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Metachromatic leukodystrophy

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https://www.readbyqxmd.com/read/29672630/nonclinical-comparability-studies-of-recombinant-human-arylsulfatase-a-addressing-manufacturing-process-changes
#1
Teresa Wright, Aiqun Li, Jason Lotterhand, Anne-Renee Graham, Yan Huang, Nancy Avila, Jing Pan
Recombinant human arylsulfatase A (rhASA) is in clinical development for the treatment of patients with metachromatic leukodystrophy (MLD). Manufacturing process changes were introduced to improve robustness and efficiency, resulting in higher levels of mannose-6-phosphate and sialic acid in post-change (process B) compared with pre-change (process A) rhASA. A nonclinical comparability program was conducted to compare process A and process B rhASA. All doses were administered intrathecally. Pharmacodynamic comparability was evaluated in immunotolerant MLD mice, using immunohistochemical staining of lysosomal-associated membrane protein-1 (LAMP-1)...
2018: PloS One
https://www.readbyqxmd.com/read/29544907/mendelian-adult-onset-leukodystrophy-genes-in-alzheimer-s-disease-critical-influence-of-csf1r-and-notch3
#2
Celeste Sassi, Michael A Nalls, Perry G Ridge, Jesse R Gibbs, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Jenny Lord, James Turton, Jose Bras, Sonja Blumenau, Mareike Thielke, Christa Josties, Dorette Freyer, Annette Dietrich, Monia Hammer, Michael Baier, Ulrich Dirnagl, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Alison M Goate, Andrew B Singleton, Rita Guerreiro, Angela Hodges, John Hardy
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively...
June 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29494779/gallbladder-polyps-in-metachromatic-leukodystrophy
#3
Saeeda Almarzooqi, Asif Quadri, Alia Albawardi
BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease, caused by a deficiency of arylsulfatase A, and leads to demyelination of the nervous system. A putative association between MLD and gallbladder pathology including malignancy is documented in the medical literature. CASE REPORT: A 10-year-old boy with MLD was found to have a papillary growth within a cystically dilated gallbladder. The lesion was confirmed to be papillomatosis/polyp with focal intestinal metaplasia...
April 2018: Fetal and Pediatric Pathology
https://www.readbyqxmd.com/read/29413149/slowly-progressive-psychiatric-symptoms-think-metachromatic-leukodystrophy
#4
EDITORIAL
Diane F van Rappard, Annelou L C de Vries, Kim J Oostrom, Jaap Jan Boelens, Carla E M Hollak, Marjo S van der Knaap, Nicole I Wolf
No abstract text is available yet for this article.
February 2018: Journal of the American Academy of Child and Adolescent Psychiatry
https://www.readbyqxmd.com/read/29397290/complex-care-of-individuals-with-multiple-sulfatase-deficiency-clinical-cases-and-consensus-statement
#5
Rebecca Ahrens-Nicklas, Lars Schlotawa, Andrea Ballabio, Nicola Brunetti-Pierri, Mauricio De Castro, Thomas Dierks, Florian Eichler, Can Ficicioglu, Alan Finglas, Jutta Gaertner, Brian Kirmse, Joerg Klepper, Marcus Lee, Amber Olsen, Giancarlo Parenti, Arastoo Vossough, Adeline Vanderver, Laura A Adang
Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis...
March 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29385852/clinical-trial-of-mgmt-p140k-gene-therapy-in-the-treatment-of-pediatric-patients-with-brain-tumors
#6
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Dent, Amanda Rush, Shiloh Middlemiss, Yu Wooi Ching, Ian E Alexander, Geoffrey McCowage
Gene transfer targeting hematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in severe combined immunodeficiencies affecting T-cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit...
March 23, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29383515/diffusion-tensor-imaging-in-metachromatic-leukodystrophy
#7
Diane F van Rappard, Marsh Königs, Marjan E Steenweg, Jaap Jan Boelens, Jaap Oosterlaan, Marjo S van der Knaap, Nicole I Wolf, Petra J W Pouwels
OBJECTIVE: We aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up. METHODS: Four late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS)...
