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Lysosomal storage disease

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https://www.readbyqxmd.com/read/29916295/trehalose-reduces-retinal-degeneration-neuroinflammation-and-storage-burden-caused-by-a-lysosomal-hydrolase-deficiency
#1
Parisa Lotfi, Dennis Y Tse, Alberto di Ronza, Michelle L Seymour, Giuseppe Martano, Jonathan D Cooper, Fred A Pereira, Maria Passafaro, Samuel M Wu, Marco Sardiello
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose...
June 19, 2018: Autophagy
https://www.readbyqxmd.com/read/29916124/ocular-changes-in-nephropathic-cystinosis-the-course-of-the-gold-dust
#2
Elias Flockerzi, Loay Daas, Ursula Schlötzer-Schrehardt, Annette Zimpfer, Rainer Bohle, Berthold Seitz
PURPOSE: Cystinosis is an autosomal recessive inherited lysosomal storage disease with an incidence of 1:100.000 up to 1:200.000 caused by a gene mutation of a lysosomal transport protein resulting in deposition of cystine in lysosomes in all cells and tissues. In the cornea, crystalline, gold-dust deposition of cystine leads to visual impairment, recurrent erosions, photophobia, epiphora and blepharospasmus. Standard therapy is topical and systemic application of cysteamine which may resolve the accumulated cystine crystals...
June 18, 2018: International Ophthalmology
https://www.readbyqxmd.com/read/29909504/anderson-fabry-disease-in-heart-failure
#3
REVIEW
M M Akhtar, P M Elliott
Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry's disease is reported to be in the range of 1 in 40,000-117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system...
June 16, 2018: Biophysical Reviews
https://www.readbyqxmd.com/read/29908121/pathological-manifestations-of-farber-disease-in-a-new-mouse-model
#4
Nadine Beckmann, Stephanie Kadow, Fabian Schumacher, Joachim R Göthert, Stefanie Kesper, Annette Draeger, Walter J Schulz-Schaeffer, Jiang Wang, Jan U Becker, Melanie Kramer, Claudine Kühn, Burkhard Kleuser, Katrin Anne Becker, Erich Gulbins
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of Farber Disease is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of Farber Disease and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence...
June 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29905968/skeletal-consequences-of-nephropathic-cystinosis
#5
Pablo Florenzano, Carlos Ferreira, Galina Nesterova, Mary Scott Ramnitz, Sri Harsha Tella, Luis Fernandez de Castro, Sydney M Brown, Adom Whitaker, Renata C Pereira, Dorothy Bulas, Rachel I Gafni, Isidro B Salusky, William A Gahl, Michael T Collins
Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (N = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound...
June 15, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29901418/systemic-delivery-of-aavb1-gaa-clears-glycogen-and-prolongs-survival-in-a-mouse-model-of-pompe-disease
#6
Allison May Keeler, Marina Zieger, Sophia Todeasa, Angela Mccall, Jennifer Gifford, Samantha Bircsak, Sourav Roy Choudhury, Barry J Byrne, Miguel Sena-Esteves, Mai K ElMallah
Pompe disease is an autosomal recessive glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption in muscle and central nervous system (CNS). Adeno-associated virus (AAV) gene therapy is ideal for Pompe disease since a single systemic injection may correct both muscle and CNS pathologies. Using the Pompe mouse, we sought to explore if AAVB1, a newly engineered vector with a high affinity for muscle and CNS, reduces systemic weakness and improves survival in adult mice...
June 14, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29900785/the-lysosomal-storage-disease-gm2-gangliosidosis-in-captive-banded-mongoose-siblings-mungos-mungo
#7
Julia Wimmershoff, Kathrin Kuehni-Boghenbor, Adrian C Sewell, Anna Oevermann, Hany Farwanah, Nadia Robert, Stefan Hoby, Christian Wenker, Michael H Stoffel
  This study reports the occurrence of the lysosomal storage disease GM2 gangliosidosis (Sandhoff disease) in two 11-mo-old captive-bred, male and female mongoose siblings ( Mungos mungo). The clinical signs and the pathological findings reported here were similar to those reported in other mammalian species. Light microscopy revealed an accumulation of stored material in neurons and macrophages accompanied by a significant neuronal degeneration (swelling of neuronal soma, loss of Nissl substance, and neuronal loss) and gliosis...
