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CLN3 disease is a rare inherited neurodegenerative disease that typically starts in childhood. Given the progressive nature of the disease, it likely affects the health-related quality of life (HRQOL) of both the child and the family unit. In this study, we evaluated HRQOL and family function in individuals with CLN3 disease and their families. Data were obtained from longitudinal observational studies on CLN3 disease at the University of Rochester Batten Center. Assessments were completed at variable intervals from 2006 to 2024. Parents completed the PedsQL, which assesses child HRQOL, and the PedsQL FIM, which assess family impact. In a subset of participants, we concurrently administered the Unified Batten Disease Rating Scale, a global assessment of CLN3 disease. Data from 71 participants were included in this study, of which 21 participants had concurrent Unified Batten Disease Rating Scale data. Mean (SD) PedsQL Total (48.2 (19.7)) and PedsQL FIM Total (51.2 [16.5]) scores were low. Worse child HRQOL was associated with physical impairment from more severe CLN3 disease (r Children with CLN3 disease and their families are at high risk of impaired HRQOL and function. This information may provide important information for clinical care and trial design in CLN3 disease. 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

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

The neuronal ceroid lipofuscinoses (NCLs) are rare and fatal autosomal pediatric neurodegenerative disorders. The most prevalent subtype, CLN3, arises from a mutation in the CLN3 gene. Common phenotypic hallmarks include lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and reduced Bcl-2 expression, however the underlying pathophysiology is not well understood. No effective treatment option exists. Herein, we report the synthesis and characterization of bicyclic analogues of the bioisosteric non-opioid analgesics Flupirtine and Retigabine, previously shown to exhibit neuroprotective effects. These analogues were strategically modified to prevent formation of toxic reactive diamine/diimine intermediates characteristic of the parent compounds. Novel 1 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

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

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

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

An association has been observed between alcohol and cheese intake and the onset of inflammatory bowel disease (IBD), necessitating further exploration from a genetic structural perspective. The present analysis was focused on the intake of alcohol and cheese in conjunction with IBD genome-wide association study (GWAS) data, with the objective of exploring genetic correlations and identifying common loci. Initially, overall genetic correlations were assessed employing two methodologies: linkage disequilibrium score regression (LDSC) and genetic covariance analyzer (GNOVA). Subsequently, local correlations were examined through the SUPERGNOVA method. A genetic overlap analysis between various traits was then conducted based on the statistical theory of conditional/conjunctional false discovery rate (cond/conjFDR). Ultimately, shared loci between the two traits were identified via conjFDR analysis and multi-trait analysis of GWAS (MTAG). Substantial overall correlations were noted at the genome-wide level between alcohol and cheese intake and both IBD and Crohn's disease (CD), whereas the association with ulcerative colitis (UC) was of lesser significance. In the local genetic analysis, chromosome 16 emerged as a key region implicated in the relationship between alcohol and cheese intake and IBD (including both CD and UC). The conjFDR analysis confirmed the genetic overlap between the two diseases. Furthermore, both conjFDR and MTAG analyses identified multiple shared genetic loci, with nine genes ( The present study provides genetic evidence supporting the comorbidity of alcohol and cheese intake with IBD, offering novel insights into potential strategies for the prevention and treatment of IBD through the modulation of alcohol and cheese consumption. 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

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

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

Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorder's like CLN3 disease. However, the retina is a functional composite Acid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease. Show less

We analyzed the genotypic and phenotypic features of patients with psychosis of epilepsy (POE). Patients with POE recruited to an epilepsy genetics research program underwent phenotyping and genetic analysis. The latter included screening for rare pathogenic variants in epilepsy genes, and polygenic risk score (PRS) calculation for common risk variants associated with schizophrenia. One hundred twenty-two individuals with POE were identified. Eighty-six of 122 of the individuals (70%) had interictal psychosis, with schizophrenia the most common interictal phenotype (36/86, 42%). Twenty-eight of 122 of the individuals (23%) had postictal psychosis (PIP), 2 of 122 of the individuals (2%) had antiseizure medication-induced psychosis, and 6 of 122 of the individuals (5%) had substance-induced psychosis. Focal epilepsies were more frequently associated with PIP (24/28, 86%) compared to interictal psychosis (39/86, 45%; p < 0.05). Twenty-nine percent of the patients with POE with genetic data had a rare pathogenic variant: 19 in an epilepsy gene (PCDH19, SCN1A, DEPDC5, KCNT1, CHD2, SLC2A1, NPRL3, CLN3, NPRL3, ATP1A3, and CACNA1A) and 4 had a chromosomal anomaly. Fifty-seven percent of the patients with a rare pathogenic variant had interictal schizophrenia/schizophreniform disorder rather than PIP (9%; p < 0.05). PRSs showed that schizophrenia-related common risk variants were enriched in patients with POE compared to population controls (p = 0.0007), however, among the POE phenotypes, a raised PRS was only observed in interictal schizophrenia (p = 0.015) and not in those with PIP or other interictal POEs. Interictal POE is threefold more common than PIP, and more likely to be associated with both rare pathogenic variants for epilepsy and common risk variants for schizophrenia. Distinguishing between different POE phenotypes enhances clinical practice and our understanding of etiology, paving the way for precision medicine. ANN NEUROL 2025;98:35-47. Show less

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes. 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

