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Annals of Indian Academy of Neurology 2021Lysosomal storage disorders (LSDs) are a heterogeneous group of large molecule inborn errors of metabolism, rather commonly seen by clinician.
INTRODUCTION
Lysosomal storage disorders (LSDs) are a heterogeneous group of large molecule inborn errors of metabolism, rather commonly seen by clinician.
OBJECTIVES
This study aims to highlight the more common type of LSDs, their frequency, clinical spectrum and outcome from Rare disease centre in Rajasthan.
METHODS
The retrospective data were collected including clinical profile, investigations, screening test and enzyme analysis results. All outcomes were recorded from follow-up clinic.
RESULTS
This cohort comprised 65 children with different type of LSDs including 54 males and 11 females. The average age of presentation of the LSD patients was 3.5 years (range 6 months to 13 years). Gaucher disease was the most commonly found LSD (46.1%) followed by mucopolysaccharidosis (35.3%). Common presentations among GD patients were anemia, thrombocytopenia, and abdominal distension due to splenohepatomegaly/hepatomegaly. Among MPS Disorder, MPS type 2 (Hunter syndrome) was the most common (39.1%), followed by MPS type 1(Hurler syndrome) (30%) and MPS type IVA (Morquio syndrome) (17.3%). Non GD non MPS group comprised most commonly of GM1 gangliosidosis followed by pompe disease, Metachromatic Leucodystrophy, Mucolipidosis type II (I cell disease), and Sandhoff disease.
CONCLUSIONS
LSDs comprises an important group of genetic metabolic disorders. Among these GD are the most common, followed by MPS.
PubMed: 35002125
DOI: 10.4103/aian.AIAN_1009_20 -
Child Neurology Open 2022Infantile Sandhoff Disease (SD) is a subtype of GM2 gangliosidosis, which is never been reported in Sri Lanka. Data of eight children, who were diagnosed with SD during...
Infantile Sandhoff Disease (SD) is a subtype of GM2 gangliosidosis, which is never been reported in Sri Lanka. Data of eight children, who were diagnosed with SD during the period of 2017 to 2021, were analyzed retrospectively. The aim of this study was to analyze genotypic and phenotypic variations of native SDs. Café-au-lait spots, mitral regurgitation and atrial septal defect were found in our patients but never reported in the literature. We found c.1417 + 5G>A and c.1303_1304insCT p.(Arg435Thrfs*10) novel variants of gene among the nine different gene mutations that were identified. The commonest gene variant identified in India was c.850 C4T (p.R284X) but was not noticed among Sri Lankan patients. In contrast to other studies, all our patients died within the age of two years. This is the first Sri Lankan study that expands the clinical and molecular basis of SD with its novel findings.
PubMed: 36407556
DOI: 10.1177/2329048X221139495 -
PloS One 2022Clathrin-mediated endocytosis (CME) is one of the best studied cellular uptake pathways and its contributions to nutrient uptake, receptor signaling, and maintenance of...
Clathrin-mediated endocytosis (CME) is one of the best studied cellular uptake pathways and its contributions to nutrient uptake, receptor signaling, and maintenance of the lipid membrane homeostasis have been already elucidated. Today, we still have a lack of understanding how the different components of this pathway cooperate dynamically in vivo. Therefore, we generated a reporter mouse model for CME by fusing eGFP endogenously in frame to clathrin light chain a (Clta) to track endocytosis in living mice. The fusion protein is expressed in all tissues, but in a cell specific manner, and can be visualized using fluorescence microscopy. Recruitment to nanobeads recorded by TIRF microscopy validated the functionality of the Clta-eGFP reporter. With this reporter model we were able to track the dynamics of Alexa594-BSA uptake in kidneys of anesthetized mice using intravital 2-photon microscopy. This reporter mouse model is not only a suitable and powerful tool to track CME in vivo in genetic or disease mouse models it can also help to shed light into the differential roles of the two clathrin light chain isoforms in health and disease.
Topics: Animals; Clathrin; Clathrin Light Chains; Endocytosis; Lipids; Mice; Microscopy, Fluorescence
PubMed: 36149863
DOI: 10.1371/journal.pone.0273660 -
Molecular Biology of the Cell Feb 2018Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis...
Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pathology is complex and incompletely understood. Besides accumulation of peroxisomal educts (like very-long-chain fatty acids [VLCFAs] or branched-chain fatty acids) and lack of products (like bile acids or plasmalogens), many peroxisomal defects lead to detrimental mitochondrial abnormalities for unknown reasons. We generated mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs. We present a model of hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of free fatty acids as the cause for mitochondrial damage in consequence of peroxisome loss in mutants. Hyperactive Hnf4 signaling leads to up-regulation of lipase 3 and enzymes for mitochondrial β-oxidation. This results in enhanced lipolysis, elevated concentrations of free fatty acids, maximal β-oxidation, and mitochondrial abnormalities. Increased acid lipase expression and accumulation of free fatty acids are also present in a -deficient patient skin fibroblast line, suggesting the conservation of key aspects of our findings.
Topics: Animals; Disease Models, Animal; Drosophila; Fatty Acids; Humans; Lipolysis; Membrane Proteins; Mitochondria; Mutation; Peroxisomal Disorders; Peroxisomes
PubMed: 29282281
DOI: 10.1091/mbc.E17-08-0535 -
Biomedicines Apr 2021Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson's disease (PD) and related synucleinopathies. Investigate several mouse...
Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson's disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann-Pick A (NPA), Hurler, Pompe and Niemann-Pick C (NPC) diseases and assessed for the presence of Lewy body-like pathology (proteinase K-resistant α-synuclein and tau aggregates) and neuroinflammation (microglial Iba1 and astrocytic GFAP) by immunofluorescence. All seven LSD models exhibited evidence of proteinopathy and/or inflammation in the central nervous system (CNS). However, these phenotypes were divergent. Gaucher and Fabry mouse models displayed proteinase K-resistant α-synuclein and tau aggregates but no neuroinflammation; whereas Sandhoff, NPA and NPC showed marked neuroinflammation and no overt proteinopathy. Pompe disease animals uniquely displayed widespread distribution of tau aggregates accompanied by moderate microglial activation. Hurler mice also demonstrated proteinopathy and microglial activation. The present study demonstrated additional links between LSDs and pathogenic phenotypes that are hallmarks of synucleinopathies. The data suggest that lysosomal dysregulation can contribute to brain region-specific protein aggregation and induce widespread neuroinflammation in the brain. However, only a few LSD models examined exhibited phenotypes consistent with synucleinopathies. While no model can recapitulate the complexity of PD, they can enable the study of specific pathways and mechanisms contributing to disease pathophysiology. The present study provides evidence that there are existing, previously unutilized mouse models that can be employed to study pathogenic mechanisms and gain insights into potential PD subtypes, helping to determine if they are amenable to pathway-specific therapeutic interventions.
PubMed: 33919140
DOI: 10.3390/biomedicines9050446 -
IBRO Neuroscience Reports Jun 2022Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer's disease (AD), which appear early and are progressive in nature. Sandhoff disease...
Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer's disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of β-hexosaminidase) result in accumulation of amyloid-β (Aβ) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for β-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between β-hexosaminidase and AD, we investigated whether a heterozygous deletion of , the gene that encodes the beta subunit of β-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in mice. and mice were crossed and evaluated in a behavioural test battery. Neuropathological hallmarks of AD and ganglioside levels in the brain were also examined. Heterozygosity of in mice reduced learning flexibility during the Reversal Phase of the Morris water maze. Contrary to expectation, heterozygosity of caused a small but significant decrease in amyloid beta deposition and an increase in the microglial marker IBA1 that was region- and age-specific. heterozygosity caused detectable changes in the brain and in the behaviour of an AD model mouse, consistent with previous reports that described a biochemical relationship between HEXB and AD. This study reveals that the lysosomal enzyme gene is not haplosufficient in the mouse AD brain.
PubMed: 35146484
DOI: 10.1016/j.ibneur.2022.01.004 -
Neuroscience Jan 2017Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme β-N-acetylhexosaminidase (Hex), which results in storage of GM2...
Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme β-N-acetylhexosaminidase (Hex), which results in storage of GM2 ganglioside in neurons and unremitting neurodegeneration. Neuron loss initially affects fine motor skills, but rapidly progresses to loss of all body faculties, a vegetative state, and death by five years of age in humans. A well-established feline model of SD allows characterization of the disease in a large animal model and provides a means to test the safety and efficacy of therapeutic interventions before initiating clinical trials. In this study, we demonstrate a robust central nervous system (CNS) inflammatory response in feline SD, primarily marked by expansion and activation of the microglial cell population. Quantification of major histocompatibility complex II (MHC-II) labeling revealed significant up-regulation throughout the CNS with areas rich in white matter most severely affected. Expression of the leukocyte chemokine macrophage inflammatory protein-1 alpha (MIP-1α) was also up-regulated in the brain. SD cats were treated with intracranial delivery of adeno-associated viral (AAV) vectors expressing feline Hex, with a study endpoint 16weeks post treatment. AAV-mediated gene delivery repressed the expansion and activation of microglia and normalized MHC-II and MIP-1α levels. These data reiterate the profound inflammatory response in SD and show that neuroinflammation is abrogated after AAV-mediated restoration of enzymatic activity.
