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Enzyme replacement therapy has transformed the clinical trajectory of CLN2 disease, and early genetic testing is crucial because enzyme replacement therapy cannot reverse clinical progression. Lack of clinician awareness of early clinical symptomatology, initially normal language development, and history of provoked or treatment-responsive seizures may contribute to diagnostic and treatments delays. There remain challenges in equitable enzyme replacement therapy access globally and implementation of dual treatment to address retinopathy. There is a need to better understand the phenotype of CLN2 disease in the era of enzyme replacement therapy, including children who receive treatment presymptomatically. Gene therapy is a promising curative treatment, notwithstanding the mixed clinical evidence on efficacy and challenges achieving widespread brain transgene expression. This review explores our current understanding of early clinical presentation of CLN2 disease, epilepsy phenotype, role of genetic testing, novel biomarkers, and precision treatments including enzyme replacement therapy.<\/jats:p>","DOI":"10.1177\/08830738251374539","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T16:03:51Z","timestamp":1758211431000},"page":"118-134","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["CLN2 Disease: Current Understandings, Challenges, and Future Directions"],"prefix":"10.1177","volume":"41","author":[{"given":"Maria","family":"Shock","sequence":"first","affiliation":[{"name":"McMaster University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Nigro","sequence":"additional","affiliation":[{"name":"Hospital for Sick Children, University of 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