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

Juvenile neuronal ceroid lipofuscinosis (CLN3) is a rare neurodegenerative disorder lacking effective therapies. This study aimed at developing a drug repurposing approach to identify potential therapeutic candidates for CLN3 using its protein expression profile (CPEP) constructed from proteomics data. Differentially expressed proteins were identified and applied to query the iLINCS database, resulting in 60 FDA-approved drugs with reversal effects on CPEP. These candidates were further prioritized based on regulation strength, coverage, and blood-brain barrier permeability. Top candidates include Vorinostat and Cyclosporine, which have shown promise due to their significant regulation scores and blood-brain barrier permeation probability. These results provide opportunities for further investigation on novel therapies for CLN3. Show less

To describe the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of neuronal ceroid lipofuscinosis (NCL)-associated retinal disease. Multicenter retrospective cohort study complemented by a cross-sectional examination. Twelve pediatric subjects with biallelic variants in 5 NCL-causing genes (CLN3 lysosomal/endosomal transmembrane protein [ Review of clinical notes, retinal imaging, electroretinography (ERG), and molecular genetic testing. Two subjects underwent a cross-sectional examination comprising adaptive optics scanning laser ophthalmoscopy imaging of the retina and optoretinography (ORG). Clinical/demographic data, multimodal retinal imaging data, electrophysiology parameters, and molecular genetic testing. Our cohort included a diverse set of subjects with Our cohort data demonstrates that the underlying genetic variants drive the phenotypic diversity in different forms of NCL. Genetic testing can provide molecular diagnosis and ensure appropriate disease management and support for children and their families. With intravitreal enzyme replacement therapy on the horizon as a potential treatment option for NCL-associated retinal degeneration, precise structural and functional measures will be required to more accurately monitor disease progression. We show that adaptive optics imaging and ORG can be used as highly sensitive methods to track early retinal changes, which can be used to establish eligibility for future therapies and provide metrics for determining the efficacy of interventions on a cellular scale. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Show less

The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients from 13 unrelated families who carried biallelic variants in the We detected 21 variants in three Patients with variants in the three Show less

CLN8-Batten disease is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 result in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subtypes of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, a Cln8mnd mouse model was utilized to measure the impact and progression of histopathological and motor-behavioral outcomes between sexes. Immunohistochemistry staining utilized markers for intracellular storage materials, astrocytes, and microglial cells; sections were obtained of the thalamus and the somatosensory cortex of Cln8mnd mice. Several notable sex differences were observed in the presentation of brain pathology, including Cln8mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex and ventral posteromedial/ventral posterolateral nuclei of the thalamus when compared to Cln8mnd male mice. Female Cln8mnd mice experienced a diminished lifespan by 0.5 months compared to their male counterparts (p less than 0.05). Furthermore, sex differences in motor-behavioral assessments identified Cln8mnd female mice experience poorer motor performance in the Morris Water Maze assessment, reverse Morris Water Maze, and increased tremors. Female Cln8mnd mice perished earlier, performed worse on motor-behavioral assessments, and demonstrated marked microglial and astrocyte reactivity compared to their male counterparts. Taken together, the results provide further evidence of biological sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact. Show less

Cell phase engineering can significantly impact protein synthesis and cell size, potentially enhancing the production of lipophilic products. This study investigated the impact of G1 phase extension on resource allocation, metabolic functions, and the unfolded protein response (UPR) in yeast, along with the potential for enhancing the production of lipophilic compounds. In brief, the regulation of the G1 phase was achieved by deleting Show less

Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease. Show less

Lysosomes are implicated in a wide spectrum of human diseases, including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration, and cancer. Profiling lysosomal content using tag-based lysosomal immunoprecipitation (LysoTagIP) in cell and animal models has substantially moved the field forward, but studying lysosomal dysfunction in patients remains challenging. Here, we report the development of the 'tagless LysoIP' method, designed to enable the rapid enrichment of lysosomes, via immunoprecipitation, using the endogenous integral lysosomal membrane protein TMEM192, directly from clinical samples and human cell lines (e.g., induced pluripotent stem cell-derived neurons). Isolated lysosomes were intact and suitable for subsequent multimodal omics analyses. To validate our approach, we applied the tagless LysoIP to enrich lysosomes from peripheral blood mononuclear cells derived from fresh blood of healthy donors and patients with CLN3 disease, an autosomal recessive neurodegenerative LSD. Metabolic profiling of isolated lysosomes revealed massive accumulation of glycerophosphodiesters (GPDs) in patients' lysosomes. Interestingly, a patient with a milder phenotype and genotype displayed lower accumulation of lysosomal GPDs, consistent with their potential role as disease biomarkers. Altogether, the tagless LysoIP provides a framework to study native lysosomes from patient samples, identify disease biomarkers, and discover human-relevant disease mechanisms. Show less

CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease induced pluripotent stem cell-RPE cells show defective phagocytosis of photoreceptor outer segment (POS). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect. Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3Δ7-8/Δ7-8 (CLN3) Yucatan miniswine was also used to study the impact of CLN3Δ7-8/Δ7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3Δ7-8/Δ7-8 and wild-type miniswine eyes were carried out at 6, 36, or 48 months of age. CLN3Δ7-8/Δ7-8 RPE (CLN3 RPE) displayed decreased POS binding and consequently decreased uptake of POS compared with isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3Δ7-8/Δ7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36 months of age and was followed by almost complete loss of photoreceptors at 48 months of age. CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease. Show less