Article
Clinical Neurology
Jillian M. Cameron, John A. Damiano, Bronwyn Grinton, Patrick W. Carney, Penny McKelvie, Peter Silbert, Nicholas Lawn, Ingrid E. Scheffer, Karen L. Oliver, Michael S. Hildebrand, Samuel F. Berkovic
Summary: This study analyzed the phenotypic features of a group of patients with protracted CLN3 disease in order to improve recognition of the disorder. The results showed that visual impairment was the initial symptom, with onset at 5-9 years, similar to classic CLN3 disease. The disease is often accompanied by progressive generalized and focal seizures.
Review
Biochemistry & Molecular Biology
I. Basak, H. E. Wicky, K. O. McDonald, J. B. Xu, J. E. Palmer, H. L. Best, S. Lefrancois, S. Y. Lee, L. Schoderboeck, S. M. Hughes
Summary: Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease caused by mutations in thirteen CLN genes. Mutations in the CLN5 gene lead to a form of variant late-infantile NCL, with widespread protein expression in various tissues. Research on CLN5 helps to understand lysosomal biology and develop efficient therapies for CLN5 Batten disease.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Cell Biology
Marcel Klein, Guido Hermey
Summary: Evidence from genetics and cellular and animal models suggests a link between early and late neurodegenerative disorders. This review summarizes the connection between Alzheimer's disease and neuronal ceroid lipofuscinoses. Genetic studies have found overlapping mutations between clinically diagnosed Alzheimer's and neuronal ceroid lipofuscinoses. Dysfunctions in intracellular trafficking mechanisms and the autophagy-endolysosome system are believed to be shared cytopathological processes. Understanding these common mechanisms is important for finding therapeutic targets and tailored treatments.
NEURAL REGENERATION RESEARCH
(2023)
Review
Clinical Neurology
Keigo Takahashi, Hemanth R. Nelvagal, Jenny Lange, Jonathan D. Cooper
Summary: This article summarizes the latest understanding of glial pathologies and their contribution to the pathogenesis of NCLs, highlighting the challenges that require further research.
FRONTIERS IN NEUROLOGY
(2022)
Article
Clinical Neurology
Eva Wibbeler, Miriam Nickel, Christoph Schwering, Angela Schulz, Jonathan W. Mink
Summary: This study aimed to determine the validity and reliability of the UBDRS rating scale for CLN3 disease in an independent sample. After evaluating 13 individuals with CLN3 disease, it was concluded that UBDRS has excellent interrater reliability and construct validity.
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
(2022)
Article
Endocrinology & Metabolism
Joanna Karolina Purzycka-Olewiecka, Katarzyna Hetmanczyk-Sawicka, Tomasz Kmiec, Dominika Szczesniak, Joanna Trubicka, Maciej Krawczynski, Maciej Pronicki, Agnieszka Lugowska
Summary: Ceroid lipofuscinosis type 3 (CLN3) is a neurodegenerative metabolic disease characterized by progressive visual loss, epilepsy, and dementia. Lipofuscin deposits and vacuolized lymphocytes are indicative of CLN3 diagnosis. The most common cause of CLN3 is a large deletion of 1.02 kb in exons 7 and 8 of the CLN3 gene. This study reports 4 patients from 2 families who experienced visual deterioration as the initial clinical sign, followed by neurological symptoms. All patients had the 1.02 kb deletion in the CLN3 gene detected. The presence of abnormal structures and the economic feasibility of the 1.02 kb deletion test support its use in diagnosing CLN3.
