CLN3 Batten disease, also known as Juvenile Neuronal Ceroid Lipofuscinosis, is a childhood-onset neurodegenerative disorder caused by mutations in the CLN3 gene, frequently accompanied by emotional and behavioral symptoms. Although these symptoms and a reduced quality of life have been previously reported in individuals with CLN3 disease and their parents, no published comparisons with siblings exist. Furthermore, age and sex differences require further study. In a nationally representative sample (n = 20, age 7-29 years), the present study applied the ASEBA Behavior Checklists, the Inventory of Life Quality to examine the prevalence of emotional and behavioral problems and quality of life in affected individuals and sibling controls. Additionally, we assessed parental quality of life using the Satisfaction With Life Scale. We found that individuals with CLN3 disease scored in the borderline clinical range for the ASEBA total problem scores (mean 63.1, SD 11.6), whereas siblings fell within the normal variation range (mean 46.4, SD 11.4). A severely reduced quality of life was reported for both affected individuals and their parents, while siblings scored within the normal range. No significant sex differences were found. Despite facing significant challenges, families also reported strengths in their offspring: grit, determination and a sense of humor in affected individuals, and empathy and dutifulness in sibling controls. This study underscores the significant emotional and behavioral challenges faced by individuals with CLN3 Batten disease, which affect the quality of life for them and their parents. These findings emphasize the need for targeted interventions for both the patients and their families.

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3−/−)mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found thatCln3−/−mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions inCln3−/−mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system ofCln3−/−mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

BackgroundJuvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease) is a childhood-onset, neurodegenerative, lysosomal storage disorder caused by mutations in the lysosomal gene CLN3. Progressive cognitive decline is characteristic clinical feature, and no definitive treatment is currently available. The neuronal function of CLN3 is unknown, and the pathomechanisms leading to cognitive impairment are poorly understood hindering the development of targeted therapies.MethodsWhole-cell patch clamp and high-density microelectrode array recordings were performed in acute brain slices from Cln3Δex7/8 mice to assess synaptic properties, intrinsic excitability, and network activity. High-resolution confocal imaging was used to quantify dendritic spine density. To explore pre- and postsynaptic roles of CLN3, adeno-associated viral (AAV) re-expression of CLN3 was combined with optogenetics, allowing assessment of CLN3 function in each compartment selectively.ResultsLoss of CLN3 caused defective synaptic vesicle release and reduced synaptic strength, reflecting impairments in both pre- and postsynaptic function in Cln3Δex7/8 mice. We also observed reduced network bursting and deficits in intrinsic neuronal excitability, indicating early functional disturbances independent of storage burden and neuronal loss. Further, we report non-redundant requirements for CLN3 at both pre- and postsynaptic sites to sustain function. Importantly, AAV9-mediated gene rescue at early disease stages corrected preexisting synaptic defects and restored function.ConclusionsOur findings demonstrate a critical requirement for CLN3 in maintaining synaptic function and show that targeted gene therapy can restore established functional deficits in Cln3-deficient mice. This suggests that the therapeutic window may extend to stages already characterized by functional impairments, raising hope that targeted interventions could not only slow disease progress but to also potentially restore neuronal function and thereby improve clinical outcome. Moreover, these early synaptic deficits provide sensitive and robust functional readouts that can support preclinical research.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-026-08304-w.

