Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Neuronal Ceroid Lipofuscinosis. Core disease mechanisms, molecular and cel...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Recent insights into the networking of CLN genes and proteins in mammalian cells

• Authors: R. Huber
• Year: 2023
• Venue: Journal of Neurochemistry
• URL: https://www.semanticscholar.org/paper/cc429c474e95d5a631782adfbe20b36532519e9c
• DOI: 10.1111/jnc.15822
• PMID: 37022340
• Citations: 11
• Summary: A deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen the knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.
• Evidence snippets:
• Snippet 1 (score: 0.570) > Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. In humans, mutations in CLN genes cause a devastating form of neurodegeneration called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Each CLN gene is associated with a specific subtype of the disease that differ from each other in severity and age of onset. The NCLs affect all ages and ethnicities worldwide but primarily affect children. The pathology underlying the NCLs is poorly understood, which has prevented the development of a cure or effective therapy for most subtypes of the disease. A growing body of literature supports the networking of CLN genes and proteins within cells, which aligns with the broadly similar cellular and clinical manifestations among the different subtypes of NCL. Here, all relevant literature is reviewed to provide a comprehensive overview of our current understanding of how CLN genes and proteins are networked in mammalian cells with an aim toward revealing new molecular targets for therapy development. Intriguingly, CLN gene and protein networking extends beyond the NCLs as recent work has linked several CLN genes and proteins to other forms of neurodegeneration such as Alzheimer's disease and Parkinson's disease. Thus, a deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen our knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.

[2] Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

• Authors: Sabateeshan Mathavarajah, D. O’Day, R. Huber
• Year: 2018
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/3d007c8ea7ed8f4da2c267fc85c5aa5f10a1c1d1
• DOI: 10.3390/cells7110188
• PMID: 30380624
• PMCID: 6262527
• Citations: 13
• Summary: It is shown that 11 of the 13 NCL proteins contain putative CaM-binding domains (CaMBDs), which indicates that targeting CaM may be a valid therapeutic approach for treating the disease.
• Evidence snippets:
• Snippet 1 (score: 0.540) > The first clinical diagnosis of Batten disease was in 1903, and since then, great strides have been made in our understanding of the cellular and molecular mechanisms underlying this devastating neurological disorder [1].Batten disease, which is clinically known as neuronal ceroid lipofuscinosis (NCL), is a form of neurodegeneration that has a global distribution and affects people of all ages [2].Clinical manifestations of the disease include vision loss, seizures, progressive loss of motor function and cognitive ability, and a reduced lifespan [3].The only clinically-approved therapeutic for the NCLs is Brineura, which is an enzyme replacement therapy specific for only one subtype of the disease (i.e., CLN2 disease) [4].The absence of therapeutics stems from our poor understanding of NCL proteins and their primary functions.In total, 13 genetically distinct genes are linked to the disease (CLN1-8, CLN10-14) [2].These 13 genes encode enzymes (CLN1, CLN2, CLN5, CLN10, and CLN13), transmembrane proteins (CLN3, CLN7, and CLN12), membrane proteins that localize to the endoplasmic reticulum (CLN6 and CLN8), cytoplasmic proteins (CLN11 and CLN14), and a protein found on synaptic vesicles (CLN4) [2].Along with distinct localizations, the NCL proteins have been linked to fundamental cellular processes, including sphingolipid metabolism, protein degradation, and lysosomal pH homeostasis, among others [5][6][7][8][9][10].Since mutations in NCL proteins cause nearly identical clinical phenotypes, they are thought to participate in shared or convergent biological pathways [11].However, the common link between the proteins has yet to be revealed. > For clues to explain the molecular networking of NCL proteins, research groups have looked for reoccurring phenotypes in NCL patients [12].

