Articles are linked to in each heading.
Whiteman IT, Cook AL, Augustine EF, Bindoff AD, Johnson AM, Mason HL, Mink JW, Østergaard JR, Schulz A, Vermilion J, Vierhile A, Adams HR Orphanet J Rare Dis. 2026 Jan 7. doi: 10.1186/s13023-025-04174-5. Online ahead of print. PMID: 41501856 No abstract available. Summary: CLN3 disease is one of the most prevalent forms of Batten disease, usually beginning in the first decade of life and progressing in severity, with life expectancy in the 20’s or 30’s. Despite two decades of natural history studies, there has been no clearly defined timeline describing when key symptoms appear and how the disease progresses, making it difficult to plan optimal care and design effective clinical trials. Inspired by conversations with families and clinicians, and led by BDSRA’s Dr Ineka Whiteman together with investigators from the original natural history studies, this comprehensive meta-analysis brings together data from over 400 affected individuals to map the onset and progression of 13 core symptoms of classical CLN3 disease. The findings reveal a clear chronological pattern, beginning with early vision loss and advancing through cognitive, behavioural and motor decline, cardiac manifestations, feeding difficulties and end of life. By defining a clearer disease trajectory, this study offers practical anticipatory guidance for clinicians and families. It also highlights the need for standardised longitudinal natural history data to improve care and support future therapeutic development for CLN3 disease.
Zió?kowska EA, Williams LL, Jansen MJ, Wang SH, Eultgen EM, Sharma J, Sardiello M, Bradley RP, Whiteman IT, Sands MS, Heuckeroth RO, Cooper JD. Acta Neuropathol Commun. 2025 Dec 22. doi: 10.1186/s40478-025-02205-7. Online ahead of print. PMID: 41430350 No abstract available. Summary: Individuals with CLN3 disease frequently experience severe gastrointestinal (GI) problems that can significantly reduce quality of life and may contribute to death. This study shows a substantial loss of neurons and glia in the enteric nervous system – the master regulator of the bowel function – leading to bowel distension and impaired gut function. Importantly, AAV-mediated CLN3 gene therapy delivered systemically in CLN3-deficient mice prevented much of this nerve damage and preserved bowel function later in disease. This preclinical study provides early evidence that gene therapy may help address GI complications by targeting the underlying cause, expanding the field beyond our traditional understanding of Batten disease as a disorder of the central nervous system (CNS) only. This study also highlights the profound impact of patient organ donation. Examining bowel samples from individuals affected by Batten disease enables researchers to confirm that the disease effects observed in animal models is present, and therefore clinically relevant, in human patients. The generosity of families who choose to donate tissue makes it possible to study the disease directly, validate animal models, and move the field forward in meaningful ways.
Zió?kowska EA, Pagán Torres NA, Chen H, Williams LL, Eultgen EM, Nowacka A, Dearborn JT, Nelvagal HR, Whiteman IT, Platt FM, Cooper JD. Sci Rep. 2025 Dec 29. doi: 10.1038/s41598-025-32984-x. Online ahead of print. PMID: 41466111 No abstract available. Summary: N-acetyl-L-leucine (NALL) is an oral compound with reported neuroprotective, anti-inflammatory and metabolic effects, recently approved for treatment of the lysosomal storage disorder Niemann-Pick disease type C. Researchers at The Washington University tested this agent in a mouse model of CLN1 disease to see whether NALL as a monotherapy (single therapy) could alleviate symptoms. Treatment was started either before symptoms appeared or after symptoms had begun and continued through advanced disease stages. The results showed that NALL alone did not meaningfully slow disease progression, improve overall motor function, reduce brain inflammation, or extend survival in this model, although a a modest, quantifiable benefit was observed on locomotor (walking) stability when treatment began early. These findings, although overall non-significant, provide important information in understanding the underlying biology of CLN1 disease. Moreover, as the authors state, “these negative results should not be interpreted as a dismissal of NALL’s therapeutic potential in general but rather as a demonstration of its limited value as a monotherapy in CLN1 disease.” Future research may be well directed toward testing NALL in combination therapy, in other NCL subtypes, or both.
Della Vecchia S, Simonati A, Manca ML, Pietrafusa N, Trivisano M, Calabrese C, Specchio N, Santorelli FM; A-NCL-ETS. Neurogenetics. 2025 Dec 11;26(1):88. doi: 10.1007/s10048-025-00871-2. PMID: 41379326 Summary:
Severe gastrointestinal (GI) symptoms are commonly reported in children and young people with Batten disease and represent a significant yet under-recognised contributor to disease burden. For the first time in humans, a cross-sectional study in an Italian NCL cohort has systematically assessed the burden of GI manifestations using a standardized assessment tool combined with structured caregiver interviews. More than 60% of individuals experienced GI issues, with constipation frequently appearing early and dysphagia emerging later, both having a profound impact on quality of life. Notably, swallowing and feeding problems correlated with neurological disease severity, whereas constipation did not, suggesting distinct underlying mechanisms. These findings highlight the need for routine, proactive GI screening in individuals with Batten disease and recognises the importance of considering GI outcomes in the design and evaluation of future therapeutic trials.