BackgroundCLN3 Batten disease is a severe pediatric neurodegenerative disorder caused by mutations in the CLN3 gene, most commonly a 1 kb deletion encompassing exons 7 and 8. CLN3 deficiency is associated with lysosomal dysfunction, impaired cellular clearance and disrupted metabolism. While neurons are particularly vulnerable in CLN3 Batten disease and have been the primary focus of research, glial cells are increasingly recognized as active contributors to disease pathology. Among them, astrocytes—the most abundant glial cell type in the brain—play critical roles in maintaining neuronal health and homeostasis. However, astrocytes remain understudied in CLN3 patient-derived models.MethodsWe present the first iPSC-derived astrocyte model from a skin biopsy of a CLN3 patient carrying the common 1 kb deletion. Cellular and molecular features of iPSC and astrocytes derived from both healthy controls and the CLN3 patient were characterized via qPCR, immunocytochemistry and targeted mass spectrometry. In addition, comprehensive omics-based profiling, through transcriptomic and label-free quantitative proteomics, was performed to uncover novel molecular mechanisms and generate hypotheses that can guide future mechanistic and functional studies.ResultsTranscriptomic and proteomic analyses during astrocyte differentiation revealed an upregulation of mitochondrial respiratory chain complexes I and IV—contrasting with the downregulation typically observed in CLN3-deficient neurons. We also identified a metabolic shift favoring the elongation of very-long-chain saturated fatty acids, accompanied by reduced lipid synthesis and enhanced fatty acid oxidation. These metabolic alterations were paralleled by an upregulation of proteins involved in oxidative stress responses, likely reflecting a compensatory adaptation to mitochondrial and lipid metabolic dysregulation. Furthermore, we observed significant changes in chromatin organization during astrocyte differentiation in CLN3 cells, suggesting epigenetic remodeling as a contributing factor to disease pathology.ConclusionOur findings prompt the hypothesis that mitochondrial dysfunction may precede lysosomal defects in CLN3-deficient astrocytes. Restoring mitochondrial health could improve brain metabolism, inflammation control, neurotransmitter regulation, and neuronal survival, highlighting mitochondria as promising therapeutic targets in CLN3 Batten disease.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12929-026-01253-y.

Neuronal ceroid lipofuscinosis or Batten disease comprises a category of autosomal recessive neurodegenerative disorders that primarily affect children. Mutations in different genes lead to different forms of neuronal ceroid lipofuscinoses (CLN1–14). At present, there is no established therapy to cure most of the neuronal ceroid lipofuscinoses and the treatments are symptomatic. Enzyme replacement therapy, gene therapy, stem cell transplantation, and pharmacological chaperone therapy are being tested in different animal models and human patients. Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear hormone receptor superfamily, which along with its transcription partner retinoid X receptor alpha (RXRα) regulates the expression of their target genes. This review highlights the potential role of PPARα and RXRα in the regulation of CLN genes. Here, using the MatInspector program of the Genomatix software, we performed promoter analyses of all CLN genes and observed that most of the CLN genes harbor one or more potential binding sites for PPAR and RXR in their promoter region. We further grouped them according to a binding prediction of the transcription factors to indicate high affinity binding of PPAR to CLN2, CLN3, CLN4, CLN5, CLN7, CLN10, CLN11, CLN12, and CLN14. On the other hand, we observed high affinity binding of RXR to CLN1, CLN3, CLN6, CLN7, CLN8, CLN10, and CLN13. Since PPARα and RXRα have been demonstrated to control the transcription of CLN2 gene, our current promoter analysis findings highlight a possible treatment strategy for neuronal ceroid lipofuscinoses using agonists of PPARα and RXRα.

CLN5 disease-causing mutations impact lysosomal biology by affecting intracellular degradation and protein trafficking.

CLN5 Batten disease, caused by biallelic mutations in CLN5, is a rare, early-onset neurodegenerative lysosomal storage disorder that has no cure and lacks validated biomarkers, hindering accurate diagnosis and assessment of therapeutic response. We recently identified CLN5 as the synthase of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid crucial for lysosome function and lipid catabolism. This suggested BMP and its precursor lysophosphatidylglycerol (LPG) as clinically relevant biomarkers. It also prompted in vivo confirmation of CLN5 as the biologically relevant lysosomal BMP synthase. Here we show that murine and ovine disease models lacking CLN5 show significant and universal depletion of BMP and elevation of LPG across tissues and brain regions, consistent with the biochemical function of CLN5. Additionally, lysosomal lysates from murine models of CLN5 Batten disease lack the ability to synthesize BMP from its precursor LPG, establishing CLN5 as the main BMP synthase in vivo. Of importance, CLN5 patient-derived fibroblasts show BMP depletion and LPG elevation. Translating these results towards clinical utility, we demonstrate BMP and LPG to be accessible biomarkers for CLN5 Batten disease in both plasma and dried blood spots, enabling early diagnosis and patient screening.