[3] An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

• Authors: William D. Kim, R. Huber
• Year: 2022
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/efb8f8960b6eb7c4d516f1194de8dbffd5d61fb0
• DOI: 10.3389/fgene.2022.1045738
• PMID: 36437924
• PMCID: 9686302
• Citations: 1
• Summary: The impact of cln5-deficiency on gene expression in D. discoideum is revealed, insight is provided on the genes and proteins that play a role in regulating ClN5-dependent processes, and light is shed on the molecular mechanisms underlying CLN5 disease.
• Evidence snippets:
• Snippet 1 (score: 0.539) > The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a family of neurodegenerative diseases linked to mutations in 13 ceroid lipofuscinosis neuronal (CLN) genes (CLN1-8, CLN10-14) (Schulz et al., 2013;Mole and Cotman, 2015). Each of the 13 different subtypes of NCL are characterized by the lysosomal accumulation of autoflourescent lipid-protein aggregates called ceroid lipofuscin in neurons, as well as other cell types outside the central nervous system (Palmer et al., 1992;Mole and Cotman, 2015). The accumulation of ceroid lipofuscin has been associated with numerous clinical symptoms, including seizures, reduced motor, visual, and cognitive function, as well as a reduced lifespan (Schulz et al., 2013;Mole and Cotman, 2015). While most of the CLN genes have been studied, the precise cellular mechanisms impacted by CLN gene mutations remain elusive. > Mutations in CLN5 cause the CLN5 disease subtype of NCL (Schulz et a., 2013;Mole and Cotman, 2015). CLN5 is a soluble lysosomal and extracellular protein that is predicted to function as either a glycoside hydrolase or depalmitoylase (Isosomppi et al., 2002;Hughes et al., 2014;Jules et al., 2017;Huber and Mathavarajah, 2018a;Basak et al., 2021b;Luebben et al., 2022). CLN5 has been linked to several cellular processes including, but not limited to, endosomal sorting, biometal homeostasis, sphingolipid metabolism, and autophagy (El Haddad et al., 2012;Mamo et al., 2012;Grubman et al., 2014;Doccini et al., 2020;McLaren et al., 2021). However, like most CLN proteins, the association of CLN5 with a defined biological pathway is still under investigation.

[4] Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

• Authors: K. Uusi-Rauva, T. Blom, Carina von Schantz-Fant, Tomas Blom, A. Jalanko et al.
• Year: 2017
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/be3792a8185e9d7a32a9b59780e8ec7c1f39220a
• DOI: 10.3390/ijms18050955
• PMID: 28468312
• PMCID: 5454868
• Citations: 33
• Summary: Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late inf...
• Evidence snippets:
• Snippet 1 (score: 0.537) > Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases.

[5] Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

• Authors: A. Simonati, Ruth E. Williams
• Year: 2022
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/958b94cb5357170fef4d725e2b10655492abf845
• DOI: 10.3389/fneur.2022.811686
• PMID: 35359645
• PMCID: 8961688
• Citations: 59
• Influential citations: 2
• Summary: The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis, a group of rare neurodegenerative disorders, and describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology.
• Evidence snippets:
• Snippet 1 (score: 0.525) > The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.

[6] Current Insights in Elucidation of Possible Molecular Mechanisms of the Juvenile Form of Batten Disease

• Authors: E. Shematorova, G. V. Shpakovski
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/140bc3d40a51eb872ceb3c3d39dcc450eff8c479
• DOI: 10.3390/ijms21218055
• PMID: 33137890
• PMCID: 7663513
• Citations: 4
• Summary: The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.
• Evidence snippets:
• Snippet 1 (score: 0.524) > The neuronal ceroid lipofuscinoses (NCLs) collectively constitute one of the most common forms of inherited childhood-onset neurodegenerative disorders. They form a heterogeneous group of incurable lysosomal storage diseases that lead to blindness, motor deterioration, epilepsy, and dementia. Traditionally the NCL diseases were classified according to the age of disease onset (infantile, late-infantile, juvenile, and adult forms), with at least 13 different NCL varieties having been described at present. The current review focuses on classic juvenile NCL (JNCL) or the so-called Batten (Batten-Spielmeyer-Vogt; Spielmeyer-Sjogren) disease, which represents the most common and the most studied form of NCL, and is caused by mutations in the CLN3 gene located on human chromosome 16. Most JNCL patients carry the same 1.02-kb deletion in this gene, encoding an unusual transmembrane protein, CLN3, or battenin. Accordingly, the names CLN3-related neuronal ceroid lipofuscinosis or CLN3-disease sometimes have been used for this malady. Despite excessive in vitro and in vivo studies, the precise functions of the CLN3 protein and the JNCL disease mechanisms remain elusive and are the main subject of this review. Although the CLN3 gene is highly conserved in evolution of all mammalian species, detailed analysis of recent genomic and transcriptomic data indicates the presence of human-specific features of its expression, which are also under discussion. The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.