June 2018: Journal of Zoo and Wildlife Medicine: Official Publication of the American Association of Zoo Veterinarians
https://www.readbyqxmd.com/read/29900534/absence-of-infiltrating-peripheral-myeloid-cells-in-the-brains-of-mouse-models-of-lysosomal-storage-disorders
#8
REVIEW
Soo Min Cho, Ayelet Vardi, Nicolas Platt, Anthony H Futerman
Approximately 70 lysosomal storage diseases are currently known, resulting from mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in lysosomal enzymes that hydrolyze sphingolipids have been relatively well studied. Gaucher disease is caused by the loss of activity of glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease exhibits a number of subtypes, with types 2 and 3 showing significant neuropathology. Sandhoff disease results from the defective activity of β-hexosaminidase, leading to accumulation of ganglioside GM2...
June 14, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29900402/neuromelanin-organelles-are-specialized-autolysosomes-that-accumulate-undegraded-proteins-and-lipids-in-aging-human-brain-and-are-likely-involved-in-parkinson-s-disease
#9
Fabio A Zucca, Renzo Vanna, Francesca A Cupaioli, Chiara Bellei, Antonella De Palma, Dario Di Silvestre, Pierluigi Mauri, Sara Grassi, Alessandro Prinetti, Luigi Casella, David Sulzer, Luigi Zecca
During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion...
2018: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29899471/human-ipsc-based-models-highlight-defective-glial-and-neuronal-differentiation-from-neural-progenitor-cells-in-metachromatic-leukodystrophy
#10
Giacomo Frati, Marco Luciani, Vasco Meneghini, Silvia De Cicco, Marcus Ståhlman, Maria Blomqvist, Serena Grossi, Mirella Filocamo, Francesco Morena, Andrea Menegon, Sabata Martino, Angela Gritti
The pathological cascade leading from primary storage to neural cell dysfunction and death in metachromatic leukodystrophy (MLD) has been poorly elucidated in human-derived neural cell systems. In the present study, we have modeled the progression of pathological events during the differentiation of patient-specific iPSCs to neuroepithelial progenitor cells (iPSC-NPCs) and mature neurons, astrocytes, and oligodendrocytes at the morphological, molecular, and biochemical level. We showed significant sulfatide accumulation and altered sulfatide composition during the differentiation of MLD iPSC-NPCs into neuronal and glial cells...
June 13, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29884776/lysosomal-acid-lipase-deficiency-a-rare-pathology-the-first-pediatric-patient-reported-in-colombia
#11
Verónica Botero, Victor H Garcia, Catalina Gomez-Duarte, Ana M Aristizabal, Ana M Arrunategui, Gabriel J Echeverri, Harry Pachajoa
BACKGROUND Lysosomal acid lipase deficiency is a rare genetic metabolic lipid storage disease, with a high morbidity, and mortality, in children and adults. It is characterized by a mutation in the LIPA gene that causes an alteration of lipid metabolism, resulting in deposits of cholesterol esters and triglycerides in organs such as the liver, blood vessels, and gastrointestinal tract. Lysosomal acid lipase deficiency is predominantly caused by the mutation c.894G>A, seen in approximately 50-70% of patients...
June 9, 2018: American Journal of Case Reports
https://www.readbyqxmd.com/read/29884617/brain-targeted-stem-cell-gene-therapy-corrects-mucopolysaccharidosis-type-ii-via-multiple-mechanisms
#12
Hélène Fe Gleitz, Ai Yin Liao, James R Cook, Samuel F Rowlston, Gabriella Ma Forte, Zelpha D'Souza, Claire O'Leary, Rebecca J Holley, Brian W Bigger
The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS...
June 8, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29883718/genetically-modified-mouse-models-to-study-hepatic-neutral-lipid-mobilization
#13
REVIEW
Guenter Haemmerle, Achim Lass
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals...
June 5, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29880804/lysosomal-targeting-enhancement-by-conjugation-of-glycopeptides-containing-mannose-6-phosphate-glycans-derived-from-glyco-engineered-yeast
#14
Ji-Yeon Kang, Keun Koo Shin, Ha Hyung Kim, Jeong-Ki Min, Eun Sun Ji, Jin Young Kim, Ohsuk Kwon, Doo-Byoung Oh
Many therapeutic enzymes for lysosomal storage diseases require a high content of mannose-6-phosphate (M6P) glycan, which is important for cellular uptake and lysosomal targeting. We constructed glyco-engineered yeast harboring a high content of mannosylphosphorylated glycans, which can be converted to M6P glycans by uncapping of the outer mannose residue. In this study, the cell wall of this yeast was employed as a natural M6P glycan source for conjugation to therapeutic enzymes. The extracted cell wall mannoproteins were digested by pronase to generate short glycopeptides, which were further elaborated by uncapping and α(1,2)-mannosidase digestion steps...