Topics: Adaptor Proteins, Signal Transducing; Animals; Astrocytes; Brain; Cats; Dependovirus; Disease Models, Animal; Genes, MHC Class II; Genetic Therapy; Genetic Vectors; Gliosis; Immunohistochemistry; Microglia; Neurons; Polymerase Chain Reaction; Sandhoff Disease; Transcription Factors
PubMed: 27793778
DOI: 10.1016/j.neuroscience.2016.10.047 -
Orphanet Journal of Rare Diseases Aug 2020As part of a late onset GM2 gangliosidosis natural history study, digital health technology was utilized to monitor a group of patients remotely between hospital visits....
BACKGROUND
As part of a late onset GM2 gangliosidosis natural history study, digital health technology was utilized to monitor a group of patients remotely between hospital visits. This approach was explored as a means of capturing continuous data and moving away from focusing only on episodic data captured in traditional study designs. A strong emphasis was placed on real-time capture of symptoms and mobile Patient Reported Outcomes (mPROs) to identify the disease impact important to the patients themselves; an impact that may not always correlate with the measured clinical outcomes assessed during patient visits. This was supported by passive, continuous data capture from a wearable device.
RESULTS
Adherence rate for wearing the device and completing the mPROs was 84 and 91%, respectively, resulting in a rich multidimensional dataset. As expected for a six-month proof-of-concept study in a disease that progresses slowly, statistically significant changes were not expected or observed in the clinical, mPROs, or wearable device data.
CONCLUSIONS
The study demonstrated that patients were very enthusiastic and motivated to engage with the technology as demonstrated by excellent compliance. The combination of mPROs and wearables generates feature-rich datasets that could be a useful and feasible way to capture remote, real-time insight into disease burden.
Topics: Feasibility Studies; Humans; Sandhoff Disease; Tay-Sachs Disease; Telemedicine; Wearable Electronic Devices
PubMed: 32746863
DOI: 10.1186/s13023-020-01473-x -
Molecular Genetics and Metabolism Feb 2018GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside...
BACKGROUND
GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied.
OBJECTIVES
The goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials.
METHODS
Brain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype.
RESULTS
The infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P<0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P=0.004).
CONCLUSIONS
The disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.
Topics: Child; Child, Preschool; Disease Progression; Female; Gangliosides; Gangliosidoses, GM2; Gangliosidosis, GM1; Humans; Infant; Longitudinal Studies; Magnetic Resonance Imaging; Male
PubMed: 29352662
DOI: 10.1016/j.ymgme.2017.12.432 -
Molecular Genetics and Metabolism Feb 2015The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity...
The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity deficiencies and consequent accumulation of gangliosides in the central nervous system (CNS). The infantile forms are distinguished from the juvenile forms by age of onset, rate of disease progression, and age of death. There are no approved treatments for the gangliosidoses. In search of potential biomarkers of disease, we quantified 188 analytes in CSF and serum from living human patients with longitudinal (serial) measurements. Notably, several associated with inflammation were elevated in the CSF of infantile gangliosidosis patients, and less so in more slowly progressing forms of juvenile gangliosidosis, but not in MPS disease. Thirteen CSF and two serum biomarker candidates were identified. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, and TNFR2. Correspondence of abnormal elevation with other variables of disease-i.e., severity of clinical phenotype, differentiation from changes in serum, and lack of abnormality in other neurodegenerative lysosomal diseases-identifies these analytes as biomarkers of neuropathology specific to the gangliosidosis diseases.
Topics: Adolescent; Biomarkers; Central Nervous System; Chemokine CCL2; Chemokine CCL4; Chemokine CXCL5; Child; Child, Preschool; Female; Gangliosidoses; Gangliosidosis, GM1; Humans; Infant; Inflammation; Male; Receptors, Tumor Necrosis Factor, Type II; Sandhoff Disease; Tay-Sachs Disease; Transcription Factors
PubMed: 25557439
DOI: 10.1016/j.ymgme.2014.11.015