EM as an important diagnostic tool in neuronal ceroid-lipofuscinosis (NCL, Batten's disease)

1992 ◽  
Vol 50 (1) ◽  
pp. 628-629
Author(s):  
Wolfgang H. Muss ◽  
Rudolf Puttinger ◽  
Josef Thurner
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Autosomal Recessive Inheritance ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Mitochondrial Atp Synthase ◽  
Important Diagnostic Tool ◽  
Storage Products ◽  
Batten's Disease ◽  
Nerve System ◽  
Ceroid Lipofuscin

Neuronal Ceroid-Lipofuscinoses (NCL) are a group of neurometabolic/neurodegenerative disorders characterized by an accumulation of metabolites (autofluorescent “1ipopigments-Ceroid-Lipofuscin”) in central and peripheral nerve system as well as in retina, skeletal muscle, fibroblasts, histiocytes and other body organs. Batten's Disease (syn:SPIELMEYER-VOGT Disease; iuvenile onset NCL) presents with an autosomal recessive inheritance (1). Immunochemical studies (2) suggest that subunit c of mitochondrial ATP-Synthase is stored in the late infantile, iuvenile and adult forms of NCL ; chromosome studies indicate Batten's Disease maps to human chromosome 16 (3); erythrocyte and platelet phospholipids and fatty acids have been reported to be decreased (4), also concentrations of phosphorylated dolichol are reported to be 10 to 20-fold higher in brain from NCL than age-matched controls (5). Intracel1ular/lysosomal storage products histologically are PAS-positive, extractable and, ultrastructurally, the inclusions/accumulation products display characteristic recti-and curvilinear profiles as well as fingerprint bodies (for histological / ultrastructural classification criteria cf. (6)).

scholarly journals Neuronal Ceroid-lipofuscinosis in a Cat

1995 ◽  
Vol 32 (5) ◽  
pp. 485-488 ◽  
Author(s):  
R. Bildfell ◽  
C. Matwichuk ◽  
S. Mitchell ◽  
P. Ward
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Clinical Signs ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Neurologic Disease ◽  
Ceroid Lipofuscinosis ◽  
Neural Tissues ◽  
Retinal Atrophy ◽  
The Brain ◽  
Reactive Astrocytosis ◽  
Ceroid Lipofuscin

Neuronal ceroid-lipofuscinosis was diagnosed in a young adult domestic short-haired cat euthanatized because of severe progressive neurologic disease. Clinical signs included blindness, seizures, and decreased mentation. An autofluorescent pigment, identified as ceroid-lipofuscin by electron microscopy and staining properties, was found within neurons of the central and peripheral nervous systems. A diffuse reactive astrocytosis accompanied by multifocal microgliosis was visible in all areas of the brain. Retinal atrophy with intraneuronal lipopigment accumulation was also identified. Contrary to the human neuronal ceroid-lipofuscinoses, pigment deposition appeared to be restricted to neural tissues.

scholarly journals Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner

2009 ◽  
Vol 29 (3) ◽  
pp. 173-181 ◽  
Author(s):  
Kristina Oresic ◽  
Britta Mueller ◽  
Domenico Tortorella
Keyword(s):  
Quality Control ◽  
Protein Extraction ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Point Mutations ◽  
Lysosomal Storage Diseases ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Dependent Manner ◽  
Lysosomal Storage ◽  
Er Quality Control ◽  
Recessive Mutations

NCLs (neuronal ceroid lipofuscinoses), a group of inherited neurodegenerative lysosomal storage diseases that predominantly affect children, are the result of autosomal recessive mutations within one of the nine cln genes. The wild-type cln gene products are composed of membrane and soluble proteins that localize to the lysosome or the ER (endoplasmic reticulum). However, the destiny of the Cln variants has not been fully characterized. To explore a possible link between ER quality control and processing of Cln mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6G123D and Cln6M241T) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most probably generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6G123D and Cln6M241T polypeptides. The results implicate ER quality control in the instability of the Cln variants that probably contributes to the development of NCL.

VALPROIC ACID EXTENDS LIFESPAN OF THE ZEBRAFISH MODEL OF CLN2 DISEASE (LATE INFANTILE NEURONAL CEROID LIPOFUSCINOSIS)

2015 ◽  
Vol 86 (11) ◽  
pp. e4.153-e4
Author(s):  
Fahad Mahmood ◽  
Anselm Zdebik ◽  
Alexandra Au ◽  
Jennifer Cooke ◽  
Claire Russell
Keyword(s):  
Seizure Activity ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Epileptiform Activity ◽  
Intractable Epilepsy ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Zebrafish Model ◽  
Lysosomal Protease