June 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29880732/a-liquid-chromatography-quadrupole-time-of-flight-mass-spectrometric-assay-for-the-quantification-of-fabry-disease-biomarker-globotriaosylceramide-gb3-in-fabry-model-mouse
#15
Seok-Ho Shin, Min-Ho Park, Jin-Ju Byeon, Byeong Ill Lee, Yuri Park, Ah-Ra Ko, Mi-Ran Seong, Soyeon Lee, Mi Ra Kim, Jinwook Seo, Myung Eun Jung, Dong-Kyu Jin, Young G Shin
Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to determine this biomarker in plasma and in all relevant tissues related to this disease simultaneously is required. However, the limited sample volume, as well as the various levels of GB3 in different matrices makes the GB3 quantitation very challenging...
June 7, 2018: Pharmaceutics
https://www.readbyqxmd.com/read/29878115/aav9-intracerebroventricular-gene-therapy-improves-lifespan-locomotor-function-and-pathology-in-a-mouse-model-of-niemann-pick-type-c1-disease
#16
Michael P Hughes, Dave A Smith, Lauren Morris, Claire Fletcher, Alexandria Colaco, Mylene Huebecker, Julie Tordo, Nuria Palomar, Giulia Massaro, Els Henckaerts, Simon N Waddington, Frances M Platt, Ahad A Rahim
Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative lysosomal storage disorder. It is caused in 95% of cases by a mutation in the NPC1 gene that encodes NPC1, an integral transmembrane protein localised to the limiting membrane of the lysosome. There is no cure for NP-C but there is a disease-modifying drug (miglustat) that slows disease progression but with associated side effects. Here, we demonstrate in a well-characterised mouse model of NP-C that a single administration of AAV-mediated gene therapy to the brain can significantly extend lifespan, improve quality of life, prevent or ameliorate neurodegeneration, reduce biochemical pathology and normalize or improve various indices of motor function...
June 5, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29876240/galactosialidosis-in-a-newborn-with-a-novel-mutation-in-the-ctsa-gene-presenting-with-transient-hyperparathyroidism
#17
Okulu E, Tunc G, Eminoglu T, Erdeve O, Atasay B, Arsan S
Galactosialidosis is a lysosomal storage disease caused by deficiency of protective protein that is encoded by the cathepsin A ( CTSA ) gene localized on chromosome 20q13.1. Mutations of this gene are the cause of galactosialidosis that result in loss of function of protective protein. Galactosialidosis is an autosomal recessive inherited disease and has been divided into three subtypes based on age of onset and the severity of clinical manifestations. We report an early infantile form of galactosialidosis in a newborn with a novel mutation on the CTSA gene...
December 2017: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/29875421/a-cross-sectional-quantitative-analysis-of-the-natural-history-of-free-sialic-acid-storage-disease-an-ultra-orphan-multisystemic-lysosomal-storage-disorder
#18
Matthias Zielonka, Sven F Garbade, Stefan Kölker, Georg F Hoffmann, Markus Ries
PURPOSE: Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5. METHODS: Analysis of published cases with SASD (N = 116) respecting STROBE criteria. MAIN OUTCOME PARAMETERS: survival and diagnostic delay. Phenotype, phenotype-biomarker associations, and geographical patient distribution were explored. RESULTS: Median age at disease onset was 0...
June 6, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29873075/caspase-1-activity-influences-juvenile-batten-disease-cln3-pathogenesis
#19
Maria Burkovetskaya, Megan E Bosch, Nikolay Karpuk, Rachel Fallet, Tammy Kielian
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5-10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3Δex7/8 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3Δex7/8 microglia are primed towards a pro-inflammatory phenotype typified by exaggerated caspase-1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3Δex7/8 mouse brain...
June 5, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29872134/identification-of-predominant-gnptab-gene-mutations-in-eastern-chinese-patients-with-mucolipidosis-ii-iii-and-a-prenatal-diagnosis-of-mucolipidosis-ii
#20
Yu Wang, Jun Ye, Wen-Juan Qiu, Lian-Shu Han, Xiao-Lan Gao, Li-Li Liang, Xue-Fan Gu, Hui-Wen Zhang
Mucolipidosis II α/β, mucolipidosis III α/β, and mucolipidosis III γ are autosomal recessive disorders belonging to the family of lysosomal storage disorders caused by deficiency of the UDP-N-acetylglucosamine, a lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) localized in the Golgi apparatus, which is essential for normal processing and packaging of soluble lysosomal enzymes with initiating the first step of tagging lysosomal enzymes with mannose-6-phosphate (M6P)...
June 5, 2018: Acta Pharmacologica Sinica
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