Wang Y, Li K, Chen W, Chen C, Yong AJH, Zhang X, Tynan-La Fontaine M, Jan YN, Jan LY. Neuron. 2026 Jan 19:S0896-6273(25)00886-4. doi: 10.1016/j.neuron.2025.11.013. Online ahead of print. PMID: 41558486
Summary: CLN3 disease is caused by mutations in the CLN3 gene which leads to non-functional protein synthesis and lysosomal dysfunction. However, the precise role of CLN3 protein in lysosomal function remains poorly understood. This new study reveals a critical role for CLN3 in regulating lysosomal chloride transport and cellular health, serving - at least in part - as a gatekeeper that regulates the internal environment of the lysosome. When the CLN3 protein is missing or non-functional, chloride (an ‘ion’ or particle that that helps control fluid balance, acidity, and electrical signals within cells) builds up in the lysosome, reducing its ability to clear cellular waste and leading to the toxic build-up of lysosomal storage material. Excitingly, this research also identified that the protein CLN7 performs a similar, parallel role to CLN3, potentially explaining the convergent NCL pathologies seen in CLN3 and CLN7 diseases. The researchers also demonstrated that a promising curcumin-based compound called C1 could enhance CLN3 activity, improve lysosomal function, and activate TFEB, a master regulator of cellular clearance pathways. Understanding CLN3’s role in lysosomal function brings researchers a step closer in developing targeted therapies that can restore cellular health for those living with CLN3 Batten disease.
Nishi E, Yanagi K, Shima M, Yamazaki N, Kawato K, Narita A, Sakai N, Okamoto N, Yanagihara K, Kaname T. Clin Case Rep. 2025 Dec 30;14(1):e71739. doi: 10.1002/ccr3.71739. eCollection 2026 Jan. PMID: 41479428 Free PMC article.
Liu W, Geard AF, Massaro G, Hughes MP, Aristorena M, Coombe-Tennant O, Xu L, Semenyuk O, Bush R, Te Vruchte D, Priestman D, Laban R, Veleva E, Heslegrave AJ, Zetterberg H, Platt FM, Smith AJ, Mole SE, Ali RR, Rahim AA. Hum Gene Ther. 2025 Dec 16. doi: 10.1177/10430342251403448. Online ahead of print. PMID: 41457644
Auvin S, Hamandjian MA, Karam P, Hoebeke C. Eur J Paediatr Neurol. 2025 Dec 3;60:44-49. doi: 10.1016/j.ejpn.2025.12.001. Online ahead of print. PMID: 41354011
Kajiwara K, Liang Q, Uchiyama Y, Chong PF, Ichimiya Y, Monji N, Shimokawa S, Sonoda M, Watanabe E, Sakata A, Sonoda Y, Akamine S, Ishimura M, Murakami Y, Kunisaki Y, Sonoda KH, Matsumoto N, Sakai Y, Ohga S. Eur J Med Genet. 2025 Dec;78:105058. doi: 10.1016/j.ejmg.2025.105058. Epub 2025 Nov 5. PMID: 41203069
Bojanek EK, Lang ER, Adams HR, Vermilion J, Augustine EF, Brima T, Nasimjonova S, Freedman EG, Foxe JJ. bioRxiv [Preprint]. 2025 Nov 20:2025.11.19.689311. doi: 10.1101/2025.11.19.689311. PMID: 41332681. Free PMC article. Preprint.
Raman R, Horst B, Shahrokh Z, Hatambeygi N, Zare M, Leszczyniecka M, Harris JS, Banks WA, Hansen KM, Erickson MA, Ekins S. Mol Genet Metab. 2026 Jan 16;147(3):109733. doi: 10.1016/j.ymgme.2026.109733. Online ahead of print. PMID: 41576655
Oerbeck B, Helland IB, Adams HR, Overgaard KR. J Child Neurol. 2026 Feb 5:8830738251413827. doi: 10.1177/08830738251413827. Online ahead of print. PMID: 41642869
Tong J, Liu W, Wang Q, Yang H, Gao Z, Wu W, Liu J, Li W, Lu C. Transl Psychiatry. 2026 Feb 2;16(1):106. doi: 10.1038/s41398-026-03843-8. PMID: 41629288
Rebecca Atkinson British Journal of Music Therapy doi: 10.1177/13594575261423388. First published online February 15, 2026