Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder

2017 ◽  
Vol 49 (02) ◽  
pp. 150-153 ◽  
Author(s):  
K. Varvagiannis ◽  
S. Hanquinet ◽  
M. Billieux ◽  
R. De Luca ◽  
P. Rimensberger ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Molecular Genetic ◽  
Bioinformatic Analysis ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Gene Encoding ◽  
Functional Studies ◽  
Ceroid Lipofuscinosis ◽  
Similar Phenotype

AbstractNeuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis

2018 ◽  
Vol 33 (13) ◽  
pp. 837-850 ◽  
Author(s):  
Lv Ge ◽  
Han Yun Li ◽  
Yuan Hai ◽  
Liu Min ◽  
Li Xing ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Hereditary Disease ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Neuronal Protein ◽  
Ceroid Lipofuscinosis ◽  
Visual Problems ◽  
Homozygous Mutations

Neuronal ceroid lipofuscinosis is a hereditary disease, and ceroid-lipofuscinosis neuronal protein 5 (CLN5) has been proved to be associated with neuronal ceroid lipofuscinosis. Here we report 3 patients from 2 families diagnosed with CLN5 neuronal ceroid lipofuscinosis. Whole genome sequencing of DNAs from 3 patients and their families revealed 3 novel homozygous mutations, including 1 deletion CLN5.c718 719delAT and 2 missense mutations c.1082T>C and c.623G>A. We reviewed 278 papers about neuronal ceroid lipofuscinosis resulting from CLN5 mutations and compared Chinese cases with 27 European and American cases. The overall age of onset of European and American patients occur mainly at 3 to 6 years (66%, 18/27), 100% (27/27) of patients had psychomotor regression, 99% (26/27) patients presented vision decline, and 70% (19/27) of patients suffered seizures. In China, the age of onset in 3 patients was 5 years, but for 1 patient it was at 17 months. Four Chinese patients presented psychomotor deterioration and seizures; only 1 had visual problems.

scholarly journals Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis

2020 ◽  
Vol 40 (19) ◽  
Author(s):  
Yasir H. Qureshi ◽  
Penelope Baez ◽  
Christiane Reitz
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Endosomal Trafficking ◽  
Lysosomal Storage ◽  
Ceroid Lipofuscinosis ◽  
Common Neurodegenerative Disorder

ABSTRACT Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson’s disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer’s disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL’s causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway’s role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.

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 CLN5 and CLN3 function as a complex to regulate endolysosome function

2020 ◽  
Author(s):  
Seda Yasa ◽  
Etienne Sauvageau ◽  
Graziana Modica ◽  
Stephane Lefrancois
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Integral Membrane Protein ◽  
Common Pathway ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Sorting ◽  
Summary Statement ◽  
Sorting Receptor ◽  
Golgi Network ◽  
Lysosomal Protein

AbstractCLN5 is a soluble endolysosomal protein that regulates the itinerary of the lysosomal sorting receptor sortilin. Mutations in this protein cause neuronal ceroid lipofuscinosis, a rare neurodegenerative disorder, and have also been associated with Alzheimer’s disease, suggesting functional defects in a common pathway. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an integral membrane protein, Rab7A and a subset of Rab7A effectors. Mutations in CLN3 are also a cause of neuronal ceroid lipofuscinosis. Our data supports a model where CLN3 and CLN5 function as an endolysosome complex regulating several endosomal functions.Summary StatementWe have previously demonstrated that CLN3 is required for efficient endosome-to-trans Golgi Network (TGN) trafficking of sortilin by regulating retromer function. In this work, we show that CLN5, which interacts with CLN3, regulates retromer function by modulating key interactions between CLN3, Rab7A, retromer, and sortilin. Therefore, CLN3 and CLN5 serve as endosomal switch regulating the itinerary of the lysosomal sorting receptors.

