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Juvenile neuronal ceroid lipofuscinosis, linked to mutations in the ceroid lipofuscinosis, neuronal 3 (CLN3) gene, is a childhood-onset neurodegenerative disorder. Although mood and behavioral symptoms are described in this group, it's unclear whether these meet diagnostic criteria. We investigated the occurrence of neurodevelopmental and psychiatric disorders in a nationally representative sample, using a semistructured psychiatric interview, as well as the use of psychotropic medication. Ten of 20 individuals met the criteria for one or more current diagnoses, with an additional 5 having past diagnoses, resulting in a lifetime occurrence in 15 individuals. Anxiety disorders were the most frequent diagnostic group, followed by neurodevelopmental disorders. Attention-deficit hyperactivity disorder was the most common single diagnosis. Subthreshold psychiatric symptoms were present in all individuals. Although psychiatric disorders were frequent, few used psychotropic medication. These findings underscore the need for routine monitoring of neurodevelopmental and psychiatric disorders in individuals with CLN3 and the provision of evidence-based treatments. Show less

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. The online version contains supplementary material available at 10.1186/s13023-026-04298-2. Show less

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 Show less

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. Show less

Efficient utilization of complex biomass-derived sugars and tolerance to inhibitors are key requirements for the viability of lignocellulosic-based biorefineries. In this study, a two-stage evolution of an industrial yeast strain engineered with a xylose isomerase pathway yielded strain AceY.14, which exhibited improved fermentative performance and increased tolerance to acetic acid. Whole-genome sequencing of the evolved strain identified SNPs in ZWF1, a component of the pentose phosphate pathway (PPP), and in the G1 cyclin gene CLN3, both of which were functionally validated through CRISPR and reverse engineering. The zwf1 Show less

Neuronal ceroid lipofuscinosis type 3 (CLN3) disease is a rare, life-limiting pediatric neurodegenerative disorder with no approved disease-modifying therapy. We conducted a prospective case report from October 2023 to April 2025 involving two female siblings with genetically confirmed CLN3 disease (homozygous for the common 1 kb deletion). Both patients were treated with oral, weight-based miglustat for 18 months. Miglustat was supplied as off-label use in the absence of a therapeutic alternative for this severe neurodegenerative disorder. Clinical outcomes were assessed using comprehensive ophthalmologic evaluation, the Unified Batten Disease Rating Scale (UBDRS), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). At the time of report, patients were aged 13 and 10 years. Both had been diagnosed at age 7 years and commenced miglustat at ages 11 and 9 years, respectively. Over the treatment period, both patients demonstrated improvement in visual acuity and clinical stabilization on the Unified Batten Disease Rating Scale. One patient showed measurable improvement in adaptive functioning as assessed by Vineland-3. No significant adverse effects were reported. These preliminary findings suggest potential short-term clinical benefit of miglustat in pediatric patients with CLN3 disease, particularly when initiated early in the disease course. Further studies involving larger cohorts and longer follow-up are warranted to evaluate the safety and long-term efficacy of miglustat in this population. Show less

Although aneuploidy is generally detrimental to the survival and growth of normal cells, it can be beneficial under certain stress conditions, such as those caused by harmful mutations. In Saccharomyces cerevisiae, we find that duplication of chromosome III accelerates cell proliferation in the orc5-1 mutant. Enhanced proliferation is also observed when a fragment from a different chromosome is introduced, demonstrating that the benefit is not simply due to extra copies of specific genes. A comparable growth-enhancing effect of an extra chromosome is observed for mutations affecting other proteins involved in DNA replication licensing. The suppression of orc5-1 growth defect is also observed in the absence of the G1 cyclin Cln3, which lengthens the G1 phase, while overexpressing CLN3, which shortens G1, has the opposite effect. Additionally, Cln3 loss mirrors the effect of an extra chromosome for other mutations. These findings indicate that the severity of mutations impacting origin licensing hinges on the length of the G1 phase. Thus, we propose that the fitness-enhancing effect of an extra chromosome in DNA replication licensing mutants largely stems from its ability to extend G1, compensating for inefficient origin licensing. Show less

CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression. A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA. We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease. The online version contains supplementary material available at 10.1186/s13023-025-04174-5. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a rare neurodegenerative disorder caused by mutations in the CLN3 gene and characterized by early vision loss and a progressive neurological decline. To characterize the progression of retinal pathology, we conducted a 15-month study using the Cln3Δex7/8 mouse model which carries the most common causative mutation of JNCL. Retinal function was assessed every three months from the age of 3-15 months using electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunohistochemistry. OCT and fundus imaging in the Cln3Δex7/8 mice revealed a progressive thinning of the inner nuclear layer (INL) and an accumulation of subretinal drusenoid deposits. We detected a progressive loss of rod bipolar cells (RBCs) with immunofluorescence staining which was accompanied by ubiquitin-positive punctae, indicative of a potential role of the ubiquitin-proteasome system (UPS) in the selective loss of RBCs and the associated inner retinal dysfunction. Furthermore, late-stage immune cell activity was observed in the subretinal space of the Cln3Δex7/8 mice. ERG measurements confirmed previous findings of a predominant inner retinal dysfunction and revealed also a more pronounced photoreceptor impairment, as well as an earlier onset of retinal dysfunction than previously reported. These findings provide new insights into the pathological features of retinal degeneration in Cln3Δex7/8 mice, including subretinal drusenoid deposits, tubular subretinal fluid, and ubiquitin accumulation as well as a better overview of the rate of the degeneration process, thus expanding our understanding of JNCL pathogenesis. Show less

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, Show less

Development of therapies for CLN3 disease, a rare pediatric lysosomal storage disorder, has been hindered by the lack of etiological insights and translatable biomarkers to clinics. We used a deep multi-omics approach to discover blood-based biomarkers using longitudinal serum samples from a porcine model of CLN3 disease. Comprehensive metabolomics was combined with a nanoparticle-based LC-MS-based proteomic profiling coupled with TMTpro 18-plex to generate quantitative data on 769 metabolites and 2634 proteins, collectively the most exhaustive multi-omics profile conducted on serum from a porcine model. This was previously impossible due to lack of efficient deep serum proteome profiling technologies compatible with model organisms. Here we show that the presymptomatic disease state is characterized by elevations in glycerophosphodiester species and lysosomal proteases, while later timepoints are enriched with species involved in immune cell activation and sphingolipid metabolism. Cathepsin S (CTSS), Cathepsin B (CTSB), glycerophosphoinositol, and glycerophosphoethanolamine captured a large portion of the genotype-correlated variation between healthy and diseased animals, suggesting that an index score based on these analytes could have great utility in the clinic. This study's findings demonstrate the potential of deep multi-omics profiling for uncovering disease-specific biomarkers, providing valuable insights for understanding disease and facilitating the identification of potential drug targets, thus offering valuable insights for therapeutic interventions. Show less

Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American veterans with vascular and Alzheimer's dementia, respectively, and in a case series of patients with CLN3 (juvenile neuronal ceroid lipofuscinosis), this was found to be the most common neurodegenerative disease leading to dementia in childhood. In both case series, the measurement of the autonomic system disclosed a parasympathetic withdrawal and sympathetic hyperactivity in the temporal context with agitated behavior. If the time-wise-related autonomic imbalance shown previously can be demonstrated in a larger cohort of patients with Alzheimer's disease, the use of transcutaneous vagal stimulation might be a potential paradigm shift in the treatment of agitation in Alzheimer's disease. Show less

Obesity and autoimmune disorders represent a significant comorbidity burden, yet their shared genetic architecture is not fully understood. Elucidating the pleiotropic genetic basis underlying both conditions is crucial for unraveling the mechanisms driving their co-occurrence and advancing therapeutic strategies. We conducted a large-scale cross-trait analysis integrating genome-wide association study (GWAS) summary data for obesity and 17 autoimmune diseases. Genetic correlations were assessed using LD score regression and high-definition likelihood. Cross-trait pleiotropic analysis was performed using Stratified Pleiotropic Locus Mapping (PLACO) to identify shared loci, followed by Bayesian colocalization to confirm shared causal variants. Gene-level and tissue-specific heritability analyses were conducted, and drug targets were prioritized via summary-based Mendelian randomization (SMR). Finally, immune co-localization and bidirectional Mendelian randomization were employed to elucidate immunological mechanisms and causal relationships. Our analysis identified eight autoimmune diseases with significant genetic correlations to obesity. We discovered 10,324 pleiotropic SNPs, which mapped to 52 independent risk loci, with nine loci confirmed as shared causal variants by colocalization. Gene-level analysis revealed 133 unique pleiotropic genes, including CLN3, SH2B1, and MMEL1, enriched in pathways of hematopoietic cell differentiation and immune homeostasis. Tissue-specific heritability was most prominent in the spleen, whole blood, and EBV-transformed lymphocytes. Immuno-co-localization implicated six IgD+ CD38- %B cell-related traits as key pathological conduits. Bidirectional Mendelian randomization established a causal role of obesity in hypothyroidism, psoriasis, and multiple sclerosis, while revealing an inverse causal association of type 1 diabetes with obesity risk. This study demonstrates a robust shared genetic foundation between obesity and multiple autoimmune diseases, pinpointing specific pleiotropic loci, genes, and immune cell subsets. Our findings provide a mechanistic framework for their comorbidity and highlight potential targets for therapeutic intervention. The online version contains supplementary material available at 10.1186/s12967-025-07422-1. Show less