[7] Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics

• Authors: Betül Teker, Gokce Akan, H. Kazan, Özge Özgen, S. Tatonyan et al.
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/17ab4c1d747ef2acbf7649f4009dc7c8e878e55f
• DOI: 10.3390/ijms26115037
• PMID: 40507848
• PMCID: 12155472
• Summary: This study aimed to benchmark the performance of Oxford Nanopore long-read sequencing (ONT-LRS) for targeted TPP1 mutation detection in a Turkish CLN2 cohort and to assess its concordance with orthogonal validation methods, including Sanger sequencing and enzymatic activity assays.
• Evidence snippets:
• Snippet 1 (score: 0.521) > Neuronal ceroid lipofuscinosis type 2 (CLN2) disease (OMIM 204500), also known as Jansky-Bielschowsky, represents an exceptionally rare lysosomal storage disorder within the neuronal ceroid lipofuscinosis (NCL) family, collectively termed Batten disease. Previously known as late-infantile neuronal ceroid lipofuscinosis (LINCL), CLN2 disease is an early childhood onset disorder caused by autosomal recessive mutations in the TPP1 gene (GenBank accession no. NM_000391.3) localized on chromosome 11p15. These mutations result in deficient activity of the lysosomal exopeptidase tripeptidyl peptidase 1 (TPP1) (EC 3.4.14.9) [1]. Similar to other NCL disorders (CLN1-CLN14), CLN2 disease involves lysosomal dysfunction, which culminates in the accumulation of autofluorescent storage materials, subsequent neuronal loss, and neurodegeneration. However, the precise in vivo substrates and the complete pathologic mechanisms remain incompletely characterized [2]. > Pathogenic TPP1 gene variants, including splice site, missense, and nonsense mutations, as well as small deletions or insertions, primarily result in diminished or absent enzyme activity, impaired neuropeptide degradation, and the accumulation of subunit c of ATP synthase. This results in the lysosomal accumulation of ceroid lipofuscin, glial activation, and neuronal loss [3]. These mutations lead to reduced or absent TPP1 activity, resulting in lysosomal accumulation of ceroid lipofuscin, a hallmark of the CLN2 phenotype [4][5][6]. Ultrastructural analysis of lysosomal storage in CLN2 disease reveals a characteristic curvilinear profile [6,7]. Clinically, symptom onset correlates with peak TPP1 expression (ages 2-4) and includes new-onset seizures, ataxia, and a history of language delay [8].

[8] Behavioural and Medical Differentials of Cognitive Decline and Dementia in Dogs and Cats

• Authors: S. Denenberg, F. Liebel, J. Rose
• Year: 2017
• Venue: Canine and Feline Dementia
• URL: https://www.semanticscholar.org/paper/c55376bb9d5213c0a38e6aa0bffd5f54e6bd5df6
• DOI: 10.1007/978-3-319-53219-6_2
• PMCID: 7121040
• Citations: 9
• Summary: Cognitive dysfunction syndrome (CDS) is a diagnosis of exclusion given that there is no specific diagnostic test or tool and that medical disorders can cause the same set of signs.
• Evidence snippets:
• Snippet 1 (score: 0.520) > Aetiopathogenesis Ceroid lipofuscinosis is a neurodegenerative disease characterised by the accumulation of autofluorescent lipopigments (ceroid-or lipofuscin-like lipopigments) in neurons and other cells within the body. While most affected dogs and cats will present with signs early in life (within the first 2 years), ceroid lipofuscinosis is one of the few storage diseases that can present in adulthood. This is particularly true in the Tibetan terrier and dachshund breeds who may develop obvious signs when 6 years or older and can survive past 10 years of age. The pathophysiology of the disease is yet to be elucidated as it is unclear whether the mechanism of injury is a direct consequence of the pigment accumulation in cells or if it involves an abnormal mitochondrial function. The advances of molecular genetics have permitted the identification of multiple gene defects causing enzymatic dysfunction, leading to ceroid lipofuscinosis in specific dog breeds.

