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Metachromatic leukodystrophy

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https://www.readbyqxmd.com/read/27904824/metachromatic-leukodystrophy-biochemical-characterization-of-two-p-307glu%C3%A2-lys-p-318trp%C3%A2-cys-arylsulfatase-a-mutations
#1
Adem Özkan, Hatice Asuman Özkara
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by Arylsulfatase A (ASA) deficiency. The hallmark of the disease is central and peripheral neurodegeneration. More than 200 mutations have been identified in ARSA gene so far. Some of these mutations were characterized. The aim of this study is to reinforce genotype-phenotype correlation and to understand the effect of mutations on the enzyme by biochemical characterization. Two missense mutations (c.919G→A, p.307Glu→Lys and c.954G→T, p...
November 2016: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/27779215/the-use-of-targeted-genomic-capture-and-massively-parallel-sequencing-in-diagnosis-of-chinese-leukoencephalopathies
#2
Xiaole Wang, Fang He, Fei Yin, Chao Chen, Liwen Wu, Lifen Yang, Jing Peng
Leukoencephalopathies are diseases with high clinical heterogeneity. In clinical work, it's difficult for doctors to make a definite etiological diagnosis. Here, we designed a custom probe library which contains the known pathogenic genes reported to be associated with Leukoencephalopathies, and performed targeted gene capture and massively parallel sequencing (MPS) among 49 Chinese patients who has white matter damage as the main imaging changes, and made the validation by Sanger sequencing for the probands' parents...
October 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27750026/gene-therapy-with-hematopoietic-stem-cells-the-diseased-bone-marrow-s-point-of-view
#3
Marina Cavazzana, Jean-Antoine Ribeil, Chantal Lagresle-Peyrou, Isabelle André-Schmutz
When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and β-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics...
October 16, 2016: Stem Cells and Development
https://www.readbyqxmd.com/read/27638920/generation-of-human-induced-pluripotent-stem-cell-derived-bona-fide-neural-stem-cells-for-ex-vivo-gene-therapy-of-metachromatic-leukodystrophy
#4
Vasco Meneghini, Giacomo Frati, Davide Sala, Silvia De Cicco, Marco Luciani, Chiara Cavazzin, Marianna Paulis, Wieslawa Mentzen, Francesco Morena, Serena Giannelli, Francesca Sanvito, Anna Villa, Alessandro Bulfone, Vania Broccoli, Sabata Martino, Angela Gritti
: : Allogeneic fetal-derived human neural stem cells (hfNSCs) that are under clinical evaluation for several neurodegenerative diseases display a favorable safety profile, but require immunosuppression upon transplantation in patients. Neural progenitors derived from patient-specific induced pluripotent stem cells (iPSCs) may be relevant for autologous ex vivo gene-therapy applications to treat genetic diseases with unmet medical need. In this scenario, obtaining iPSC-derived neural stem cells (NSCs) showing a reliable "NSC signature" is mandatory...
September 16, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/27638615/port-to-port-delivery-mobilization-of-toxic-sphingolipids-via-extracellular-vesicles
#5
Giuseppe Scesa, Ana Lis Moyano, Ernesto R Bongarzone, Maria I Givogri
The discovery that most cells produce extracellular vesicles (EVs) and release them in the extracellular milieu has spurred the idea that these membranous cargoes spread pathogenic mechanisms. In the brain, EVs may have multifold and important physiological functions, from deregulating synaptic activity to promoting demyelination to changes in microglial activity. The finding that small EVs (exosomes) contain α-synuclein and β-amyloid, among other pathogenic proteins, is an example of this notion, underscoring their potential role in the brains of patients with Parkinson's and Alzheimer's diseases...
November 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/27638601/gene-therapy-for-metachromatic-leukodystrophy
#6
REVIEW
Jonathan B Rosenberg, Stephen M Kaminsky, Patrick Aubourg, Ronald G Crystal, Dolan Sondhi
Leukodystrophies (LDs) are rare, often devastating genetic disorders with neurologic symptoms. There are currently no disease-specific therapeutic approaches for these diseases. In this review we use metachromatic leukodystrophy as an example to outline in the brief the therapeutic approaches to MLD that have been tested in animal models and in clinical trials, such as enzyme-replacement therapy, bone marrow/umbilical cord blood transplants, ex vivo transplantation of genetically modified hematopoietic stem cells, and gene therapy...
November 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/27606023/diffusion-weighted-magnetic-resonance-imaging-findings-in-a-case-of-metachromatic-leukodystrophy
#7
Paramdeep Singh, Rupinderjeet Kaur
Metachromatic leukodystrophy (MLD) is caused by insufficiency of arylsulfatase A resulting in impaired myelination. Diffusion magnetic resonance (MR) imaging features of this disease have been rarely reported. We report diffusion MR imaging of MLD in a 12-month-old male who presented with regression of milestones and progressive spasticity.
