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Metachromatic leukodystrophy

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https://www.readbyqxmd.com/read/29152458/lysosomal-storage-diseases
#1
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
#2
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/29104953/exploring-the-multiligand-binding-specificity-of-saposin-b-reveals-two-binding-sites
#3
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 KD 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
#4
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...
October 12, 2017: Pediatric Radiology
https://www.readbyqxmd.com/read/28936078/clinical-and-genetic-characteristics-of-leukodystrophies-in-africa
#5
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
#6
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
#7
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...
September 9, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28799099/metachromatic-leukodystrophy-mld-a-pakistani-family-with-novel-arsa-gene-mutation
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28667691/subacute-demyelinating-peripheral-neuropathy-as-a-novel-presentation-of-late-infantile-metachromatic-leukodystrophy
#11
Hernan D Gonorazky, Kimberly Amburgey, Grace Yoon, Jiri Vajsar, Elysa Widjaja, James J Dowling
No abstract text is available yet for this article.
July 1, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28592657/induced-pluripotent-stem-cell-models-of-lysosomal-storage-disorders
#12
REVIEW
Daniel K Borger, Benjamin McMahon, Tamanna Roshan Lal, Jenny Serra-Vinardell, Elma Aflaki, Ellen Sidransky
Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses...
June 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28589167/demyelination-load-as-predictor-for-disease-progression-in-juvenile-metachromatic-leukodystrophy
#13
Manuel Strölin, Ingeborg Krägeloh-Mann, Christiane Kehrer, Marko Wilke, Samuel Groeschel
OBJECTIVE: The aim of this study was to investigate whether the extent and topography of cerebral demyelination correlates with and predicts disease progression in patients with juvenile metachromatic leukodystrophy (MLD). METHODS: A total of 137 MRIs of 46 patients with juvenile MLD were analyzed. Demyelination load and brain volume were quantified using the previously developed Software "clusterize." Clinical data were collected within the German Leukodystrophy Network and included full scale intelligence quotient (FSIQ) and gross motor function data...
June 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28566233/expanding-the-genetic-cause-of-multiple-sulfatase-deficiency-a-novel-sumf1-variant-in-a-patient-displaying-a-severe-late-infantile-form-of-the-disease
#14
Ilona Jaszczuk, Lars Schlotawa, Thomas Dierks, Andreas Ohlenbusch, Dominique Koppenhöfer, Mariusz Babicz, Monika Lejman, Karthikeyan Radhakrishnan, Agnieszka Ługowska
Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c...
May 22, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28560469/gene-therapy-for-lysosomal-storage-disorders-recent-advances-for-metachromatic-leukodystrophy-and-mucopolysaccaridosis-i
#15
REVIEW
Rachele Penati, Francesca Fumagalli, Valeria Calbi, Maria Ester Bernardo, Alessandro Aiuti
Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset...
July 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28526683/autoreactivity-to-sulfatide-by-human-invariant-nkt-cells
#16
Annelein M Stax, Jessica Tuengel, Enrico Girardi, Naoki Kitano, Lenka L Allan, Victor Liu, Dongjun Zheng, William J Panenka, Joren Guillaume, Chi-Huey Wong, Serge van Calenbergh, Dirk M Zajonc, Peter van den Elzen
Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize lipid Ags presented by CD1d. The prototypical Ag, α-galactosylceramide, strongly activates human and mouse iNKT cells, leading to the assumption that iNKT cell physiology in human and mouse is similar. In this article, we report the surprising finding that human, but not mouse, iNKT cells directly recognize myelin-derived sulfatide presented by CD1d. We propose that sulfatide is recognized only by human iNKT cells because of the unique positioning of the 3-O-sulfated β-galactose headgroup...
July 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28524215/-novel-therapies-in-neurometabolic-diseases-the-importance-of-early-intervention
#17
L G Gutierrez-Solana
INTRODUCTION: Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. DEVELOPMENT: Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28456990/prenatal-diagnosis-of-lysosomal-storage-disorders-using-chorionic-villi
#18
Jyotsna Verma, Sunita Bijarnia-Mahay, Ishwar C Verma
Prenatal enzymatic diagnosis for an array of lysosomal storage disorders (LSDs) can be performed accurately, provided that a confirmed diagnosis by biochemical/molecular study in the index case is available and a strict defined protocol, specific to each individual disorder is followed. The present chapter describes the protocols for reliable and accurate prenatal enzymatic diagnoses by fluorometric and spectrophotometric methods of lysosomal storage disorders: Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandhoff, GM1, Mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy, and Batten diseases using uncultured chorionic villi samples...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28215668/potential-of-surfactant-coated-nanoparticles-to-improve-brain-delivery-of-arylsulfatase-a
#19
Tilman Schuster, Astrid Mühlstein, Claudia Yaghootfam, Olga Maksimenko, Elena Shipulo, Svetlana Gelperina, Jörg Kreuter, Volkmar Gieselmann, Ulrich Matzner
The lysosomal storage disorder (LSD) metachromatic leukodystrophy (MLD) is caused by a deficiency of the soluble, lysosomal hydrolase arylsulfatase A (ASA). The disease is characterized by accumulation of 3-O-sulfogalactosylceramide (sulfatide), progressive demyelination of the nervous system and premature death. Enzyme replacement therapy (ERT), based on regular intravenous injections of recombinant functional enzyme, is in clinical use for several LSDs. For MLD and other LSDs with central nervous system (CNS) involvement, however, ERT is limited by the blood-brain barrier (BBB) restricting transport of therapeutic enzymes from the blood to the brain...
May 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28193373/-metachromatic-leukodystrophy-case-presentation
#20
Lina María Espejo, Ricardo de la Espriella, José Fernando Hernández
Metachromatic leukodystrophy (MLD) is a rare demyelinating disease (prevalence 1:40 000), also called arylsulfatase A deficiency (ARS-A), which may present with neurological and psychiatric symptoms. Clinical assessment may be difficult, due to unspecific signs and symptoms. A case is presented of a 16 year-old female patient seen in psychiatry due to behavioural changes, psychosis, and with impaired overall performance. She was initially diagnosed with schizophrenia, but the Nuclear Magnetic Resonance (NMR) scan and laboratory tests lead to the diagnosis of MLD...
January 2017: Revista Colombiana de Psiquiatría
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