[9] Editorial: Neuronal ceroid lipofuscinosis: A multidisciplinary update

• Authors: Alessandro Simonati, R. E. Williams, Angela Schulz
• Year: 2022
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/c6c2f43109e69130ad717ac0c0cac6dac945c199
• DOI: 10.3389/fneur.2022.1083113
• PMID: 36468054
• PMCID: 9710275
• Summary: a
• Evidence snippets:
• Snippet 1 (score: 0.520) > Eleven papers and fifty-one authors from seven countries have contributed to the Research Topic Neuronal Ceroid Lipofuscinosis: a Multidisciplinary Update. Both clinical and research issues have been addressed in this collection of articles. The first paper provides a broad introduction and subsequent articles cover epidemiology and genetics, diagnosis, natural history studies, treatment and ethical implications of novel therapies, cardiac involvement in the later stages of disease and the underlying pathological mechanisms. > The state-of-art in the field of childhood NCLs was described from a number of perspectives in the first review paper of the series (Simonati and Williams). Following a brief historical survey, a clinically-oriented approach was used to describe how the early symptoms and signs represent topographical signatures of the underlying brain dysfunction and may provide clues helping clinicians to reach a conclusive NCL diagnosis rapidly. The paper goes on to document advances in NCL research and the contributions of different experimental models to enhance knowledge of the pathogenic mechanisms underlying cellular pathology in this group of diseases. Lastly, translation of experimental data into novel therapeutic approaches and the importance of symptomatic treatments, which remain the main available therapeutic approaches, were outlined. > The world-wide distribution of NCL was emphasized by the retrospective epidemiological study from South America and the Caribbean region, in which CLN2, CLN6, and CLN3 disorders were identified as the most common NCL types in those regions (Guelbert et al.). The authors have stressed that synergy between health providers, parent support organizations and the pharmaceutical industry have accelerated the use of modern diagnostic procedures. > The significance of the advances in genetic studies in NCL was discussed in the review article by Gardner and Mole which focuses on the genetic basis of phenotypic heterogeneity (Gardner and Mole). Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 NCL genes. Increasing numbers of variant disease phenotypes are being described. Identification of phenotypic heterogeneity combined with the genetic background of each patient is necessary in order to facilitate individually tailored precision medicine in order to modify disease progression in the approaching genomic medicine era.

[10] Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

• Authors: Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, N. Rensing, H. Nelvagal et al.
• Year: 2023
• Venue: The Journal of Clinical Investigation
• URL: https://www.semanticscholar.org/paper/d4b32684c244c570a7ff5c79b249440a291ee06b
• DOI: 10.1172/JCI165908
• PMID: 37104037
• PMCID: 10266778
• Citations: 13
• Summary: Investigation of the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype, and highlights the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
• Evidence snippets:
• Snippet 1 (score: 0.508) > Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

[11] The converging roles of Batten disease proteins in neurodegeneration and cancer

• Authors: S. Q. Yap, Sabateeshan Mathavarajah, R. Huber
• Year: 2021
• Venue: iScience
• URL: https://www.semanticscholar.org/paper/d5a9630c4e492fd532c0ccc5c7543b976dd78e6a
• DOI: 10.1016/j.isci.2021.102337
• PMID: 33889828
• PMCID: 8050770
• Citations: 16
• Influential citations: 1
• Summary: It is proposed that further research on the relationship between cancer and the NCLs may help shed light on the roles of NCL genes in both diseases and possibly guide therapy development.
• Evidence snippets:
• Snippet 1 (score: 0.507) > patient-database). Each gene is associated with a different subtype of NCL (Mole and Cotman, 2015). A recent study showed that mutations in the TBCK (TBC1 domain-containing kinase) gene present characteristics and clinical pathology that resemble other NCL subtypes, and thus, may be classified as a new NCL subtype, CLN15 disease (Beck- Wo ¨dl et al., 2018). The NCL family of proteins comprises soluble lysosomal enzymes (CLN1/PPT1, palmitoyl protein thioesterase 1; CLN2/TPP1, tripeptidyl peptidase 1; CLN5, ceroid lipofuscinosis neuronal 5; CLN10/CTSD, cathepsin D; CLN13/CTSF, cathepsin F), lysosomal transmembrane proteins (CLN3, ceroid lipofuscinosis neuronal 3; CLN7/MFSD8, major facilitator superfamily domain-containing 8; CLN12/ATP13A2, ATPase 13A2), proteins associated with vesicular membranes (CLN4/DNAJC5, DnaJ heat shock protein family member C5; CLN14/KCTD7, potassium channel tetramerization domain-containing 7), membrane proteins that reside in the endoplasmic reticulum (ER) (CLN6, ceroid lipofuscinosis neuronal 6; CLN8, ceroid lipofuscinosis neuronal 8) and a secreted glycoprotein (CLN11/ PGRN, progranulin) (Ca ´rcel-Trullols et al., 2015). Despite the molecular genetic heterogeneity of these proteins, research in non-mammalian and mammalian models suggests that the NCL proteins may participate in shared or converging pathways (Huber, 2020;Persaud-Sawin et al., 2007). However, the precise functions of NCL proteins, their interactions with one another, and the underlying mechanisms that lead to NCL pathology are poorly understood, which has severely hindered therapy development.