CLN3 mutation causes Juvenile neuronal ceroid lipofuscinosis (JNCL, also known as Batten disease), an early onset neurodegenerative disorder. Patients who suffer from Batten disease often die at an early age. However, the mechanisms underlying how CLN3 loss develops Batten disease remain largely unclear. Here, using Show less

Although rare, CLN3 disease is the most common neurodegenerative disorder of childhood. Here, we present a protocol for screening small molecules in a CLN3 disease patient-specific induced pluripotent stem cell (iPSC)-derived neuronal progenitor cell (NPC) model. We describe steps for converting human iPSCs (hiPSCs) to neural stem cells (NSCs) and developing NPCs using feeder-free medium and cytokine-based differentiation. We then detail procedures for achieving access to mature neurons. For complete details on the use and execution of this protocol, please refer to Simeon et al. Show less

The proportion of mutations that are dominant is a fundamental genetic parameter affecting the rate of adaptation, the efficacy of selection, and the maintenance of variation in populations. Yet, estimates for this parameter vary greatly. Here we directly quantify the rates and genetic targets of dominant and recessive mutations in the yeast mating pathway by performing parallel genetic screens in haploid ( Show less

CLN3 disease is a neuronopathic lysosomal storage disorder that severely impacts the central nervous system (CNS) while also inducing notable peripheral neuromuscular symptoms. Although considerable attention has been directed towards the neurodegenerative consequences within the CNS, the involvement of peripheral tissues, including skeletal muscles and their innervation, has been largely neglected. We hypothesized that, CLN3 deficiency could directly influence peripheral nerves and investigated the neuromuscular system in Cln3 Show less

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterizsed by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease that deteriorate the patients' life quality, yet this is understudied and has not been delineated in animal models of the disease. The current study utilised PiezoSleep, a non-invasive, automated piezoelectric motion sensing system, to classify sleep and wakefulness in a Cln3 Show less

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. 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. 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. 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. Show less

CLN3 disease is a rare fatal juvenile neurodegenerative lysosomal storage disease. Challenges in tracking underlying disease biology have hindered the identification of effective therapeutic targets and the ability to execute clinical trials in this rare disease. While diagnostic biomarkers are readily available, biomarkers that reflect the underlying core lysosome dysfunction are lacking. In the present study, CLN3 Show less

Cell volume, a key determinant of physiology, is maintained by cell size homeostasis. Large deviations from typical size are often harmful, yet cell sizes have diverged drastically in evolution. How does size homeostasis evolve to support such diversity without impairing physiology? To address this, we used experimental evolution to select progressively smaller Show less

Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM₀₀₁₀₄₂₄₃₂.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178₁₈₀delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM₀₀₁₀₄₂₄₃₂.2:c.[295-2A > C]; [178₁₈₀delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients. Show less

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 Cln3 Show less

Severe gastrointestinal (GI) symptoms occur in people with CLN3 disease, a neurodegenerative disorder. If left untreated these GI symptoms compromise life quality and may contribute to death. We hypothesized GI symptoms in CLN3 disease are at least partially due to neurodegeneration in the enteric nervous system (ENS), the master regulator of bowel function. We examined the integrity of the ENS in human CLN3 autopsy small bowel and colon, and in CLN3 deficient ( The online version contains supplementary material available at 10.1186/s40478-025-02205-7. Show less

CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout (Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease. Show less