March 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29344584/early-and-late-outcomes-after-cord-blood-transplantation-for-pediatric-patients-with-inherited-leukodystrophies
#8
Brigitte T A van den Broek, Kristin Page, Annalisa Paviglianiti, Janna Hol, Heather Allewelt, Fernanda Volt, Gerard Michel, Miguel Angel Diaz, Victoria Bordon, Tracey O'Brien, Peter J Shaw, Chantal Kenzey, Amal Al-Seraihy, Peter M van Hasselt, Andrew R Gennery, Eliane Gluckman, Vanderson Rocha, Annalisa Ruggeri, Joanne Kurtzberg, Jaap Jan Boelens
Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013...
January 9, 2018: Blood Advances
https://www.readbyqxmd.com/read/29340559/serial-magnetic-resonance-imaging-changes-in-a-patient-with-late-onset-cobalamin-c-disease-with-a-misdiagnosis-of-metachromatic-leukodystrophy
#9
Chujun Wu, Qingli Sun, Dongsheng Fan
No abstract text is available yet for this article.
March 1, 2018: JAMA Neurology
https://www.readbyqxmd.com/read/29302065/adulthood-leukodystrophies
#10
REVIEW
Wolfgang Köhler, Julian Curiel, Adeline Vanderver
The leukodystrophies are a group of inherited white matter disorders with a heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. This Review focuses on leukodystrophies with major prevalence or primary onset in adulthood. We summarize 20 leukodystrophies with adult presentations, providing information on the underlying genetic mutations and on biochemical assays that aid diagnosis, where available. Definitions, clinical characteristics, age of onset, MRI findings and treatment options are all described, providing a comprehensive overview of the current knowledge of the various adulthood leukodystrophies...
February 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29152458/lysosomal-storage-diseases
#11
REVIEW
Carlos R Ferreira, William A Gahl
Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy...
May 25, 2017: Translational Science of Rare Diseases
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
#12
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...
October 2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/29104953/exploring-the-multiligand-binding-specificity-of-saposin-b-reveals-two-binding-sites
#13
Jay Tinklepaugh, Britannia M Smith, Etta Hanlon, Chloe Zubieta, Fadi Bou-Abdallah, Robert P Doyle
Saposin B (SapB) is a human lysosomal protein, critical for the degradation of O -sulfogalactosylceramide (sulfatide). SapB binds sulfatide and presents it to the active site of the enzyme arylsulfatase A. Deficiency of SapB leads to fatal activator-deficient metachromatic leukodystrophy. Given the conformational flexibility and the large hydrophobic "pocket" produced upon (physiologically relevant) homodimerization, SapB may have broader substrate diversity than originally thought. Herein, we present evidence using fluorescence spectroscopy and computational docking studies that SapB binds a wide variety of ligands at K D values varying from micromolar to nanomolar, with entropy being the primary driving force...
October 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/29022088/enhancement-of-multiple-cranial-and-spinal-nerves-in-vanishing-white-matter-expanding-the-differential-diagnosis
#14
Thomas Jose Eluvathingal Muttikkal, Denia Ramirez Montealegre, Julie Ann Matsumoto
Abnormal cranial or spinal nerve contrast enhancement on MRI in cases of suspected pediatric leukodystrophy is recognized as an important clue to the diagnosis of either metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). We report a case of genetically confirmed childhood vanishing white matter with enhancement of multiple cranial and spinal nerves in addition to the more typical intracranial findings. This case expands the limited differential diagnosis of cranial nerve or spinal nerve enhancement in cases of suspected leukodystrophy and may aid in more efficient work-up and earlier diagnosis of vanishing white matter...
March 2018: Pediatric Radiology
https://www.readbyqxmd.com/read/28936078/clinical-and-genetic-characteristics-of-leukodystrophies-in-africa
#15
REVIEW
Mutaz Amin, Liena Elsayed, Ammar Eltahir Ahmed
Recent understanding of the genetic basis of neurological disorders in Africa has grown rapidly in the last two decades. Africa harbors the largest genetic repertoire in the world which gives unique opportunity to discover novel variant, genes, and molecular pathways associated with various neurological diseases. Despite that, large-scale genomic and exome studies are severely lacking especially for neglected diseases such as leukodystrophies. This review aims to shed light on the currently developed research in leukodystrophies in Africa...
