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Lysosomal storage diseases

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https://www.readbyqxmd.com/read/29147032/emptying-the-stores-lysosomal-diseases-and-therapeutic-strategies
#1
REVIEW
Frances M Platt
Lysosomal storage disorders (LSDs) - designated as 'orphan' diseases - are inborn errors of metabolism caused by defects in genes that encode proteins involved in various aspects of lysosomal homeostasis. For many years, LSDs were viewed as unattractive targets for the development of therapies owing to their low prevalence. However, the development and success of the first commercial biologic therapy for an LSD - enzyme replacement therapy for type 1 Gaucher disease - coupled with regulatory incentives rapidly catalysed commercial interest in therapeutically targeting LSDs...
November 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29146937/tfeb-regulates-lysosomal-positioning-by-modulating-tmem55b-expression-and-jip4-recruitment-to-lysosomes
#2
Rose Willett, José A Martina, James P Zewe, Rachel Wills, Gerald R V Hammond, Rosa Puertollano
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29143201/newborn-screening-for-lysosomal-storage-disorders-by-tandem-mass-spectrometry-in-north-east-italy
#3
Alberto B Burlina, Giulia Polo, Leonardo Salviati, Giovanni Duro, Carmela Zizzo, Andrea Dardis, Bruno Bembi, Chiara Cazzorla, Laura Rubert, Roberta Zordan, Robert J Desnick, Alessandro P Burlina
BACKGROUND: Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases...
November 15, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29140481/excessive-burden-of-lysosomal-storage-disorder-gene-variants-in-parkinson-s-disease
#4
Laurie A Robak, Iris E Jansen, Jeroen van Rooij, André G Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M Shulman
Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk...
November 13, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29128371/assessments-of-neurocognitive-and-behavioral-function-in-the-mucopolysaccharidoses
#5
REVIEW
Elsa G Shapiro, Maria L Escolar, Kathleen A Delaney, John J Mitchell
The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families...
September 15, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29119347/n-glycan-structures-and-downstream-mannose-phosphorylation-of-plant-recombinant-human-alpha-l-iduronidase-toward-development-of-enzyme-replacement-therapy-for-mucopolysaccharidosis-i
#6
Owen M Pierce, Grant R McNair, Xu He, Hiroyuki Kajiura, Kazuhito Fujiyama, Allison R Kermode
Arabidopsis N-glycan processing mutants provide the basis for tailoring recombinant enzymes for use as replacement therapeutics to treat lysosomal storage diseases, including N-glycan mannose phosphorylation to ensure lysosomal trafficking and efficacy. Functional recombinant human alpha-L-iduronidase (IDUA; EC 3.2.1.76) enzymes were generated in seeds of the Arabidopsis thaliana complex-glycan-deficient (cgl) C5 background, which is deficient in the activity of N-acetylglucosaminyl transferase I, and in seeds of the Arabidopsis gm1 mutant, which lacks Golgi α-mannosidase I (GM1) activity...
November 8, 2017: Plant Molecular Biology
https://www.readbyqxmd.com/read/29119141/case-report-ursodeoxycholic-acid-treatment-in-niemann-pick-disease-type-c-clinical-experience-in-four-cases
#7
William R H Evans, Elena-Raluca Nicoli, Raymond Y Wang, Nina Movsesyan, Frances M Platt
In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment...
2017: Wellcome Open Research
https://www.readbyqxmd.com/read/29118420/aav-mediated-transcription-factor-eb-tfeb-gene-delivery-ameliorates-muscle-pathology-and-function-in-the-murine-model-of-pompe-disease
#8
Francesca Gatto, Barbara Rossi, Antonietta Tarallo, Elena Polishchuk, Roman Polishchuk, Alessandra Carrella, Edoardo Nusco, Filomena Grazia Alvino, Francesca Iacobellis, Elvira De Leonibus, Alberto Auricchio, Graciana Diez-Roux, Andrea Ballabio, Giancarlo Parenti
Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29111890/polyethylene-glycol-b-poly-lactic-acid-polymersomes-as-vehicles-for-enzyme-replacement-therapy
#9
Jessica M Kelly, Amanda L Gross, Douglas R Martin, Mark E Byrne
AIM: Polymersomes are created to deliver an enzyme-based therapy to the brain in lysosomal storage disease patients. MATERIALS & METHODS: Polymersomes are formed via the injection method using poly(ethylene glycol)-b-poly(lactic acid) (PEGPLA) and bound to apolipoprotein E, to create a brain-targeted delivery vehicle. RESULTS: Polymersomes have a smallest average diameter of 145 ± 21 nm and encapsulate β-galactosidase at 72.0 ± 12...