[12] CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses

• Authors: R. Sharkia, Abdelnaser Zalan, Hazar Zahalka, Amit Kessel, Ayman Asaly et al.
• Year: 2022
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/10d2f0913f50a81aa537459dbb641e38b708009c
• DOI: 10.3390/genes13081393
• PMID: 36011304
• PMCID: 9407845
• Citations: 5
• Summary: Two patients who presented with atypical phenotypic manifestation and protracted clinical course of CLN8 carrying a novel compound heterozygous variant at theCLN8 gene are described, which confirmed and expanded the effect of compoundheterozygous variants in CLn8 disease.
• Evidence snippets:
• Snippet 1 (score: 0.506) > Neuronal ceroid lipofuscinosis (NCL) refers to a group of rare disorders that affects human neurons which is one of the most common causes of progressive neurological deterioration in childhood. It involves the buildup of an abnormal material called lipofuscin in the brain. NCL is inherited from the parents by their progeny in an autosomal recessive manner. There are three main types of NCL namely, Adult (Kufs or Parry disease), Juvenile (Batten disease), and Late infantile (Jansky-Bielschowsky disease) [1]. The late infantile type is the most heterogeneous one, with several variants and four genes identified: CLN2, CLN5, CLN6, and CLN8 [2]. > The accumulation of autofluorescent lysosomal storage material in the central nervous system is a key pathological finding of NCL. Several possible candidate genes (13 genes) are involved in this process, namely, CLN1 to CLN8, and CLN10 to CLN14 [3]. To date, more than 430 pathogenic variants in the above 13 candidate genes have been reported in human NCLs, and most have been registered in the NCL Mutation Database [4][5][6]. As a collective group, NCL patients are typically defined by observation of cognitive and visual impairments, epileptic seizures, and deterioration of motor skills and balance issues [7]. Unfortunately, there is no cure for NCL disorders. Therapeutic approaches for the treatment of many NCLs include the administration of immunosuppressive agents to antagonize neuroinflammation associated with neurodegeneration, the use of various small molecules, stem cell therapy, and gene therapy [8]. > The CLN8 disease type is clinically recognized during childhood in which two main clinical phenotypes were described, namely "Northern Epilepsy" known as the Finnish type characterized by intractable epilepsy and cognitive regression at the ages 5-10 years [9]. The second phenotype was the late-infantile NCL characterized by earlier onset and more rapid progressive course with visual failure, ataxia, mental decline, and epilepsy [10,11].

[13] Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

• Authors: Konrad Kaminiów, S. Kozak, J. Paprocka
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/afdbc0b7fdf7649d5c1ae6309a182f7c4c222633
• DOI: 10.3390/ijms23105729
• PMID: 35628533
• PMCID: 9145894
• Citations: 30
• Influential citations: 2
• Summary: An overview of the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis is provided.
• Evidence snippets:
• Snippet 1 (score: 0.499) > The situation is different, for example, in infantile neuronal ceroid lipofuscinosis type 1 (CLN1), where seizure frequency tends to decrease in the later stages of the disease, or in patients with classic juvenile CLN3, where seizures are rare and only moderate severity occurs in the later stages of the disease [3,[141][142][143]. As the disease progresses, the benefits and harms of specific medications should be reconsidered, as these drugs, while tolerable and effective in the earlier stages of the disease, may prove ineffective after progression and cause only side effects [143]. > Typical neurological manifestations of NCL also include motor symptoms, such as ataxia, dysphagia, myoclonus, chorea, tremors, and dystonia [3]. These especially occur in the classic and late infantile phenotypes [3,13]. In addition, parkinsonism is also present, especially in juvenile CLN3 disease, and some stereotypic movements have also been described in various types of NCL with late infantile and juvenile onset [3,13]. Table 3 shows the clinical characteristics of the different subtypes of neuronal ceroid lipofuscinoses.

[14] Epilepsy in neurodegenerative diseases.