METABOLIC BRAIN DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Hannah L. Best, Alison J. Clare, Kirstin O. McDonald, Hollie E. Wicky, Stephanie M. Hughes
Summary: Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited childhood neurodegenerative disorders characterized by neuroinflammation and alterations in the extracellular environment. This study investigated the secretome in the CLN6 variant of NCL and found significant changes that could be partially corrected with gene therapy, suggesting potential biomarkers for disease monitoring. Overall, the secretome plays a role in CLN6 pathogenesis and may serve as an in vitro model for future studies.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Cell Biology
Vicki J. Swier, Katherine A. White, Tyler B. Johnson, Xiaojun Wang, Jimin Han, David A. Pearce, Ruchira Singh, Arlene V. Drack, Wanda Pfeifer, Christopher S. Rogers, Jon J. Brudvig, Jill M. Weimer
Summary: This study presents a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, showing consistent pathology and behavioral impairment mirroring clinical presentation. The model demonstrates its value in studying the role of CLN3 and safety/efficacy of novel disease-modifying therapeutics.
DISEASE MODELS & MECHANISMS
(2023)
Article
Multidisciplinary Sciences
Nouf N. Laqtom, Wentao Dong, Uche N. Medoh, Andrew L. Cangelosi, Vimisha Dharamdasani, Sze Ham Chan, Tenzin Kunchok, Caroline A. Lewis, Ivonne Heinze, Rachel Tang, Christian Grimm, An N. Dang Do, Forbes D. Porter, Alessandro Ori, David M. Sabatini, Monther Abu-Remaileh
Summary: Lysosomes play crucial roles in cellular function, and dysfunction is associated with various human diseases. The study reveals the importance of CLN3 protein in glycerophospholipid metabolism within lysosomes, as its loss leads to massive accumulation of GPDs.
Article
Clinical Neurology
Mette Moller Handrup, Henning Molgaard, Brian N. Andersen, John R. Ostergaard
Summary: The article "Translation: The use of pacemaker treatment in Juvenile Neuronal Ceroid Lipofuscinosis" introduces the application of pacemaker treatment for patients with Juvenile Neuronal Ceroid Lipofuscinosis and conducts a follow-up study on the original Danish CLN3-heart population, indicating that pacemaker treatment has a significant impact on the quality of life of patients.
FRONTIERS IN NEUROLOGY
(2022)
Review
Biochemistry & Molecular Biology
Robert J. J. Huber
Summary: Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that play a role in regulating cellular processes in the endomembrane system. Mutations in CLN genes cause neuronal ceroid lipofuscinosis (NCL), a severe neurodegenerative disease. This review summarizes the current understanding of CLN gene and protein networking in mammalian cells, with a focus on identifying new molecular targets for therapy development. Interestingly, CLN genes and proteins have also been linked to other forms of neurodegeneration, such as Alzheimer's disease and Parkinson's disease, suggesting potential insights into related diseases.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Endocrinology & Metabolism
David E. Sleat, Whitney Banach-Petrosky, Katherine E. Larrimore, Yuliya Nemtsova, Jennifer A. Wiseman, Allison Najafi, Dymonn Johnson, Timothy A. Poole, Keigo Takahashi, Jonathan D. Cooper, Peter Lobel
Summary: Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins TPP1 and CLN3, respectively. While enzyme replacement therapy has been successful for LINCL, effective treatments for JNCL are lacking due to unknown CLN3 protein function and limited robust animal models. Through creating a double mutant mouse model, this study found that the phenotype of the double mutant closely resembled that of the single TPP1 mutant, indicating potential use in JNCL therapy development. Additionally, analysis of brain proteomic changes in these models identified potential biomarker candidates for LINCL and altered lysosomal proteins in the Cln3 mutant animals.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Clinical Neurology
Giancarlo Todiere, Stefania Della Vecchia, Maria Aurora Morales, Andrea Barison, Ivana Ricca, Alessandra Tessa, Elisa Colombi, Filippo Maria Santorelli
Summary: Cardiac MRI is essential for diagnosing hypertrophic cardiomyopathy and may play a role in neuronal ceroid lipofuscinosis, allowing for early diagnosis and treatment monitoring.
FRONTIERS IN NEUROLOGY
(2022)
Review
Clinical Neurology
Emily Gardner, Sara E. Mole
Summary: Neuronal ceroid lipofuscinoses are a group of inherited neurodegenerative disorders affecting children and adults, sharing similar clinical features and accumulation of storage material. Over 530 mutations have been identified in 13 genes, encoding various proteins including lysosomal enzymes. While many mutations are associated with typical disease phenotypes, there is an increasing description of variant disease phenotypes.