November 7, 2017: Nanomedicine
https://www.readbyqxmd.com/read/29111560/identification-of-a-novel-mutation-in-arsa-gene-in-three-patients-of-an-iranian-family-with-metachromatic-leukodystrophy-disorder
#10
Neda Golchin, Mohammadreza Hajjari, Reza Azizi Malamiri, Majid Aminzadeh, Javad Mohammadi-Asl
Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive and lysosomal storage disease. The disease is caused by the deficiency of the enzyme arylsulfatase A (ARSA) which is encoded by the ARSA gene. Different mutations have been reported in different populations. The present study was aimed to detect the mutation type of the ARSA gene in three relative Iranian patients. We found a novel homozygous missense mutation c.1070 G > T (p.Gly357Val) in exon 6 of these patients. The mutation was found to be reported for the first time in MLD patients...
November 6, 2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/29111092/quantitative-neuroimaging-in-mucopolysaccharidoses-clinical-trials
#11
REVIEW
Igor Nestrasil, Leonardo Vedolin
The mucopolysaccharidosis (MPS) disorders are rare lysosomal storage disorders caused by mutations in lysosomal enzymes involved in glycosaminoglycan (GAG) degradation. The resulting intracellular accumulation of GAGs leads to widespread tissue and organ dysfunction. In addition to somatic signs and symptoms, patients with MPS can present with neurological manifestations such as cognitive decline, behavioral problems (e.g. hyperactivity and aggressiveness), sleep disturbances, and/or epilepsy. These are associated with significant abnormalities of the central nervous system (CNS), including white and gray matter lesions, brain atrophy, ventriculomegaly, and spinal cord compression...
September 15, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29106755/canine-gm2-gangliosidosis-sandhoff-disease-associated-with-a-3-base-pair-deletion-in-the-hexb-gene
#12
P Wang, P S Henthorn, E Galban, G Lin, T Takedai, M Casal
BACKGROUND: GM2-gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either β-hexosaminidase A (Hex-A) and β-hexosaminidase B (Hex-B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency. OBJECTIVES: To characterize the phenotype and genotype of GM2-gangliosidosis disease in an affected dog. ANIMALS: One affected Shiba Inu and a clinically healthy dog...
November 6, 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/29100912/fabry-disease-review-and-experience-during-newborn-screening
#13
REVIEW
Ting-Rong Hsu, Dau-Ming Niu
Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life...
October 20, 2017: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29099167/separation-and-analysis-of-lactosylceramide-galabiosylceramide-and-globotriaosylceramide-by-lc-ms-ms-in-urine-of-fabry-disease-patients
#14
Michel Boutin, Iskren Menkovic, Tristan Martineau, Vanessa Vaillancourt-Lavigueur, Amanda Toupin, Christiane Auray-Blais
Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-GAL A) deficiency. This enzyme contributes to the cellular recycling of glycosphingolipids such as galabiosylceramide (Ga2), globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) by hydrolysing the terminal alpha-galactosyl moiety. Urine and plasma α-GAL A substrates are currently analyzed as biomarkers for the detection, monitoring and follow-up of Fabry disease patients. The sensitivity of the analysis of Ga2 is decreased by the co-analysis of its structural isomer, lactosylceramide (LacCer), which is not an α-GAL A substrate...