• Authors: S. Neri, G. Mastroianni, E. Gardella, U. Aguglia, G. Rubboli
• Year: 2022
• Venue: Epileptic disorders : international epilepsy journal with videotape
• URL: https://www.semanticscholar.org/paper/3a35529b660901b3c98f454b81976b96a350406c
• DOI: 10.1684/epd.2021.1406
• PMID: 35596580
• Citations: 56
• Influential citations: 1
• Summary: An updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies) is provided to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.
• Evidence snippets:
• Snippet 1 (score: 0.498) > Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, comprises a group of neurodegenerative lysosomal storage disorders resulting in excessive accumulation of lipopigments [96]. NCLs are characterized by progressive decline of cognitive and motor functions, retinopathy with evolution to blindness, varying degrees of brain atrophy, and myoclonic epilepsy [95]. There are 14 forms of neuronal ceroid lipofuscinosis, classified according to age of symptom onset (varying from infancy and childhood to adulthood) and causative gene mutation [96]. ASMs commonly used are lamotrigine and valproic acid. Topiramate and levetiracetam can be also effective while carbamazepine, phenytoin and gabapentin may worsen myoclonic seizures [95]. Infantile NCL is a severe disease of infancy, which presents with seizures, developmental arrest and regression, and visual loss. The main gene involved in this form is CLN1, which encodes a lysosomal palmitoyl protein thioesterase. More severe than CLN1 is CLN10, which is a congenital fatal condition characterized by encephalopathy with respiratory insufficiency and status epilepticus. CLN10 encodes the lysosomal protease, cathepsin D [96]. Late-infantile NCL presents with onset in early childhood and is caused by pathogenic variants of the CLN2 gene. This disorder is characterized at the onset by a very severe myoclonic epilepsy, followed during the course of the disease, by cognitive and motor decline, and later by visual loss. CLN2 encodes a lysosomal tripeptidyl peptidase. Other NCLs such as CLN5, CLN6, CLN7, CLN8, and CLN14 mimic, to various extents, the clinical phenotype of the classic CLN2. Mild CLN6 mutations are another cause of adolescence or adult-onset PME [96]. CLN6 encodes an endoplasmic reticulum protein of unclear function.

[15] MRI findings of neuronal ceroid lipofuscinosis in a cat

• Authors: Crystal White, J. Mortier, R. Verin, T. Maddox, R. Gonçalves et al.
• Year: 2018
• Venue: JFMS Open Reports
• URL: https://www.semanticscholar.org/paper/0a2ded6cbd632857d491140a57f2773c3610b10b
• DOI: 10.1177/2055116918757330
• PMID: 29531776
• PMCID: 5843104
• Citations: 6
• Influential citations: 1
• Summary: MRI examination revealed generalised cerebral and cerebellar atrophy, diffuse T2-weighted hyperintensity of the white matter and meningeal thickening, the first report of the MRI findings of neuronal ceroid lipofuscinosis in a cat.
• Evidence snippets:
• Snippet 1 (score: 0.492) > Traditionally and still commonly encountered in the literature, nomenclature was based on the age of clinical presentation, for example infantile/juvenile/adult. The storage material, along with its ultrastructure, is variable for each neuronal ceroid lipofuscinosis type, and, although similar, the clinical course is slightly altered for each one. Molecular analysis has identified the genetic loci for the neuronal ceroid lipofuscinosis types in humans, with the exception of the CLN9 gene, which remains elusive. 23 The differences in the mutations account for the variable phenotypes between the types. 24 ][27][28] Sequencing of the exons of CLN1, CLN3, CLN5, CLN8 and CLN10 in a confirmed case of feline neuronal ceroid lipofuscinosis failed to identify the molecular cause in that patient. 4 The genes involved in the development of feline neuronal ceroid lipofuscinosis remain unidentified. > In humans and dogs, neuronal ceroid lipofuscinosis has been shown to be a recessively inherited disease with the progeny of two carrier parents having a one in four chance of developing the disease. 14 A second cat, from the same litter as the cat in this case, developed similar clinical signs 4 weeks after its littermate and was euthansed owing to severity of clinical signs. Histopathology and TEM confirmed neuronal ceroid lipofuscinosis in this second cat with central nervous system morphological changes similar to the cat described in this case. MRI was not performed in this second case, but pathological findings and the relationship between the two littermates reinforce the hypothesis of an inherited mutation in cats. 3

[16] Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

• Authors: Gordon F. Buchanan
• Year: 2023
• Venue: Epilepsy Currents
• URL: https://www.semanticscholar.org/paper/385f73ebc8d00dc9e7c2f433dd8be7625868cc8f
• DOI: 10.1177/15357597231200702
• PMID: 38269343
• PMCID: 10805085
• Summary: Investigation of the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype, and highlights the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
• Evidence snippets:
• Snippet 1 (score: 0.491) > Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2 R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2 R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