April 2016: Journal of Pediatric Neurosciences
https://www.readbyqxmd.com/read/27570384/the-spectrum-of-leukodystrophies-in-children-experience-at-a-tertiary-care-centre-from-north-india
#8
Sheffali Gulati, Puneet Jain, Biswaroop Chakrabarty, Atin Kumar, Neerja Gupta, Madhulika Kabra
OBJECTIVE: The objective of this study is to retrospectively collect and then describe the clinico-radiographical profile of confirmed cases of leukodystrophy who presented over a 5-year period to a tertiary care teaching hospital in North India. MATERIALS AND METHODS: The case records of 80 confirmed cases of leukodystrophy were reviewed and the cases have been described in terms of their clinical presentation and neuroimaging findings. RESULTS: The cases have been grouped into five categories: Hypomyelinating, demyelinating, disorders with vacuolization, cystic, and miscellaneous...
July 2016: Annals of Indian Academy of Neurology
https://www.readbyqxmd.com/read/27400410/long-term-outcome-of-allogeneic-hematopoietic-stem-cell-transplantation-in-patients-with-juvenile-metachromatic-leukodystrophy-compared-with-nontransplanted-control-patients
#9
Samuel Groeschel, Jörn-Sven Kühl, Annette E Bley, Christiane Kehrer, Bernhard Weschke, Michaela Döring, Judith Böhringer, Johanna Schrum, René Santer, Alfried Kohlschütter, Ingeborg Krägeloh-Mann, Ingo Müller
IMPORTANCE: Allogeneic hematopoietic stem cell transplantation (HSCT) has been the only treatment option clinically available during the last 20 years for juvenile metachromatic leukodystrophy (MLD), reported with variable outcome and without comparison with the natural course of the disease. OBJECTIVE: To compare the long-term outcome of patients who underwent allogeneic HSCT with control patients who did not among a cohort with juvenile MLD. DESIGN, SETTING, AND PARTICIPANTS: Patients with juvenile MLD born between 1975 and 2009 and who received HSCT at a median age of 7 years (age range, 1...
September 1, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27389394/metachromatic-leukodystrophy-an-assessment-of-disease-burden
#10
Florian S Eichler, Timothy M Cox, Eric Crombez, Christine Í Dali, Alfried Kohlschütter
Metachromatic leukodystrophy is accompanied by severe motor and cognitive dysfunction. This is the first survey of metachromatic leukodystrophy caregiver perspectives to identify relevant clinical/quality-of-life outcomes for patients/caregivers. Interviews and 1 focus group were conducted with 30 caregivers representing 23 patients. Caregivers were asked about their experiences, including diagnostic process, signs/symptoms, symptoms affecting caregivers' and patients' lives, and treatment priorities. Caregivers reported loss of physical autonomy, weight loss, limited social relationships, frequent crying, and challenging sibling relationships...
July 7, 2016: Journal of Child Neurology
https://www.readbyqxmd.com/read/27374302/whole-exome-sequencing-identifies-compound-heterozygous-mutations-in-arsa-of-two-siblings-presented-with-atypical-onset-of-metachromatic-leukodystrophy-from-a-chinese-pedigree
#11
Zhihong Wang, Yanhong Lin, Dezhu Zheng, Aizhen Yan, Xiangdong Tu, Juan Lin, Fenghua Lan
BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused mainly by variants in arylsulfatase A (ARSA) gene. MLD can be divided into three major clinical forms according to the age of onset: late infantile, juvenile, and adult. We report two siblings of late infantile MLD presenting with cerebellar ataxia as the only first clinical symptom. METHODS: Because of the unspecific neurological manifestation, whole-exome sequencing (WES) was performed to find disease-causing mutations for molecular diagnosis...
September 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/27365977/classical-case-of-late-infantile-form-of-metachromatic-leukodystrophy
#12
Narvir Singh Chauhan, Milap Sharma, Amit Bhardwaj
No abstract text is available yet for this article.
July 2016: Journal of Neurosciences in Rural Practice
https://www.readbyqxmd.com/read/27289174/lentiviral-haemopoietic-stem-cell-gene-therapy-in-early-onset-metachromatic-leukodystrophy-an-ad-hoc-analysis-of-a-non-randomised-open-label-phase-1-2-trial
#13
Maria Sessa, Laura Lorioli, Francesca Fumagalli, Serena Acquati, Daniela Redaelli, Cristina Baldoli, Sabrina Canale, Ignazio D Lopez, Francesco Morena, Andrea Calabria, Rossana Fiori, Paolo Silvani, Paola M V Rancoita, Michela Gabaldo, Fabrizio Benedicenti, Gigliola Antonioli, Andrea Assanelli, Maria Pia Cicalese, Ubaldo Del Carro, Maria Grazia Natali Sora, Sabata Martino, Angelo Quattrini, Eugenio Montini, Clelia Di Serio, Fabio Ciceri, Maria Grazia Roncarolo, Alessandro Aiuti, Luigi Naldini, Alessandra Biffi
BACKGROUND: Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). METHODS: This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan...
