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Chujun Wu, Dongsheng Fan
No abstract text is available yet for this article.
June 18, 2018: JAMA Neurology
Letterio S Politi, Ettore Salsano, Alessandra Biffi
No abstract text is available yet for this article.
June 18, 2018: JAMA Neurology
Xiaoming Jia, Lohith Madireddy, Stacy Caillier, Adam Santaniello, Federica Esposito, Giancarlo Comi, Olaf Stuve, Yuan Zhou, Bruce Taylor, Trevor Kilpatrick, Filippo Martinelli-Boneschi, Bruce A C Cree, Jorge R Oksenberg, Stephen L Hauser, Sergio E Baranzini
OBJECTIVE: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurologic disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurologic disorders that share features with MS contribute to risk for developing PPMS. METHODS: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry...
June 16, 2018: Annals of Neurology
Arnulf H Koeppen
This chapter summarizes the neuropathologic features of nonneoplastic disorders of the adult cerebellum. Gait ataxia and extremity dysmetria are clinical manifestations of diseases that interrupt the complex cerebellar circuitry between the neurons of the cerebellar cortex, the cerebellar nuclei (especially the dentate nuclei), and the inferior olivary nuclei. The cerebellum is a prominent target of several sporadic and hereditary neurodegenerative diseases, including multiple system atrophy, spinocerebellar ataxia, and Friedreich ataxia...
2018: Handbook of Clinical Neurology
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
Marianna Galliani, Melissa Santi, Ambra Del Grosso, Antonella Cecchettini, Filippo M Santorelli, Sandra L Hofmann, Jui-Yun Lu, Lucia Angella, Marco Cecchini, Giovanni Signore
Polymeric nanoparticles (NPs) represent one of the most promising tools in nanomedicine and have been extensively studied for the delivery of water-insoluble drugs. However, the efficient loading of therapeutic enzymes and proteins in polymer-based nanostructures remains an open challenge. Here, we report a synthesis method for a new enzyme delivery system based on cross linked enzyme aggregates (CLEAs) encapsulation into poly(lactide-co-glycolide) (PLGA) NPs. We tested the encapsulation strategy on four enzymes currently investigated for enzyme replacement therapy: palmitoyl protein thioesterase 1 (PPT1; defective in NCL1 disease), galactosylceramidase (GALC; defective in globoid cell leukodystrophy), alpha glucosidase (aGLU; defective in Pompe disease) and beta glucosidase (bGLU; defective in Gaucher's disease)...
June 12, 2018: Bioconjugate Chemistry
Alexander Conant, Julian Curiel, Amy Pizzino, Parisa Sabetrasekh, Jennifer Murphy, Miriam Bloom, Sarah H Evans, Guy Helman, Ryan J Taft, Cas Simons, Matthew T Whitehead, Steven A Moore, Adeline Vanderver
Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c...
January 1, 2018: Journal of Child Neurology
Thomas J Jentsch, Michael Pusch
CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models...
July 1, 2018: Physiological Reviews
Nikki Van Der Veldt, Diane F Van Rappard, Laura A Van De Pol, Marjo S Van Der Knaap, Willem Jr Van Ouwerkerk, Jules G Becher, Nicole I Wolf, Annemieke I Buizer
Metachromatic leukodystrophy (MLD) is a rare progressive neurological disorder, often accompanied by motor impairments that are challenging to treat. In this case series, we report the course of treatment with intrathecal baclofen (ITB), aimed at improving daily care and comfort in children and young adults with MLD. All patients with MLD in our centre on ITB treatment for a minimum of 6 months were included (n=10; 4 males, 6 females; mean age 10y 8mo [range 6-24y]). Eight patients had MLD with a predominant spastic movement disorder (sMLD) and two were mainly dyskinetic...
May 27, 2018: Developmental Medicine and Child Neurology
Y X Peng, L P Huang, J Li, Y H Yu, C H Chen, S J Chen, Q X Chang
Objective: To evaluate the clinical outcome of fetus diagnosed as mild and moderate isolated ventriculomegaly (IVM) and its correlation with imaging follow-up. Methods: Totally, 161 cases of single pregnancy whose fetus was diagnosed as mild or moderate IVM by ultrasound were administrated. Data of prenatal ultrasound examination, pregnancy outcomes, and the postnatal MRI results were collected. New borns' growth and development, language expression, movement coordination, auditory and visual function were followed up to evaluate the neurodevelopment...