[17] Visual perception and macular integrity in non-classical CLN2 disease

• Authors: Y. Atiskova, Jan Wildner, E. Wibbeler, M. Nickel, M. Spitzer et al.
• Year: 2022
• Venue: Graefe's Archive for Clinical and Experimental Ophthalmology
• URL: https://www.semanticscholar.org/paper/af4a1c78a0616dad65d14e16df890f0a22666833
• DOI: 10.1007/s00417-022-05662-1
• PMID: 35652945
• PMCID: 9581810
• Citations: 1
• Summary: The presented longitudinal study characterizes the variable ocular involvement in non-classical CLN2 disease and contributes to the natural history description, outlining the necessity of regular ophthalmic examination.
• Evidence snippets:
• Snippet 1 (score: 0.488) > Neuronal ceroid lipofuscinoses (NCLs) form a heterogeneous group of neurodegenerative lysosomal storage disorders. To date, the group consists of 13 genetically different disease entities, which are classified by the underlying gene mutation (CLN1-14) [1]. All NCL diseases except one (CLN4) are autosomal recessively inherited. Their shared clinical hallmarks encompass psychomotor regression, epilepsy and vision loss resulting in premature death [2][3][4]. An internationally agreed NCL disease nomenclature is based on both the underlying genetic defect as well as the phenotype [5]. Most NCL diseases have a most prevalent "classic" phenotype. However, due to the increasing implementation of next generation sequencing panels and exome sequencing as essential diagnostic tools for the assessment of rare diseases, more and more patients are identified with "non-classical" phenotypes caused by mutational effect that lead to varying loss of function of the associated protein. > Neuronal ceroid lipofuscinosis type 2 (CLN2; OMIM 204,500) is caused by mutations in the CLN2 gene resulting in deficient activity of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) [6]. Patients with the classic late infantile phenotype present between ages 2 and 4 years with seizures and language developmental delay, followed by rapid deterioration of motor, language and cognitive skills over a 2-to 3-year period and premature death [7,8]. In patients with the classic late infantile CLN2 phenotype, seizures and psychomotor decline precede the vision loss [9]. Electroretinogram studies reveal subnormal or completely extinguished amplitudes as well as prolonged rod responses and severely subnormal cone b-wave responses [10]. Visual deterioration seems to occur after 3 years of age, although slight retinal abnormalities can be visible in presymptomatic patients in optical coherence tomography (OCT) imaging prior to obvious funduscopic changes. In OCT imaging, a bilateral symmetric progressive loss of central retinal thickness (CRT) could be shown especially between 4 and 6 years of age.

[18] Integrative human and murine multi-omics: Highlighting shared biomarkers in the neuronal ceroid lipofuscinoses.

• Authors: N. Gammaldi, F. Pezzini, E. Michelucci, N. Di Giorgi, A. Simonati et al.
• Year: 2023
• Venue: Neurobiology of disease
• URL: https://www.semanticscholar.org/paper/2c50113653b538549410afe59f69ce70a4184a43
• DOI: 10.1016/j.nbd.2023.106349
• PMID: 37952681
• Citations: 3
• Summary: The results offer promising targets for potential new therapeutic strategies and reinforce the hypothesis of a connection between NCLs and other forms of dementia, particularly Alzheimer's disease.
• Evidence snippets:
• Snippet 1 (score: 0.483) > The collective term neuronal ceroid lipofuscinosis (NCL) refers to a group of inherited neurodegenerative disorders that affect children and young adults, and are characterized by retinopathy leading to blindness, ataxia and gait abnormalities, drug-resistant epilepsy, mental deterioration, and early death. The genetic landscape of NCL, also known as Batten disease, is highly heterogeneous with thirteen known disease forms to date (Table 1), associated with over 400 mutations in several genes entered in the NCL database (NCL resource mutation database, 2021). The NCLs are usually inherited according to an autosomal recessive pattern, although a rare, autosomal dominant adult-onset form has been identified (Mole et al., 2012). > The disease has a worldwide distribution with an incidence range calculated to be 1.28/100.000 live births, and there are about 6-700 new diagnoses each year. In around 9.7% of cases, however, mutations cannot be demonstrated in any of the known NCL genes in spite of a typical NCL clinical presentation (Santorelli et al., 2013;Simpson et al., 2014;Sleat et al., 2016). These cases remain molecularly undefined. > Cases are classified by: i) the age at disease onset (congenital, infantile, late infantile, juvenile, adult), ii) the designation of the mutated gene (CLN), iii) the characteristics of autofluorescent storage material accumulated in lysosomes and iv) the ultrastructural features of the cytosomes (Simonati and Williams, 2022). > No treatment other than palliative care is currently available for NCL (Iwan et al., 2021;Kohlschütter et al., 2019), with the exception of a cohort of patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease) undergoing enzyme replacement therapy (Brineura™, Cerliponase alfa) (Specchio et al., 2020). Poor information on disease pathophysiology, and therefore on possible disease biomarkers, is a major obstacle to clinical trials in this field.