CLN2 disease is a subtype of the neuronal ceroid lipofuscinoses (NCLs), a group of lysosomal storage disorders causing progressive, untreatable, neurodegeneration, intractable epilepsy and premature death in children. We have developed a permanent genetic zebrafish model of CLN2 disease due to a mutation in tpp1 encoding the lysosomal protease Tripeptidyl-peptidase-1 that replicates the neurodegenerative and storage phenotype. We hypothesize that CLN2 zebrafish display electrical and behavioural evidence of seizure activity that responds to established anti-convulsants and can further be used to develop novel therapeutic approaches.To validate the presence of seizures we performed single electrode electroencephalography showing CLN2 zebrafish had increased spiking activity vs wildtype with Fast-Fourier transform showing significantly increased amplitude about 2–4Hz. This was attenuated by Valproate (p=0.049), but not pentobarbitone. We also demonstrate that Valproate significantly reduces seizure-related movement bouts, thereby correlating movements and epileptiform activity. Lastly, we show exposure to Valproate significantly extends the lifespan of our zebrafish model with mortality between 3–6 days post-fertilization 8.33% in treated vs 33.3% in controls (p=0.01).The CLN2 zebrafish model thus displays electrical and behavioural seizure activity that can be attenuated by Valproate, with associated prolongation in survival. Moreover this model can utilize high-throughput in vivo screening assays to develop novel anti-convulsants.

scholarly journals Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material

2010 ◽  
Vol 428 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Su Xu ◽  
David E. Sleat ◽  
Michel Jadot ◽  
Peter Lobel
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Subcellular Fractionation ◽  
Acidic Protein ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Mitochondrial Atp Synthase

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease of children caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1. LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1. We have therefore initiated a proteomic analysis of storage material in brain from a LINCL mouse model. One protein, GFAP (glial fibrillary acidic protein), was found to be elevated in the LINCL mice compared with normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. To determine whether GFAP accumulates within the lysosome in LINCL, we examined its intracellular distribution using subcellular fractionation and morphological methods. These experiments demonstrate that GFAP is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be re-examined. A number of other proteins were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice, but it remains unclear whether these proteins are true constituents of the storage material or, like GFAP, whether they associate with this material upon purification.

scholarly journals Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

2021 ◽  
Author(s):  
Lucy A. Barry ◽  
Graham W. Kay ◽  
Nadia L. Mitchell ◽  
Samantha J. Murray ◽  
Nigel P. Jay ◽  
...  
Keyword(s):  
Vision Loss ◽  
Inflammatory Responses ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Brain Regions ◽  
Glial Activation ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Storage Body

AbstractThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles.Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras.This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

NEURONAL CEROID-LIPOFUSCINOSIS (BATTEN'S DISEASE): RELATIONSHIP TO AMAUROTIC FAMILY IDIOCY?

PEDIATRICS ◽  
1969 ◽  
Vol 44 (4) ◽  
pp. 570-583
Author(s):  
Wolfgang Zeman ◽  
Paul Dyken
Keyword(s):  
Clinical Data ◽  
Neuronal Ceroid Lipofuscinosis ◽  
The Other ◽  
Gm2 Gangliosidosis ◽  
Gm1 Gangliosidosis ◽  
Ceroid Lipofuscinosis ◽  
Intractable Seizures ◽  
Tay Sachs Disease ◽  
Batten's Disease ◽  
Ceroid Lipofuscin

From the conditions generically classified as amaurotic familial idiocy, two distinctly different groups have emerged. One is characterized by grossly abnormal profiles for cerebral sphingolipids and consists of GM1-gangliosidosis and GM2-gangliosidosis or Tay-Sachs disease. The other group is composed of cases with normal sphingolipid profiles, but with neuronal accumulation of lipopigments of the ceroid/lipofuscin type, designated as neuronal ceroid-lipofuscinosis (NCL) or Batten's disease. Clinical data on 26 patients with this disorder reveal the course and symptomatology to be variable, but pathomorphologic and biochemical findings are reasonably constant. The course of the disorder is directly influenced by the presence or absence of intractable seizures.

scholarly journals Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6235
Author(s):  
Ahmed Morsy ◽  
Angelica V. Carmona ◽  
Paul C. Trippier
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Induced Pluripotent Stem Cell ◽  
Epileptic Seizures ◽  
Premature Death ◽  
Model Systems ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Phenotypic Screening ◽  
Lysosomal Storage ◽  
Induced Pluripotent

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

scholarly journals Lysosomal storage of subunit c of mitochondrial ATP synthase in Batten's disease (ceroid-lipofuscinosis)

1991 ◽  
Vol 275 (1) ◽  
pp. 269-272 ◽  
Author(s):  
N A Hall ◽  
B D Lake ◽  
N N Dewji ◽  
A D Patrick
Keyword(s):  
Atp Synthase ◽  
Lysosomal Storage ◽  
Infantile Form ◽  
Subunit C ◽  
Ceroid Lipofuscinosis ◽  
Mitochondrial Atp Synthase ◽  
Batten's Disease ◽  
Defective Metabolism

Immunochemical studies demonstrate that subunit c of mitochondrial ATP synthase is stored in the late-infantile, juvenile and adult forms of Batten's disease. It does not accumulate in the infantile form, or in other conditions involving lysosomal hypertrophy. These results suggest that the defective metabolism of subunit c is central to the pathogenesis of these three forms of Batten's disease.

scholarly journals A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature

2021 ◽  
Vol 12 ◽  
Author(s):  
Paschalis Nicolaou ◽  
George A. Tanteles ◽  
Christina Votsi ◽  
Eleni Zamba-Papanicolaou ◽  
Savvas S. Papacostas ◽  
...  
Keyword(s):  
In Silico ◽  
De Novo ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Transmembrane Protein ◽  
Structural Modeling ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Structural Differentiation ◽  
Prediction Analysis ◽  
Loss Of Vision

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic.

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