A clinical case of neuronal ceroid lipofuscinosis type 2

Neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases characterized by age-related onset, progressive myoclonus epilepsy, visual impairment and progressive intellectual and motor disorders. In all forms of NCL, the pathological autofluorescent lipopigment accumulates in the brain and other tissues. The diagnosis is made following determination of the activity of specific enzymes in blood leukocytes or cell culture of skin fibroblasts and investigation of biopsy specimens with electron microscopy as well as molecular genetic research. The article presents a patient with the onset of the disease at the age of 3 with epileptic tonic-clonic seizures, with further progression of the disease in the form of myoclonic seizures, motor pyramidal and cerebellar disorders, as well as intellectual, mnestic and speech disturbances. The presented clinical case demonstrates difficulties in the diagnosis of neurodegenerative diseases at onset, as well as the absence of pathognomonic signs of the disease during neurophysiological and neuroimaging examinations, which makes it necessary to conduct additional molecular and genetic research

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Modelling of Neuronal Ceroid Lipofuscinosis Type 2 in Dictyostelium discoideum Suggests That Cytopathological Outcomes Result from Altered TOR Signalling

Cells ◽

10.3390/cells8050469 ◽

2019 ◽

Vol 8 (5) ◽

pp. 469 ◽

Cited By ~ 2

Author(s):

Paige K. Smith ◽

Melodi G. Sen ◽

Paul R. Fisher ◽

Sarah J. Annesley

Keyword(s):

Dictyostelium Discoideum ◽

Neuronal Ceroid Lipofuscinosis ◽

Clinical Manifestations ◽

Batten Disease ◽

Neuronal Ceroid Lipofuscinoses ◽

Antisense Inhibition ◽

Phenotypic Characterisation ◽

Cellular Slime ◽

Multiple Cell

The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative disorders with similar clinical manifestations whose precise mechanisms of disease are presently unknown. We created multiple cell lines each with different levels of reduction of expression of the gene coding for the type 2 variant of the disease, Tripeptidyl peptidase (Tpp1), in the cellular slime mould Dictyostelium discoideum. Knocking down Tpp1 in Dictyostelium resulted in the accumulation of autofluorescent material, a characteristic trait of Batten disease. Phenotypic characterisation of the mutants revealed phenotypic deficiencies in growth and development, whilst endocytic uptake of nutrients was enhanced. Furthermore, the severity of the phenotypes correlated with the expression levels of Tpp1. We propose that the phenotypic defects are due to altered Target of Rapamycin (TOR) signalling. We show that treatment of wild type Dictyostelium cells with rapamycin (a specific TOR complex inhibitor) or antisense inhibition of expression of Rheb (Ras homologue enriched in the brain) (an upstream TOR complex activator) phenocopied the Tpp1 mutants. We also show that overexpression of Rheb rescued the defects caused by antisense inhibition of Tpp1. These results suggest that the TOR signalling pathway is responsible for the cytopathological outcomes in the Dictyostelium Tpp1 model of Batten disease.

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

Neuropediatrics ◽

10.1055/s-0037-1613681 ◽

2017 ◽

Vol 49 (02) ◽

pp. 150-153 ◽

Cited By ~ 6

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.

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

10.1101/2021.12.06.471461 ◽

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.

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METASTATIC INTRAVENOUS LEIOMYOMATOSIS

Medical Visualization ◽

10.24835/1607-0763-2018-2-117-126 ◽

2018 ◽

pp. 117-126

Author(s):

S. V. Yadrentseva ◽

N. V. Nudnov

Keyword(s):

Lung Injury ◽

Clinical Case ◽

Surgical Intervention ◽

Molecular Genetic ◽

Genetic Research ◽

Final Diagnosis ◽

Intravenous Leiomyomatosis ◽

Heart Damage ◽

Metastatic Lung ◽

The Right

Сlinical case of a rare and poorly studied disease – intravenous leiomyomatosis (IVL) is presented. Presented the literature data and our own clinical case of this rare pathology with dissemination to the v. cava inferior, to the right ventricle of the heart. The radiology semiotics of metastatic intravenous leiomyomatosis is described, the advantages and limitations of the methods of radiation diagnosis are noted. The clinical case is of particular interest, because there is a combination of simultaneous intravenous injury, heart damage and benign metastatic lung injury. The final diagnosis is verified by the data of morphological and molecular-genetic research based on the results of surgical intervention.

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

Molecules ◽

10.3390/molecules26206235 ◽

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.

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Mitochondrial collapse links PFKFB3-promoted glycolysis with CLN7/MFSD8 neuronal ceroid lipofuscinosis pathogenesis

10.1101/2020.10.20.345314 ◽

2020 ◽

Author(s):

Irene Lopez-Fabuel ◽

Marina Garcia-Macia ◽

Costantina Buondelmonte ◽

Olga Burmistrova ◽

Nicolo Bonora ◽

...

