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https://www.readbyqxmd.com/read/27913587/suppressing-n-acetyl-l-aspartate-naa-synthesis-prevents-loss-of-neurons-in-a-murine-model-of-canavan-leukodystrophy
#1
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-L-aspartate (NAA) to acetate and L-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
#2
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/27860360/homozygous-variants-in-pyrroline-5-carboxylate-reductase-2-pycr2-in-patients-with-progressive-microcephaly-and-hypomyelinating-leukodystrophy
#3
Linyan Meng, Taraka Donti, Fan Xia, Zhiyv Niu, Aisha Al Shamsi, Jozef Hertecant, Fatma Al-Jasmi, James B Gibson, Honey Nagakura, Jing Zhang, Weimin He, Christine Eng, Yaping Yang, Sarah H Elsea
Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive...
November 11, 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27854160/lamin-b1-mediated-demyelination-linking-lamins-lipids-and-leukodystrophies
#4
Quasar S Padiath
Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids...
November 17, 2016: Nucleus
https://www.readbyqxmd.com/read/27852030/-a-case-of-pol-iii-related-leukodystrophy-with-homozygous-mutation-in-polr3a
#5
Tomoaki Shima, Takeshi Fujimoto, Teiichiro Miyazaki, Fumiaki Nonaka
We describe a 27-year-old man with mental retardation, symptomatic epilepsy, myopia, and cerebellar ataxia without spontaneous puberty whose brain magnetic resonance imaging showed hypomyelination. He had child-like facial appearance, with thin facial hair. He had no underarm and pubic hairs, and his penis was small. Laboratory tests showed low levels of luteinizing hormone, follicle-stimulating hormone, and testosterone. Brain MRI showed diffuse hypomyelination, atrophy of the cerebellum and brainstem, and hypoplastic corpus callosum...
November 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://www.readbyqxmd.com/read/27843092/rmnd1-related-leukoencephalopathy-with-temporal-lobe-cysts-and-hearing-loss-another-mendelian-mimicker-of-congenital-cytomegalovirus-infection
#6
Nicole Ulrick, Amy Goldstein, Cas Simons, Ryan J Taft, Guy Helman, Amy Pizzino, Miriam Bloom, Julie Vogt, Karen Pysden, Daria Diodato, Diego Martinelli, Ahmad Monavari, Daniela Buhas, Clara D M van Karnebeek, Imen Dorboz, Odile Boespflug-Tanguy, Diana Rodriguez, Martine Tétreault, Jacek Majewski, Genevieve Bernard, Yi Shiau Ng, Robert McFarland, Adeline Vanderver
BACKGROUND: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection...
September 13, 2016: Pediatric Neurology
https://www.readbyqxmd.com/read/27816769/in-vivocharacterization-of-the-aspartyl-trna-synthetase-dars-homing-in-on-the-leukodystrophy-hbsl
#7
Dominik Fröhlich, Alexandra K Suchowerska, Ziggy H T Spencer, Georg von Jonquieres, Claudia B Klugmann, Andre Bongers, Fabien Delerue, Holly Stefen, Lars M Ittner, Thomas Fath, Gary D Housley, Matthias Klugmann
BACKGROUND: The recently diagnosed leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is caused by mutations of the cytoplasmic aspartyl-tRNA synthetase geneDARS. The physiological role of DARS in translation is to accurately pair aspartate with its cognate tRNA. Clinically, HBSL subjects show a distinct pattern of hypomyelination and develop progressive leg spasticity, variable cognitive impairment and epilepsy. To elucidate the underlying pathomechanism, we comprehensively assessed endogenous DARS expression in mice...
November 2, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27799409/acbd5-deficiency-causes-a-defect-in-peroxisomal-very-long-chain-fatty-acid-metabolism
#8
Sacha Ferdinandusse, Kim D Falkenberg, Janet Koster, Petra A Mooyer, Richard Jones, Carlo W T van Roermund, Amy Pizzino, Michael Schrader, Ronald J A Wanders, Adeline Vanderver, Hans R Waterham
BACKGROUND: Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease...
October 31, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27785568/novel-mutations-in-iba57-are-associated-with-leukodystrophy-and-variable-clinical-phenotypes
#9
Alessandra Torraco, Anna Ardissone, Federica Invernizzi, Teresa Rizza, Giuseppe Fiermonte, Marcello Niceta, Nadia Zanetti, Diego Martinelli, Angelo Vozza, Daniela Verrigni, Michela Di Nottia, Eleonora Lamantea, Daria Diodato, Marco Tartaglia, Carlo Dionisi-Vici, Isabella Moroni, Laura Farina, Enrico Bertini, Daniele Ghezzi, Rosalba Carrozzo
Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system...
October 26, 2016: Journal of Neurology
https://www.readbyqxmd.com/read/27785412/neuroradiological-neurophysiological-and-molecular-findings-in-infantile-krabbe-disease-two-case-reports
#10
E Vargiami, E Papathanasiou, S Batzios, M Kyriazi, E Dimitriou, A Anastasiou, H Michelakakis, A-K Giese, D I Zafeiriou
Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme β-galactocerebrosidase (β-GALC). Depending on the age of onset, the disease is classified into infantile and later-onset forms. We report neuroradiological, neurophysiological and molecular findings in two Greek patients with the infantile form of Krabbe disease. The index patients presented at the age of 3.5 and 6 months, respectively, due to developmental delay. Magnetic resonance imaging (MRI) of the first patient's brain demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased...