August 2017: Journal of Neurosciences in Rural Practice
https://www.readbyqxmd.com/read/28923328/mutation-frequency-of-three-neurodegenerative-lysosomal-storage-diseases-from-screening-to-treatment
#16
Ana Joana Duarte, Diogo Ribeiro, Pedro Oliveira, Olga Amaral
BACKGROUND: The ascertainment of mutation frequencies in the general population may have impact on the population's wellbeing and respective healthcare services. Furthermore, it may help define which approaches will be more effective for certain patients based on the genetic cause of disease. AIM OF THE STUDY: Determine the frequency of three mutations, known to be a major cause of three distinct Lysosomal Storage Diseases (LSDs). METHODS: The following pre-requisites were met: each mutation accounted for over 55% of the disease alleles among previously reported unrelated patients, all three diseases were among the most prevalent LSDs in the population under study, they all involved devastating deterioration of the nervous system, lacked curative treatment and may be fatal in childhood or adolescence...
April 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/28889092/quantitative-mr-spectroscopic-imaging-in-metachromatic-leukodystrophy-value-for-prognosis-and-treatment
#17
Diane F van Rappard, Antoine Klauser, Marjan E Steenweg, Jaap Jan Boelens, Marianna Bugiani, Marjo S van der Knaap, Nicole I Wolf, Petra J W Pouwels
OBJECTIVE: To determine whether proton magnetic resonance spectroscopic imaging is useful in predicting clinical course of patients with metachromatic leukodystrophy (MLD), an inherited white matter disorder treatable with haematopoietic cell transplantation (HCT). METHODS: 21 patients with juvenile or adult MLD (12 HCT-treated) were compared with 16 controls in the same age range. Clinical outcome was determined as good, moderate or poor. Metabolites were quantified in white matter, and significance of metabolite concentrations at baseline for outcome prediction was assessed using logistic regression analysis...
January 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28799099/metachromatic-leukodystrophy-mld-a-pakistani-family-with-novel-arsa-gene-mutation
#18
Muhammad Aiman Shahzad, Saba Khaliq, Ali Amar, Saqib Mahmood
A deficiency of the enzyme arylsulfatase A (ARSA) causes a progressive neurodegenerative lysosomal storage disease known as metachromatic leukodystrophy (MLD). Diagnosis is based on the onset of neurological symptoms, presence of gait abnormalities, spasticity, decreased muscle stretch reflexes and neuro-radiological evidence of demyelination. The purpose of the present study was to identify any mutation in the candidate ARSA gene in a family of late infantile MLD patients. The diagnosis of suspected MLD patients was confirmed by a MRI report and low ARSA enzymatic activity in leukocytes...
September 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28762252/enzymatic-characterization-of-novel-arylsulfatase-a-variants-using-human-arylsulfatase-a-deficient-immortalized-mesenchymal-stromal-cells
#19
Judith Böhringer, René Santer, Neele Schumacher, Friederike Gieseke, Kerstin Cornils, Maria Pechan, Birgit Kustermann-Kuhn, Rupert Handgretinger, Ludger Schöls, Klaus Harzer, Ingeborg Krägeloh-Mann, Ingo Müller
Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T > C, c.195delC, c...
November 2017: Human Mutation
https://www.readbyqxmd.com/read/28670130/four-novel-arsa-gene-mutations-with-pathogenic-impacts-on-metachromatic-leukodystrophy-a-bioinformatics-approach-to-predict-pathogenic-mutations
#20
Masoumeh Dehghan Manshadi, Behnam Kamalidehghan, Omid Aryani, Elham Khalili, Sepideh Dadgar, Mahdi Tondar, Fatemeh Ahmadipour, Goh Yong Meng, Massoud Houshmand
Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the ARSA gene in 12 non-consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on ARSA were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software...
2017: Therapeutics and Clinical Risk Management
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