Keyword(s):

Clinical Symptoms ◽

Neuronal Ceroid Lipofuscinosis ◽

Batten Disease ◽

Glycolytic Enzyme ◽

Neuronal Ceroid Lipofuscinoses ◽

Loss Of Function ◽

Biochemical Processes ◽

Lysosomal Accumulation ◽

Lysosomal Membrane Glycoprotein

The neuronal ceroid lipofuscinoses (NCLs) are a family of monogenic life-limiting pediatric neurodegenerative disorders collectively known as Batten disease1. Although genetically heterogeneous2, NCLs share several clinical symptoms and pathological hallmarks such as lysosomal accumulation of lipofuscin and astrogliosis2,3. CLN7 disease belongs to a group of NCLs that present in late infancy4–6 and, whereas CLN7/MFSD8 gene is known to encode a lysosomal membrane glycoprotein4,7–9, the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments1,10. Here, we found in the Cln7Δex2 mouse model11 of CLN7 disease that failure in the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired, reactive oxygen species (ROS)-producing neuronal mitochondria that contribute to CLN7 pathogenesis. Cln7Δex2 neurons exhibit a metabolic shift mediated by pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). PFKFB3 inhibition in Cln7Δex2 mice in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, specifically targeting glycolysis may alleviate CLN7 pathogenesis.

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Autophagy and ageing: implications for age-related neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/bse0550119 ◽

2013 ◽

Vol 55 ◽

pp. 119-131 ◽

Cited By ~ 37

Author(s):

Bernadette Carroll ◽

Graeme Hewitt ◽

Viktor I. Korolchuk

Keyword(s):

Neurodegenerative Diseases ◽

Energy Availability ◽

Future Studies ◽

Intracellular Degradation ◽

Age Related ◽

Autophagy Induction ◽

Social Importance ◽

Cellular Dysfunction ◽

Autophagy Activity ◽

Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

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Myotonic dystrophy Rossolimo-Churchman-Steinert-Batten (clinical case)

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.71-72 ◽

2020 ◽

pp. 71-72

Author(s):

И.А. Синельникова ◽

И.В. Сопрунова ◽

О.П. Николаева

Keyword(s):

Case Report ◽

Myotonic Dystrophy ◽

Clinical Case ◽

Molecular Genetic ◽

Ctg Repeats ◽

Molecular Genetic Method ◽

Genetic Method ◽

Family Case ◽

Dmpk Gene

В статье представлено описание семейного случая миотонической дистрофии Россолимо-Штейнерта-Куршмана-Баттена. Диагноз подтвержден в результате ДНК-диагностики: выявлено увеличенное число копий CTG-повтора гена DMPK, ответственного за развитие миотонической дистрофии. A family case report of Rossolimo-Steinert-Curschmann myotonic dystrophy is presented. An increased number of copies of CTG-repeats of the DMPK gene responsible for the development of MD, i.e., the diagnosis was confirmed by molecular genetic method.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽

10.3390/biology10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Swapnil Gupta ◽

Panpan You ◽

Tanima SenGupta ◽

Hilde Nilsen ◽

Kulbhushan Sharma

Keyword(s):

Dna Repair ◽

Neurodegenerative Diseases ◽

3D Models ◽

Model Systems ◽

Spinocerebellar Ataxias ◽

C Elegans ◽

Cellular Processes ◽

Age Related ◽

Damage Response ◽

Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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Population Genetic Structure Analysis Reveals Decreased but Moderate Diversity for the Oriental Fire-Bellied Toad Introduced to Beijing after 90 Years of Independent Evolution

Animals ◽

10.3390/ani11051429 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1429

Author(s):

Yang Teng ◽

Jing Yang ◽

Guofen Zhu ◽

Fuli Gao ◽

Yingying Han ◽

...

Keyword(s):

Genetic Structure ◽

Structure Analysis ◽

Phylogenetic Trees ◽

Molecular Genetic ◽

Genetic Research ◽

Haplotype Diversity ◽

Botanical Garden ◽

Source Population ◽

Independent Evolution ◽

Loop Region

Detailed molecular genetic research on amphibian populations has a significant role in understanding the genetic adaptability to local environments. The oriental fire-bellied toads (Bombina orientalis) were artificially introduced to Beijing from Shandong Province in 1927, and since then, this separated population went through an independent evolution. To explore the differentiation of the introduced population with its original population, this study analyzed the genetic structure of the oriental fire-bellied toad, based on the mitochondrial genome control region and six microsatellite sites. The results showed that the haplotype diversity and nucleotide diversity of the mitochondrial D-loop region partial sequences of the Beijing Botanical Garden population and the Baiwangshan population were lower than those of the Shangdong Kunyushan population. Microsatellite marker analysis also showed that the observed heterozygosity and expected heterozygosity of the Beijing populations were lower than those of the Kunyushan population. The phylogenetic trees and network diagrams of haplotypes indicated that the three populations were not genetically separated. However, the structure analysis showed a genetic differentiation and categorized the sampling individuals into Beijing and Shandong genetic clusters, which indicated a tendency for isolated evolution in the Beijing population. Although the Beijing populations showed a decline in genetic diversity, it was still at a moderate level, which could maintain the survival of the population. Thus, there is no need to reintroduce new individuals from the Kunyushan source population.

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