November 3, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29098097/early-renal-involvement-in-a-girl-with-classic-fabry-disease
#15
Fernando Perretta, Norberto Antongiovanni, Sebastián Jaurretche
Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the enzyme alpha galactosidase A; this defect leads to the systemic accumulation of globotriaosylceramide and its metabolites. Organic involvement in men is well known, but in women it is controversial, mainly due to the random X-chromosome inactivation in each of their cells (Lyon hypothesis). This would explain why women (heterozygotes) present a wide variability in the severity of their phenotype. The manifestations are multisystemic and begin in early childhood, reaching a severe compromise in adulthood...
2017: Case Reports in Nephrology
https://www.readbyqxmd.com/read/29091883/lipophagy-and-liver-disease-new-perspectives-to-better-understanding-and-therapy
#16
REVIEW
Zili Zhang, Zhen Yao, Yifan Chen, Lei Qian, Shuoyi Jiang, Jingyi Zhou, Jiangjuan Shao, Anping Chen, Feng Zhang, Shizhong Zheng
Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. The recent finding that LDs can be selectively degraded by the lysosomal pathway of autophagy through a process termed lipophagy has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in various diseases including liver disease...
October 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29091352/type-2-gaucher-disease-in-an-infant-despite-a-normal-maternal-glucocerebrosidase-gene
#17
Ermias Hagege, Richard J Grey, Grisel Lopez, Tamanna Roshan Lal, Ellen Sidransky, Nahid Tayebi
Gaucher disease (GD) is a recessively inherited autosomal lysosomal storage disease, the most severe of which is type 2, an acute neuronopathic form. We report an affected infant who inherited one mutant allele, Arg257Gln (c.887G>A; p.Arg296Gln) from his father, while the second, Gly202Arg (c.721G>A; p.Gly241Arg) arose by either maternal germline mosaicism or as a de novo mutation. This is the first time mutation Gly202Arg has been reported to be inherited non-traditionally. This report is part of a growing literature suggesting that GD can be inherited via germline or de novo mutations, and emphasizes that it is critical for clinicians to consider such inheritance when making diagnostic decisions or providing genetic counseling...
December 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29091130/importance-of-liver-biopsy-in-the-diagnosis-of-lysosomal-acid-lipase-deficiency-a-case-report
#18
Adriana Maria Alves De Tommaso, Flávia Fonseca de Carvalho Barra, Gabriel Hessel, Carolina Araújo Moreno, Roberto Giugliani, Cecília Amélia Fazzio Escanhoela
OBJECTIVE: To describe a case of cholesteryl ester storage disease (CESD) and discuss the importance of liver biopsy for diagnosis. CASE DESCRIPTION: A female patient, aged two years and ten months, presented with an increased abdominal volume following hepatomegaly for four months. Abdominal ultrasound demonstrated hepatomegaly and hepatic steatosis. Laboratory tests showed elevated liver serum enzymes and dyslipidemia. Liver biopsy was consistent with CESD. COMMENTS: Although measuring enzyme activity is the gold standard for CESD diagnosis, liver biopsy is very helpful when investigating suspected cases of CESD, particularly upon other differential diagnoses to be considered...
October 30, 2017: Revista Paulista de Pediatria: Orgão Oficial da Sociedade de Pediatria de São Paulo
https://www.readbyqxmd.com/read/29079200/female-fabry-disease-patients-and-x-chromosome-inactivation
#19
Patrycja Juchniewicz, Anna Kloska, Anna Tylki-Szymańska, Joanna Jakóbkiewicz-Banecka, Grzegorz Węgrzyn, Marta Moskot, Magdalena Gabig-Cimińska, Ewa Piotrowska
Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (GLA). Once it was thought to affect only hemizygous males. Over the last fifteen years, research has shown that most females carrying mutated allele also develop symptoms, demonstrating a wide range of disease severity, from a virtually asymptomatic to more classical profile, with cardiac, renal, and cerebrovascular manifestations. This variable expression in females is thought to be influenced by the process of X-chromosome inactivation (XCI)...
October 24, 2017: Gene
https://www.readbyqxmd.com/read/29074317/alteration-of-cortical-excitability-and-its-modulation-by-miglustat-in-niemann-pick-disease-type-c
#20
Shady Safwat Hassan, Carlos Trenado, Saskia Elben, Alfons Schnitzler, Stefan Jun Groiss
Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment...
October 23, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
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