July 30, 2016: Lancet
https://www.readbyqxmd.com/read/27261095/gallbladder-and-the-risk-of-polyps-and-carcinoma-in-metachromatic-leukodystrophy
#14
Diane F van Rappard, Marianna Bugiani, Jaap J Boelens, Alida F W van der Steeg, Freek Daams, Tim G J de Meij, Martine M A C van Doorn, Peter M van Hasselt, Dirk J Gouma, Jonathan I M L Verbeke, Carla E M Hollak, Wim van Hecke, Gajja S Salomons, Marjo S van der Knaap, Nicole I Wolf
OBJECTIVES: To assess frequency of gallbladder polyposis and carcinoma in metachromatic leukodystrophy (MLD). METHODS: We evaluated 34 patients with MLD (average age 16.7 years, age range 2-39 years) screened for gallbladder abnormalities by ultrasound. In the case of cholecystectomy, findings at pathology were reviewed. RESULTS: Only 8 of 34 patients (23%) had a normal gallbladder at ultrasound. Gallbladder polyps were visible in 8 patients (23%)...
July 5, 2016: Neurology
https://www.readbyqxmd.com/read/27228111/fluorogenic-substrates-for-visualizing-acidic-organelle-enzyme-activities
#15
Fiona Karen Harlan, Jason Scott Lusk, Breanna Michelle Mohr, Anthony Peter Guzikowski, Robert Hardy Batchelor, Ying Jiang, John Joseph Naleway
Lysosomes are acidic cytoplasmic organelles that are present in all nucleated mammalian cells and are involved in a variety of cellular processes including repair of the plasma membrane, defense against pathogens, cholesterol homeostasis, bone remodeling, metabolism, apoptosis and cell signaling. Defects in lysosomal enzyme activity have been associated with a variety of neurological diseases including Parkinson's Disease, Lysosomal Storage Diseases, Alzheimer's disease and Huntington's disease. Fluorogenic lysosomal staining probes were synthesized for labeling lysosomes and other acidic organelles in a live-cell format and were shown to be capable of monitoring lysosomal metabolic activity...
2016: PloS One
https://www.readbyqxmd.com/read/27195181/-reverse-tigroid-pattern-in-pachygyria-a-novel-finding
#16
Ujjawal Roy, Alak Pandit, Urmila Das, Ajay Panwar
Pachygyria is considered a subtype of lissencephaly which, in turn, is a spectrum of disorders caused by abnormal neuronal migration. Clinical presentation in this disorder may be varied including microcephaly, developmental delay, facial dysmorphism, seizures, and mental retardation. Magnetic resonance imaging (MRI) of brain identifies the exact nature and extent of the disease and helps in delineating further plan of management. A Tigroid pattern on axial MRI scan and leopard pattern on a sagittal plane has been classically reported in disorders of myelin formation such as metachromatic leukodystrophy and Pelizaeus-Merzbacher disease...
2016: Journal of Clinical Imaging Science
https://www.readbyqxmd.com/read/27180966/-the-biological-role-of-sulfatides
#17
Jarosław Suchański, Maciej Ugorski
Sulfatides (3-O-sulfogalactosylceramides, sulfated galactocerebrosides, SM4) are esters of sulfuric acid with galactosylceramides. These acidic glycosphingolipids, present at the external leaflet of the plasma membrane, are synthesized by a variety of mammalian cells. They are especially abundant in the myelin sheath of oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Studies using cerebroside galactosyltransferase-deficient mice revealed that sulfatides are responsible for proper structure and functioning of myelin...
2016: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/27160716/understanding-the-metabolic-consequences-of-human-arylsulfatase-a-deficiency-through-a-computational-systems-biology-study
#18
Y Echeverri Olga, A Salazar Diego, Alexander Rodriguez-Lopez, González Janneth, J Almeciga-Diaz Carlos, A Barrera Luis
The nervous system is responsible for the communication between the organism and its environment. This task is possible by the presence of the myelin sheath, which is a double membrane formed by about 75% lipids and 25% proteins. The sulfatide represents one of the main lipids of the myelin band; its degradation is catabolized by the enzyme Arylsulfatase A (ARSA), to generated galactosylceramide. Mutations affecting ARSA function lead to the neurodegenerative disease Metachromatic Leukodystrophy. This disease is characterized by accumulation of sulfatide within the band of myelin affecting its functionality...
May 10, 2016: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27118454/efficacy-of-hematopoietic-cell-transplantation-in-metachromatic-leukodystrophy-the-dutch-experience
#19
LETTER
Diane F van Rappard, Jaap J Boelens, Martje E van Egmond, Jurgen Kuball, Peter M van Hasselt, Kim J Oostrom, Petra J W Pouwels, Marjo S van der Knaap, Carla E M Hollak, Nicole I Wolf
No abstract text is available yet for this article.
June 16, 2016: Blood
https://www.readbyqxmd.com/read/27079147/cerebral-spinal-fluid-levels-of-cytokines-are-elevated-in-patients-with-metachromatic-leukodystrophy
#20
Kathryn A Thibert, Gerald V Raymond, Jakub Tolar, Weston P Miller, Paul J Orchard, Troy C Lund
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported...
2016: Scientific Reports
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