[19] Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary Review

• Authors: Xinglong Yang, Yan-ming Xu
• Year: 2014
• Venue: BioMed Research International
• URL: https://www.semanticscholar.org/paper/b36b7be6ad6967929d150ff1d028173443266f48
• DOI: 10.1155/2014/371256
• PMID: 25197640
• PMCID: 4147200
• Citations: 59
• Influential citations: 2
• Summary: It is proposed that a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism is proposed, and how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets is highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.483) > ATP13A2 mutations have been identified not only in patients with Parkinsonism, but also in patients with neuronal ceroid lipofuscinoses (NCLs) [10]. NCLs are a group of neurodegenerative disorders that are also lysosomal storage diseases. Clinical manifestations are seizures, progressive cognitive and motor decline, and failing vision. The pathological hallmark of NCLs is accumulation of autofluorescent lipopigment within neuronal lysosomes [68]. > Recently, the mutation c.2429C>G in exon 22 of ATP13A2, predicted to result in the amino acid substitution p.Met810Arg, was identified in a Belgian family with NCLs [10]. Affected individuals showed not only typical NCL symptoms but also extrapyramidal involvement. Postmortem pathological examination revealed extensive lipofuscin deposits in the cortex, basal nuclei, cerebellum, and retina-but not the white matter-and electron microscopy showed whorled lamellar inclusions typical of NCLs [10]. A link between ATP13A2 mutations and NCL pathogenesis is further supported by studies in animal models [69,70]. In fact, mice deficient in ATP13A2 exhibited neuronal ceroid lipofuscinosis, -synuclein accumulation, and age-dependent sensorimotor deficits, suggesting that PD and NCLs share a pathogenic mechanism [71]. > A shared disease pathway may help explain earlier reports of individuals who demonstrate an "overlapping" neurodegenerative syndrome combining Parkinsonism and NCLs [72][73][74][75][76]. ATP13A2 is a lysosomal transport protein that helps maintain optimal pH in lysosomes [46], and ceramide is metabolized in lysosomes [77]. The apoptosis that appears to cause NCLs is associated with increased levels of ceramide [78,79], which have also been linked to -synuclein deposition, which may contribute to PD pathogenesis [80].

[20] S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains

• Authors: A. Buszka, Agata Pytyś, Domnic Colvin, J. Włodarczyk, T. Wójtowicz
• Year: 2023
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/e804de43357e439c5aa0f43b76899084f5414b6c
• DOI: 10.3390/cells12030387
• PMID: 36766729
• PMCID: 9913408
• Citations: 32
• Influential citations: 1
• Summary: Experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.482) > The neuronal ceroid lipofuscinoses (NCLs) (also known as Batten disease) are a class of inherited nervous system disorders associated with mutations in 13 genes (CLN1 to CLN14) that most often begin in childhood and interfere with a cell's ability to recycle a cellular residue called lipofuscin [231]. NCL-associated proteins are localized to lysosomes, endoplasmic reticulum, and other cellular locations; but CLN gene mutations lead primarily to dysfunction in lysosomes. One class of diseases called infantile neuronal ceroid lipofuscinosis (CLN1 disease) is caused by a mutation in CLN1, which encodes palmitoyl-protein thioesterase 1 (PPT1) [223] and may have several phenotypes and types of symptom progressions [232]. In the infantile form, difficulties in acquiring skills such as standing, walking, and talking occur between 6-12 months, and may progress with age into vision loss, seizures, psychomotor deterioration, and premature death [233]. > The molecular mechanism explaining how PPT1-deficiency may affect cell physiology was studied in various systems. In Drosophila, loss of PPT1 causes defects in endocytic trafficking [234] and exocytosis and endocytosis of synaptic vesicles [235]. In mice, PPT1 knockout resulted in reduced expression of presynaptic proteins (e.g., SNAP25), a smaller number of synaptic vesicles, and abnormal expression of NMDAR, contributing to excitotoxicity [223]. PPT1 deficiency caused persistent membrane anchorage of the palmitoylated SV proteins, which hindered the recycling of the vesicle components that normally fuse with the presynaptic plasma membrane during SV exocytosis both in postmortem brain tissues from patients and in brain tissues from PPT1 knockout mice [211]. Altogether, loss of PPT1 in infantile ceroid lipofuscinosis may result in degeneration of excitatory and inhibitory cells and impaired synaptic transmission [223,236].

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