The Juvenile form of Batten disease is a neurodegenerative disease with symptoms starting in the first decade and ending in death in the third decade of life.The gene defective in this form of Batten disease, CLN3, is conserved in eukaryotes, suggesting that the gene product serves a basic function in the cell, though the function is unknown. We have investigated the expression and regulation of the yeast homolog BTN1.Reanalysis of publicly available gene expression data suggests that transcription of BTN1 increases in response to oxidative stress, treatment with rapamycin or arsenate, amino acid starvation, and sporulation conditions. Similar to GCN4, there are upstream open reading frames (uORF) in front of BTN1, suggesting translational regulation. We developed reporter strains in which the HIS3 open reading frame replaced that of the BTN1 gene, with and without the uORFs.These reporters show that one or more of the uORFs decrease the expression of the HIS3 reporter.When expressed in the reporter strain using a high copy vector, GCN3, tRNA , and tRNA , increase expression, suggesting the involvement of the TORC1 pathway.BIT61 abuts BTN1 but is encoded on the opposite strand; 3' RACE analysis indicates that the mRNA of BIT61 overlaps with that of BTN1.BIT61 is involved in the TORC2 pathway, which interacts with the TORC1 pathway, suggesting a possible cis-acting mechanism of co-regulation.Lastly, we demonstrate that a yeast strain with a null mutation in BTN1 is sensitive to selective amino acid starvation, further supporting the association of BTN1 with TORC1.

CLN3 disease, also called Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease, is an ultra‑rare, neurodegenerative lysosomal storage disorder generally affecting individuals during the first decade of life. There can be a delay in diagnosis or misdiagnosis due to a lack of awareness, and when the most common presenting symptom of visual loss is attributed to more common conditions affecting vision. We used a previously published Expert Mapping Tool (EMT) to identify multidisciplinary professionals with diagnostic or clinical management expertise, as well as patient advocates with experience of CLN3 disease. A systematic literature review of published evidence using the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidance was conducted independently and simultaneously to develop key clinical care statements. Each statement was based on the strength of the evidence. The statements formed the basis of an international modified-Delphi consensus process using a virtual meeting platform (Within3). Experts were asked to agree or disagree with each statement and suggest any changes. Statements that reached a consensus of 75% or over are the guiding statements within this manuscript. The processes and manuscript have been independently assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria. Thirty‑nine international experts from eight specialities were identified, including a patient advocate. Fifty‑three recommendation statements were developed covering eleven domains: General statements, Diagnostics, Clinical Recommendations and Management, Assessments, Social Considerations, Ocular Management, Epilepsy/Seizures, Nutrition, Respiratory Health, Sleep and Rest, and End-of-Life Care. Consensus was reached after one round of voting for all except three statements. The overall AGREE II score for developing these recommendations was 6.4, where 1 represents the lowest and 7 is the highest quality. Currently, there are no comprehensive clinical recommendations for CLN3 disease. These recommendations provide a comprehensive, evidence- and consensus‑based tool that can be used by all healthcare professionals involved in the management of CLN3 disease and other similar neurodegenerative conditions. The goal is to address the unmet clinical need for CLN3 disease management and complement other information available.

Palmitoyl-protein thioesterase-1 in health and disease.

Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders.

Enzyme replacement therapy for CLN1 batten disease that crosses the blood-brain-barrier.

Lysosomal TRPML1 activation modulates synaptic transmission and intrinsic neuronal excitability.