FRONTIERS IN NEUROLOGY
(2021)
Article
Cell Biology
Meagan D. McLaren, Sabateeshan Mathavarajah, William D. Kim, Shyong Q. Yap, Robert J. Huber
Summary: The study reveals the important roles of CLN5 in growth and development processes, with CLN5 deficiency affecting cell proliferation, viability, and autophagic flux. Loss of CLN5 in the early stages of multicellular development impacts cell aggregation and autophagic levels. Post-mound formation, CLN5 deficiency results in developmental abnormalities affecting spore morphology, germination, and viability.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Clinical Neurology
Samuel F. Berkovic, Karen L. Oliver, Laura Canafoglia, Penina Krieger, John A. Damiano, Michael S. Hildebrand, Michela Morbin, Danya F. Vears, Vito Sofia, Loretta Giuliano, Barbara Garavaglia, Alessandro Simonati, Filippo M. Santorelli, Antonio Gambardella, Angelo Labate, Vincenzo Belcastro, Barbara Castellotti, Cigdem Ozkara, Adam Zeman, Julia Rankin, Sara E. Mole, Umberto Aguglia, Michael Farrell, Sulekha Rajagopalan, Alan McDougall, Susan Brammah, Frederick Andermann, Eva Andermann, Hans-Henrik M. Dahl, Silvana Franceschetti, Stirling Carpenter
Review
Clinical Neurology
Sara E. Mole, Glenn Anderson, Heather A. Band, Samuel F. Berkovic, Jonathan D. Cooper, Sophia-Martha Kleine Holthaus, Tristan R. Mckay, Diego L. Medina, Ahad A. Rahim, Angela Schulz, Alexander J. Smith
Review
Biochemistry & Molecular Biology
Elisabeth S. Butz, Uma Chandrachud, Sara E. Mole, Susan L. Cotman
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2020)
Review
Biochemistry & Molecular Biology
Jonathan D. Cooper, Sara E. Mole
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2020)
Review
Biochemistry & Molecular Biology
Wenfei Liu, Sophia-Martha Kleine-Holthaus, Saul Herranz-Martin, Mikel Aristorena, Sara E. Mole, Alexander J. Smith, Robin R. Ali, Ahad A. Rahim
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2020)
Editorial Material
Biochemistry & Molecular Biology
Ahad A. Rahim, Claire Russell, Sara E. Mole
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2020)
Article
Biotechnology & Applied Microbiology
Sophia-Martha Kleine Holthaus, Mikel Aristorena, Ryea Maswood, Olha Semenyuk, Justin Hoke, Aura Hare, Alexander J. Smith, Sara E. Mole, Robin R. Ali
HUMAN GENE THERAPY
(2020)
Article
Pediatrics
Charles M. Lourenco, Andre Pessoa, Carmen C. Mendes, Carolina Rivera-Nieto, Diane Vergara, Monica Troncoso, Emily Gardner, Francisca Mallorens, Lina Tavera, Luis A. Lizcano, Nora Atanacio, Norberto Guelbert, Norma Specola, Nury Mancilla, Carolina F. M. de Souza, Sara E. Mole
Summary: Neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative lysosomal storage disorder primarily affecting children aged 2-4 years, with seizures, language abnormalities, and behavioral disorders being the first manifestations in atypical cases observed in Latin American patients at an older age of 6 years. Early diagnosis of CLN2 in children presenting with such symptoms is crucial for timely initiation of specific therapy.
JOURNAL OF PAEDIATRICS AND CHILD HEALTH
(2021)
Article
Multidisciplinary Sciences
Katharina Iwan, Robert Clayton, Philippa Mills, Barbara Csanyi, Paul Gissen, Sara E. Mole, David N. Palmer, Kevin Mills, Wendy E. Heywood
Summary: NCL is a group of rare neurodegenerative disorders characterized by accumulation of cellular storage bodies. Current therapeutic options are limited, but urine biomarkers may help monitor disease progression and treatment response. Through proteomic analysis and a targeted assay, certain proteins were found to be increased in NCL patients, which could be used to monitor the effectiveness of future therapies.