July 1, 2016: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/27779215/the-use-of-targeted-genomic-capture-and-massively-parallel-sequencing-in-diagnosis-of-chinese-leukoencephalopathies
#11
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/27773153/sporadic-case-of-retinal-vasculopathy-with-cerebral-leukodystrophy-hereditary-endotheliopathy-retinopathy-nephropathy-stroke-with-novel-trex1-mutation
#12
Bonnie Scurry, Thomas Wellings, Himanshu Goel, Anja Pluschke
No abstract text is available yet for this article.
February 2016: Pathology
https://www.readbyqxmd.com/read/27750026/gene-therapy-with-hematopoietic-stem-cells-the-diseased-bone-marrow-s-point-of-view
#13
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/27749956/analysis-of-mutations-in-aars2-in-a-series-of-csf1r-negative-patients-with-adult-onset-leukoencephalopathy-with-axonal-spheroids-and-pigmented-glia
#14
David S Lynch, Wei Jia Zhang, Rahul Lakshmanan, Justin A Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, Hasmet Hanagasi, Georgina Burke, Nicola Foulds, Simon R Hammans, Anupam Bhattacharjee, Heather Wilson, Matthew Adams, Mark Walker, James A R Nicoll, Jeremy Chataway, Nick Fox, Indran Davagnanam, Rahul Phadke, Henry Houlden
Importance: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations...
October 17, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27743887/severe-leukoencephalopathy-with-cortical-involvement-and-peripheral-neuropathy-due-to-folr1-deficiency
#15
Yu Kobayashi, Jun Tohyama, Tomoyuki Akiyama, Shinichi Magara, Hideshi Kawashima, Noriyuki Akasaka, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto
Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy...
October 12, 2016: Brain & Development
https://www.readbyqxmd.com/read/27734837/novel-aars2-gene-mutation-producing-leukodystrophy-a-case-report
#16
Laszlo Szpisjak, Nora Zsindely, Jozsef I Engelhardt, Laszlo Vecsei, Gabor G Kovacs, Peter Klivenyi
AARS2 gene (NM_020745.3) mutations result in two different phenotypic diseases: infantile mitochondrial cardiomyopathy and late-onset leukoencephalopathy. The patient's first symptoms appeared at the age of 18 years with behavioral changes and psychiatric problems. Some years later, extrapyramidal symptoms, cognitive impairment, nystagmus, dysarthria and pyramidal symptoms also developed. The brain magnetic resonance imaging (MRI) indicated extensive white matter abnormalities. The diagnosis of AARS2 gene mutations causing leukodystrophy was confirmed by genetic testing...
October 13, 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27728533/leukodystrophy
#17
Rohit Rai, Richa Giri, Prem Singh, R K Verma
No abstract text is available yet for this article.
January 2016: Journal of the Association of Physicians of India
https://www.readbyqxmd.com/read/27721144/glycosynthase-mediated-synthesis-of-psychosine
#18
Ethan D Goddard-Borger, Christina Tysoe, Stephen G Withers
Globoid cell leukodystrophy (GCL), or Krabbe disease, is a lysosomal storage disorder characterized by a deficiency in galactosylceramidase (GALC), which hydrolyses galactosylceramide and galactosylsphingosine (psychosine). Early detection of GCL in newborns is essential for timely therapeutic intervention and could be achieved by testing infant blood samples with isotopically labeled lysosmal enzyme substrates and mass spectrometry. While isotopically labeled psychosine would be a useful tool for the early diagnosis of GCL, its synthesis is lengthy and expensive...
September 22, 2016: Carbohydrate Research
https://www.readbyqxmd.com/read/27717881/n-acetylaspartate-supports-the-energetic-demands-of-developmental-myelination-via-oligodendroglial-aspartoacylase
#19
Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
December 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27683878/transcriptional-fingerprint-of-hypomyelination-in-zfp191null-and-shiverer-mbpshi-mice
#20
Joshua D Aaker, Benayahu Elbaz, Yuwen Wu, Timothy J Looney, Li Zhang, Bruce T Lahn, Brian Popko
The transcriptional program that controls oligodendrocyte maturation and central nervous system (CNS) myelination has not been fully characterized. In this study, we use high-throughput RNA sequencing to analyze how the loss of a key transcription factor, zinc finger protein 191 (ZFP191), results in oligodendrocyte development abnormalities and CNS hypomyelination. Using a previously described mutant mouse that is deficient in ZFP191 protein expression (Zfp191(null)), we demonstrate that key transcripts are reduced in the whole brain as well as within oligodendrocyte lineage cells cultured in vitro To determine whether the loss of myelin seen in Zfp191(null) mice contributes indirectly to these perturbations, we also examined the transcriptome of a well-characterized mouse model of hypomyelination, in which the myelin structural protein myelin basic protein (MBP) is deficient...
October 2016: ASN Neuro
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