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Acknowledgements

Our work is inspired by families affected by Batten disease, and this manuscript is dedicated to them and their children. We would also like to thank the many talented individuals from our labs who have contributed so much to our research efforts. We also thank A. Barnwell for constructive comments on the manuscript. Studies in our laboratories were funded by many sources, including NIH grants R56 NS117635, R01 NS124655, R01 NS140682, R21 NS116574, R21 NS126907 and RM1 NS132962 (to J.D.C.). Foundation support was obtained from the Batten Disease Support Research and Advocacy Foundation (BDSRA Foundation), Batten Disease Family Association (BDFA), Batten Disease Global Research Initiative, Beyond Batten Disease Foundation, Children’s Brain Diseases Foundation, Fore Batten Foundation, Haley’s Heroes, Lehrman Family Fund, Noah’s Hope/Hope for Bridget and The Natalie Fund.

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Authors and Affiliations

  1. Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Ewa A. Ziółkowska, Keigo Takahashi, Patricia I. Dickson, Marco Sardiello & Jonathan D. Cooper

  2. Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Patricia I. Dickson, Mark S. Sands & Jonathan D. Cooper

  3. Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Mark S. Sands

  4. Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Jonathan D. Cooper

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The authors contributed equally to all aspects of the article. All authors contributed substantially to discussion of the content. J.D.C. wrote the first draft of the article but all authors reviewed and/or substantially edited the manuscript before submission.

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Correspondence to Jonathan D. Cooper.

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Competing interests

J.D.C. has received research support from Abeona Therapeutics Inc., BioMarin Pharmaceutical Inc., Neurogene, and REGENXBIO Inc. and is a consultant for JCR Pharmaceuticals. The remaining authors declare no conflicts of interest.

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Related links

The Batten Disease Support Research and Advocacy Foundation (BDSRA Foundation): https://bdsrafoundation.org

The NCL Resource - A gateway for Batten disease: https://www.ucl.ac.uk/ncl-disease/ncl-resource-gateway-batten-disease

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Ziółkowska, E.A., Takahashi, K., Dickson, P.I. et al. Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets. Nat Rev Neurol (2025). https://doi.org/10.1038/s41582-025-01132-4

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