Article
Genetics & Heredity
Sara E. Mole, Angela Schulz, Eben Badoe, Samuel F. Berkovic, Emily C. de Los Reyes, Simon Dulz, Paul Gissen, Norberto Guelbert, Charles M. Lourenco, Heather L. Mason, Jonathan W. Mink, Noreen Murphy, Miriam Nickel, Joffre E. Olaya, Maurizio Scarpa, Ingrid E. Scheffer, Alessandro Simonati, Nicola Specchio, Ina Von Loebbecke, Raymond Y. Wang, Ruth E. Williams
Summary: These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage CLN2 disease. The program addresses the clinical need to complement other available information.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Medicine, Research & Experimental
Chiara Soldati, Irene Lopez-Fabuel, Luca G. Wanderlingh, Marina Garcia-Macia, Jlenia Monfregola, Alessandra Esposito, Gennaro Napolitano, Marta Guevara-Ferrer, Anna Scotto Rosato, Einar K. Krogsaeter, Dominik Paquet, Christian M. Grimm, Sandro Montefusco, Thomas Braulke, Stephan Storch, Sara E. Mole, Maria A. De Matteis, Andrea Ballabio, Julio L. Sampaio, Tristan McKay, Ludger Johannes, Juan P. Bolanos, Diego L. Medina
Summary: The research found potential therapeutic effects of tamoxifen for certain types of Batten diseases, such as CLN3 and CLN7. Tamoxifen can reduce the accumulation of Gb3 in certain BD cells by activating the transcription factor EB. In a mouse model, tamoxifen reduced the accumulation of Gb3 and SCMAS, improved neuroinflammation, and enhanced motor coordination.
EMBO MOLECULAR MEDICINE
(2021)
Correction
Multidisciplinary Sciences
Christopher J. Minnis, StJohn Townsend, Julia Petschnigg, Elisa Tinelli, Juerg Baehler, Claire Russell, Sara E. Mole
SCIENTIFIC REPORTS
(2021)
Article
Medicine, Research & Experimental
Christopher D. Thornton, Stuart Fielding, Kinga Karbowniczek, Alicia Roig-Merino, Alysha E. Burrows, Lorna M. FitzPatrick, Aseel Sharaireh, John P. Tite, Sara E. Mole, Richard P. Harbottle, Lisa J. Caproni, Tristan R. Mckay
Summary: The study reports the first-ever application of doggybone DNA (dbDNA) vectors to generate human iPSCs, which showed greater stability and safety potential compared to bacterially derived vectors in cellular activities.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Review
Biochemistry & Molecular Biology
Annie McShane, Sara E. Mole
Summary: Batten disease is a neurodegenerative disorder that mainly affects children, and there is a lack of consideration for sex differences in research using animal models. However, in recent years, there has been an increasing recognition of the importance of considering sex as a biological variable, and recommendations have been made to address this issue.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Emily L. Relton, Nicolas J. Roth, Seda Yasa, Abuzar Kaleem, Guido Hermey, Christopher J. Minnis, Sara E. Mole, Tatyana Shelkovnikova, Stephane Lefrancois, Peter J. McCormick, Nicolas Locker
Summary: The assembly of membrane-less organelles called stress granules (SGs) is important for cells to respond and adapt to stress. SGs condense stalled mRNAs and proteins to modulate cellular activities and promote survival. Disassembly of SGs is crucial for cell viability, and mutations leading to persistent or aberrant SGs are associated with neurodegenerative diseases. In the case of CLN3 mutations, which cause juvenile neuronal ceroid lipofuscinosis, loss of CLN3 function disrupts SG dynamics and poses challenges for treating this childhood disease.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)