Experience in Diagnosing Neuronal Ceroid Lipofuscinosis Type-2

2021 ◽  
Vol 71 (5) ◽  
pp. 234-240
Author(s):  
Lanny Christine Gultom ◽  
Valensia Vivian The
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Early Stage ◽  
Diagnostic Delay ◽  
Compound Heterozygous ◽  
Recurrent Seizure ◽  
Enzyme Replacement ◽  
Ceroid Lipofuscinosis ◽  
Developmental Regression

Introduction: Developmental regression is always an alarming symptom in children as it is an early sign of some genetic disorders, one of which is neuronal ceroid lipofuscinosis (NCL). NCL is a group of rare neurodegenerative disorder caused by accumulation of intracellular ceroid lipofuscin. Since 2017 an enzyme replacement therapy (ERT) has been approved by Food and Drug Administration (FDA) for this disease. The symptoms of NCL could be managed by ERT if detected early, and the child could live normally.Case: We present a case of a 6-year-and-5-month-old boy with developmental regression, speech delay, recurrent seizure, and visual impairment, who was diagnosed with NCL type 2 after genetic testing. Compound heterozygous mutations in tripeptidyl-peptidase 1 (TPP1) gene was revealed, consistent with very low level of TPP1 enzyme in this patient.Discussion: NCL is a fatal disease which is often misdiagnosed in early stage. Diagnostic delay of NCL often occurs due to lack of awareness which often leads to premature death.Conclusion: Knowledge regarding the disease is important for early detection and to slow down the disease progression.  

scholarly journals Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6

2020 ◽  
Vol 10 (8) ◽  
pp. 2741-2751 ◽  
Author(s):  
Martin L. Katz ◽  
Reuben M. Buckley ◽  
Vanessa Biegen ◽  
Dennis P. O’Brien ◽  
Gayle C. Johnson ◽  
...  
Keyword(s):  
Sequence Data ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Loss Of Function ◽  
Storage Material ◽  
Ceroid Lipofuscinosis ◽  
Whole Exome ◽  
Feline Model ◽  
Exome Sequence

A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat’s clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat’s disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.

scholarly journals A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

2021 ◽  
Author(s):  
I. Basak ◽  
H. E. Wicky ◽  
K. O. McDonald ◽  
J. B. Xu ◽  
J. E. Palmer ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Transmembrane Protein ◽  
Model Organism ◽  
Batten Disease ◽  
Model Organisms ◽  
Soluble Form ◽  
Peripheral Tissues ◽  
Ceroid Lipofuscinosis ◽  
The Brain

AbstractNeuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.

scholarly journals An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Eye ◽  
2021 ◽  
Author(s):  
Dorothy A. Thompson ◽  
Siân E. Handley ◽  
Robert H. Henderson ◽  
Oliver R. Marmoy ◽  
Paul Gisson
Keyword(s):  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Fundus Autofluorescence ◽  
Batten Disease ◽  
Pattern Reversal ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Vision Assessment ◽  
Rod System ◽  
History Of

Abstract Background Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. Subjects and methods We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. Results ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. Conclusion ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.

Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis

2010 ◽  
Vol 38 (6) ◽  
pp. 1484-1488 ◽  
Author(s):  
Andrew M.S. Wong ◽  
Ahad A. Rahim ◽  
Simon N. Waddington ◽  
Jonathan D. Cooper
Keyword(s):  
Recent Progress ◽  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Transmembrane Protein ◽  
The Other ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Approaches ◽  
Enzyme Replacement ◽  
Factor Ii ◽  
Current Therapies

The NCLs (neuronal ceroid lipofuscinoses) are the most common inherited paediatric neurodegenerative disorder. Although genetically distinct, NCLs can be broadly divided into two categories: one in which the mutation results in a defect in a transmembrane protein, and the other where the defect lies in a soluble lysosomal enzyme. A number of therapeutic approaches are applicable to the soluble lysosomal forms of NCL based on the phenomenon of cross-correction, whereby the ubiquitously expressed mannose 6-phosphate/IGF (insulin-like growth factor) II receptor provides an avenue for endocytosis, trafficking and lysosomal processing of extracellularly delivered enzyme. The present review discusses therapeutic utilization of cross-correction by enzyme-replacement therapy, gene therapy and stem cell therapy for the NCLs, along with an overview of the recent progress in translating these treatments into the clinic.

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