Modeling CLN6 Batten disease using rapidly differentiated IPSC neurons

Innate lymphoid cells (ILCs) are rare, tissue-resident innate lymphocytes that functionally mirror CD4+ T helper cell lineages but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched in the gut, airways, and mucosal lymphoid tissues, where they regulate inflammation and promote barrier integrity. To define the regulatory architecture of primary human ILC3s, we map promoter-anchored chromosomal contacts using high-resolution, low-input Promoter Capture Hi-C (PCHi-C) in these cells alongside CD4+ T cells. By combining statistical detection with a PCHi-C-adapted Activity-by-Contact approach, we link promoters to distal regulatory elements, identifying hundreds of ILC3-specific contacts. We use these maps to connect genome-wide association study (GWAS) risk variants for Crohn’s disease to target genes using multiCOGS, a Bayesian framework that integrates PCHi-C with summary-statistic imputation and multivariate fine-mapping. This analysis highlights both known and unanticipated candidates, including CLN3, a causal gene for the neurodevelopmental Batten disease. Using a mouse ILC3-like cell line, we show that Cln3 is downregulated upon cytokine stimulation, and Cln3 overexpression alters stimulation-induced transcriptional programmes and cytokine secretion. Extending this approach, we generate a catalogue of ILC3-linked risk genes for five additional autoimmune conditions and show that they are enriched for regulators of the ILC3 inflammatory response identified in a CRISPR interference screen. Together, these findings illuminate long-range gene control in ILC3s and prioritise known and newly implicated autoimmune risk genes with potential roles in this clinically important cell type.

CLN5 disease, caused by mutations in the CLN5 gene, is a form of neuronal ceroid lipofuscinoses (Batten disease). Patients suffer progressive motor dysfunction, vision loss, seizures, and dementia, leading to premature death. Here, we report a preclinical study of AAV9-mediated gene therapy in a Cln5-/- mouse model. Single-dose AAV9 carrying human CLN5 driven by the CAG or human synapsin 1 promoter (hSYN) was administered via intracerebroventricular injection into neonatal and juvenile Cln5-/- mice. Treatment efficacy was evaluated by assessment of neurodegeneration, neuroinflammation, locomotor function, and survival. AAV9 expressing CLN5 driven by the hSYN promoter significantly alleviated neurodegeneration, improved biochemical and glycosphingolipid profiles, neuropathological and locomotor function, and extended lifespan of the Cln5-/- mice. However, gene transfer employing the CAG promoter demonstrated limited therapeutic efficacy. Furthermore, delayed intervention in juveniles provided superior therapeutic response compared with early neonatal intervention and normalized lifespan. Finally, blood plasma neurofilament light that is significantly elevated in the Cln5-/- mice is restored to normal wildtype levels following treatment. These results indicate that brain-directed adeno-associated virus (AAV) gene therapy could be a promising treatment strategy for CLN5 disease and efficacy might be monitored using a noninvasive blood plasma biomarker.

Neuronal ceroid lipofuscinosis type 7 (CLN7) is a devastating paediatric neurodegenerative disorder with no cure and limited natural history data to guide therapeutic development. Here, we present the first multimodal characterization of prodromal and early-stage CLN7 disease in Japanese macaques carrying a spontaneousCLN7−/−mutation.Using structural T2-weighted MRI for volumetry, [18F]FDG PET for glucose metabolism, and [11C]PBR28 PET for neuroinflammation, we observed region-dependent patterns in volumetric, molecular, and metabolic alterations.MRI confirmed the presence of disease-associated atrophy in many cortical and subcortical brain regions, consistent with human pathology, [18F]FDG PET revealed early cortical and subcortical widespread hypometabolism, and [11C]PBR28 PET imaging detected progressive neuroinflammation in the same brain areas. CSF analyses further showed age-dependent increases in neurofilament light (NfL), providing convergent evidence for neurodegeneration.Together, these results define a prodromal trajectory in CLN7 disease, establish sensitive imaging and fluid biomarkers, and validate the macaque model as a powerful platform for testing interventions.