May 25, 2018: Zhonghua Fu Chan Ke za Zhi
Paulo Victor Sgobbi Souza, Bruno Mattos Lombardi Badia, Luiz Henrique Libardi Silva, Carlos Alberto Castro Teixeira, Daniel Delgado Seneor, Vitor Dias Gomes Barrios Marin, Igor Braga Farias, Renan Braido Dias, Acary Souza Bulle Oliveira, Wladimir Bocca Vieira Rezende Pinto
BACKGROUND: Hypomyelinating leukodystrophies represent an expanding group of neurogenetic disorders characterized primarily by central nervous system hypomyelination and variable neurological and non-neurological involvement. Hypomyelinating disorders have been rarely associated with gonadal dysfunction, being mainly represented by hypogonadotrophic hypogonadism in 4H syndrome. WT1 gene-associated disorders are classically associated with complex phenotypes including early carcinogenic risk for gonadoblastoma and Wilms' tumor, chronic renal failure, nephrotic syndrome and sex developmental disorders in intersex disorders and ambiguous genitalia...
July 15, 2018: Journal of the Neurological Sciences
Oula Knuutinen, Maria Kousi, Maria Suo-Palosaari, Jukka S Moilanen, Hannu Tuominen, Leena Vainionpää, Tarja Joensuu, Anna-Kaisa Anttonen, Johanna Uusimaa, Anna-Elina Lehesjoki, Päivi Vieira
Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD...
May 25, 2018: Neuropediatrics
Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, Rosalba Carrozzo
Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis...
May 14, 2018: Human Molecular Genetics
Dan Wang, Shaoyong Li, Dominic J Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E Goetzmann, Terence R Flotte, Mavis Agbandje-McKenna, Guangping Gao
Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
I Taglia, I Di Donato, S Bianchi, A Cerase, L Monti, R Marconi, A Orrico, A Rufa, A Federico, M T Dotti
INTRODUCTION: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is the most frequent non-vascular adult-onset leukoencephalopathy. It is caused by autosomal dominant mutations in CSF1R gene. Recently, also autosomal recessive mutations in AARS2 gene were found to be the cause of an adult-onset leukodystrophy with axonal spheroids...
May 10, 2018: Acta Neurologica Scandinavica
Alexander Sosunov, Markel Olabarria, James E Goldman
Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in the CNS do not express GFAP, AxD is a primary astrocyte disease. Astrocytes acquire a large number of pathological features, including changes in morphology, the loss or diminution of a number of critical astrocyte functions and the activation of cell stress and inflammatory pathways. AxD is also characterized by white matter degeneration, a pathology that has led it to be included in the "leukodystrophies...
May 2018: Brain Pathology
Marianna Bugiani, Caroline Vuong, Marjolein Breur, Marjo S van der Knaap
VWM is one of the most prevalent leukodystrophies with unique clinical, pathological and molecular features. It mostly affects children, but may develop at all ages, from birth to senescence. It is dominated by cerebellar ataxia and susceptible to stresses that act as factors provoking disease onset or episodes of rapid neurological deterioration possibly leading to death. VWM is caused by mutations in any of the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B). Although eIF2B is ubiquitously expressed, VWM primarily manifests as a leukodystrophy with increasing white matter rarefaction and cystic degeneration, meager astrogliosis with no glial scarring and dysmorphic immature astrocytes and increased numbers of oligodendrocyte progenitor cells that are restrained from maturing into myelin-forming cells...
May 2018: Brain Pathology
Rogier Min, Marjo S van der Knaap
Electrical activity of neurons in the brain, caused by the movement of ions between intracellular and extracellular compartments, is the basis of all our thoughts and actions. Maintaining the correct ionic concentration gradients is therefore crucial for brain functioning. Ion fluxes are accompanied by the displacement of osmotically obliged water. Since even minor brain swelling leads to severe brain damage and even death, brain ion and water movement has to be tightly regulated. Glial cells, in particular astrocytes, play a key role in ion and water homeostasis...
May 2018: Brain Pathology
Marianna Bugiani, Marjolein Breur
Leukodystrophies are genetically determined disorders due to defects in any structural components of the brain white matter. This mini-symposium presents a selection of leukodystrophies due to astrocytic dysfunction, the astrocytopathies. Examples are provided of astrocytopathies due to defects in astrocyte-specific proteins and in which astrocytes play a major role in the pathophysiology. Knowledge on the disease mechanisms underlying these leukodystrophies also provides information how loss of physiologic functions and gain of detrimental functions in astrocytes leads to degeneration of the white matter...
May 2018: Brain Pathology
Mohammad Humayun, Abidullah Khan
A 30 year old married Pakistani woman presented in January 2018 with an eight month history of progressive left sided weakness, ataxia, spasticity, underdeveloped secondary sexual characteristics and primary infertility. She was the elder sister of a 19 year old bed bound woman who was diagnosed with vanishing white matter (VWM) disease 12 months previously. The MRI scan of the brain  demonstrated diffuse leukodystrophy and her hormonal assays were significant for premature ovarian insufficiency. Results from her genetic tests demonstrated a point mutation in eukaryotic initiation factor 2B (EIF2B)...
2018: F1000Research
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