Mol Genet Metab Rep
December 2023
Tokyo Women's Medical University, Department of Pediatrics, Japan.
Neuronal ceroid lipofuscinosis type1(CLN1), is a one form of the group of neuronal ceroid lipofuscinoses (NCLs), which is a neurodegenerative disorder characterized by progressive psychomotor deterioration, ataxia, epilepsy, and visual impairment. Neurological manifestations occur at a wide range of ages, from infancy to adulthood, but are most common in infancy. The prevalence of CLN1 is unclear; however, it is very rare in Japan and Europe.
View Article and Find Full Text PDFBackground/objectives: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2.
View Article and Find Full Text PDFMed Clin (Barc)
March 2024
Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China. Electronic address:
Background: Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China.
View Article and Find Full Text PDFNeurobiol Dis
December 2023
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation - Pisa, Italy. Electronic address:
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative disorders whose molecular mechanisms remain largely unknown. Omics approaches are among the methods that generate new information on modifying factors and molecular signatures. Moreover, omics data integration can address the need to progressively expand knowledge around the disease and pinpoint specific proteins to promote as candidate biomarkers.
View Article and Find Full Text PDFSci Rep
November 2023
Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th Street N., Sioux Falls, SD, 57104, USA.
Batten disease is a group of mostly pediatric neurodegenerative lysosomal storage disorders caused by mutations in the CLN1-14 genes. We have recently shown that acidified drinking water attenuated neuropathological changes and improved motor function in the Cln1 and Cln3 mouse models of infantile CLN1 and juvenile CLN3 diseases. Here we tested if acidified drinking water has beneficial effects in Cln2 mice, a nonsense mutant model of late infantile CLN2 disease.
View Article and Find Full Text PDFIntern Med
June 2024
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan.
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear.
View Article and Find Full Text PDFMol Genet Metab
December 2023
Division of Neurogenetics, Department of Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA. Electronic address:
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing.
View Article and Find Full Text PDFSci Rep
October 2023
Centogene GmbH, Am Strande 7, 18057, Rostock, Germany.
Neuronal ceroid lipofuscinosis 6 (CLN6) is a rare and fatal autosomal recessive disease primarily affecting the nervous system in children. It is caused by a pathogenic mutation in the CLN6 gene for which no therapy is available. Employing an untargeted metabolomics approach, we analyzed the metabolic changes in CLN6 subjects to see if this system could potentially yield biomarkers for diagnosis and monitoring disease progression.
View Article and Find Full Text PDFJ Neurosci
December 2023
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612.
Protein palmitoylation is the only reversible post-translational lipid modification. Palmitoylation is held in delicate balance by depalmitoylation to precisely regulate protein turnover. While over 20 palmitoylation enzymes are known, depalmitoylation is conducted by fewer enzymes.
View Article and Find Full Text PDFPract Neurol
January 2024
Neurology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
A young man from Pakistan had his first-ever tonic-clonic seizure while playing cricket. Since age 12 years, he had reported involuntary jerks and tremulousness, sometimes with falls, particularly with bright lights. Family history included a brother who developed seizures with myoclonus in his mid-20s and parental consanguinity.
View Article and Find Full Text PDFFront Neurol
September 2023
Department of Child and Adolescence, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
Background: Recurrent non-epileptic episodes of frightened facial and body expression occur in more than half of post-adolescent patients with juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease). Clinically, the episodes look similar to the attacks of paroxysmal sympathetic hyperactivity (PSH) commonly seen following traumatic brain injury (TBI). The episodes occur when the patients are exposed to separation, hear loud sounds or are otherwise bothered by discomfort and as in PSH following TBI, the attacks are difficult to prevent and/or treat.
View Article and Find Full Text PDFGenes (Basel)
August 2023
Neurodegenerative Diseases Research Laboratory, Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder.
View Article and Find Full Text PDFScience
September 2023
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Lysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels in monogenic and complex neurodegeneration suggest an essential function in human health. However, the site and mechanism responsible for BMP synthesis have been subject to debate for decades.
View Article and Find Full Text PDFHum Gene Ther
September 2023
Department of Genetic Medicine, New York, New York, USA.
CLN2 disease is a fatal, childhood autosomal recessive disorder caused by mutations in ceroid lipofuscinosis type 2 (CLN2) gene, encoding tripeptidyl peptidase 1 (TPP-1). Loss of TPP-1 activity leads to accumulation of storage material in lysosomes and resultant neuronal cell death with neurodegeneration. Genotype/phenotype comparisons suggest that the phenotype should be ameliorated with increase of TPP-1 levels to 5-10% of normal with wide central nervous system (CNS) distribution.
View Article and Find Full Text PDFNeurobiol Dis
September 2023
Department Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy. Electronic address:
The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with cerebellar involvement. They include storage diseases like Gaucher disease, Lafora disease, and forms of neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated with mutations in different genes.
View Article and Find Full Text PDFMol Neurobiol
January 2024
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Parkinsonism is a clinical syndrome that is caused by Parkinson's disease (PD) and other neurodegenerative diseases. Here, we report a patient who exhibited progressive parkinsonism, epilepsy, and cognitive impairment and was diagnosed with adult-onset neuronal ceroid lipofuscinoses (ANCLs). The patient carries a mutation (p.
View Article and Find Full Text PDFNat Commun
July 2023
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes.
View Article and Find Full Text PDFJ Proteome Res
July 2023
Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, United States.
Syndromic CLN3-Batten is a fatal, pediatric, neurodegenerative disease caused by variants in , which encodes the endolysosomal transmembrane CLN3 protein. No approved treatment for CLN3 is currently available. The protracted and asynchronous disease presentation complicates the evaluation of potential therapies using clinical disease progression parameters.
View Article and Find Full Text PDFNeuropediatrics
December 2023
Rare and Complex Epilepsy Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network: EpiCARE, Rome, Italy.
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric disorder associated with rapid neurodegeneration, and premature death in adolescence. An effective enzyme replacement therapy (cerliponase alfa) has been approved that can reduce this predictable neurological decline. The nonspecific early symptoms of CLN2 disease frequently delay diagnosis and appropriate management.
View Article and Find Full Text PDFDis Model Mech
August 2023
Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA.
Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span and inconsistent subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, thereby limiting their use in preclinical studies. Here, we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8).
View Article and Find Full Text PDFCells
May 2023
Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Dev Neurobiol
November 2023
Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.
Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end-stage disease at ≤24 months of age.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Basis Dis
August 2023
Department of Surgery, Dentistry, Paediatrics and Gynaecology (Child Neurology and Psychiatry), University of Verona, 37134 Verona, Italy. Electronic address:
• Neuronal Ceroido Lipofuscinoses (NCL) are inherited, neurodegenerative disorders associated with lysosomal storage. • Impaired autophagy plays a pathogenetic role in several NCL forms, including CLN3 disease, but study on human brains are lacking. • In post-mortem brain samples of a CLN3 patient the LC3-I to LC3-II shift was consistent with activated autophagy.
View Article and Find Full Text PDFActa Neuropathol
August 2023
Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain fatty acids (VLCFAs). We performed post-mortem neuropathological examinations on four SCA34 patients with the ELOVL4 L168F mutation and compared the findings to age-matched controls. Specific gross findings of SCA34 were limited to pontocerebellar atrophy.
View Article and Find Full Text PDFMol Genet Metab
May 2023
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
Background: CLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6 years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death.
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