Background: Batten disease (BD), or neuronal ceroid lipofuscinosis (NCL), is a group of rare, fatal neurodegenerative disorders caused by mutations in CLN genes, leading to lysosomal dysfunction and progressive neuronal loss. Gene therapy, particularly using adeno-associated virus (AAV) vectors, has emerged as a promising strategy to address the genetic basis of BD across various subtypes, including CLN2, CLN5, and CLN6. This systematic review evaluates the efficacy and challenges of gene therapy in preclinical and clinical settings. Methods: Following PRISMA guidelines, we reviewed studies from January 2000 to January 2025, sourced from PubMed, Embase, Scopus, and other databases. Included studies assessed viral and non-viral vector-mediated gene therapies for BD in preclinical (animal, in vitro) and clinical contexts. Primary outcomes were restoration of enzymatic function, reduction in neurodegeneration, improvements in motor and cognitive function, safety, and survival. Results: Preclinical studies demonstrated that AAV-based gene therapy effectively restored enzyme activity, reduced neuronal degeneration, and extended survival in models of CLN5, CLN6, and other subtypes. Clinical trials, particularly for CLN2, showed slower disease progression with intracerebroventricular AAV-TPP1 delivery. However, challenges include genetic heterogeneity, immune responses to vectors, limited central nervous system (CNS) transduction due to the blood-brain barrier, and uncertainties about long-term safety and optimal treatment timing. Conclusion: Gene therapy holds significant potential for treating BD by targeting its genetic roots, with AAV-mediated approaches showing promise in both preclinical and early clinical studies. Nonetheless, optimizing vector design, delivery methods, and immune management, alongside improving early diagnosis, remains critical to realising its therapeutic potential.

Background:There is currently limited information about sensory and perceptual abilities across the progression of CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis; Batten disease), a recessively inherited lysosomal storage disorder and a leading cause of childhood neurodegeneration. Clinical symptoms include vision loss, motor impairments, and cognitive challenges, making it difficult to accurately assess neurocognitive and perceptual abilities. Thus, there is a critical need to identify objective biomarkers that can be used to inform disease progression and track treatment response in this population.Methods:This exploratory study investigates longitudinal changes in auditory sensory perceptual processing in a small sample of individuals with genetically confirmed CLN3 disease (N=4; 3 male) compared to a cross-sectional sample of 60 neurotypical (NT) controls using high-density electroencephalography (EEG). We utilized a duration mismatch negativity (MMN) paradigm, identical to what has been used in our previous cross-sectional study. We examined the auditory evoked potentials (AEPs) of the standard tones across three different stimulus onset asynchrony conditions and examined the N1 and P2 components of the AEP.Results:We found age related differences in the amplitudes of the N1 and P2 components in individuals with CLN3 disease relative to NT controls. These amplitude differences were most notable in CLN3 disease when participants were presented with standard tones that had the slowest presentation rate. Specifically, N1 and P2 amplitudes were more negative than NT controls in childhood and adolescence and as CLN3 disease participants aged, the amplitude of the AEPs was greater than controls. Further, a more positive N1 amplitude during the longest stimulus presentation condition was associated with both reduced verbal intelligence and working memory abilities in CLN3 disease participants.Conclusions:Our preliminary findings parallel recently published work in a mouse model of CLN3 disease that showed both sex- and age-dependent disruptions in central auditory processing. Taken together, we demonstrate the utility of auditory EEG measures as a sensitive, objective and translational measure in CLN3 disease that may serve as a potential outcome measure useful in tracking disease progression. Continued work is needed in humans focused on sex-based differences and longitudinal changes of auditory processing in CLN3 disease.

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3Δ7/8 mice, an established model of Batten disease. Loss of CLN3 leads to DNA damage, activating the kinase c-Abl which phosphorylates YAP1, stimulating its pro-apoptotic signaling. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may pave a way for novel c-Abl-centric therapeutic strategies to target Batten disease.