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Lysosomal storage disorders

Lorenzo Ferri, Giuseppina Covello, Anna Caciotti, Renzo Guerrini, Michela Alessandra Denti, Amelia Morrone
Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the α-galactosidase A (α-Gal A) enzyme, which is encoded by the GLA gene. GLA transcription in humans produces a major mRNA encoding α-Gal A and a minor mRNA of unknown function, which retains a 57-nucleotide-long cryptic exon between exons 4 and 5, bearing a premature termination codon. NM_000169.2:c.639+861C>T and NM_000169.2:c.639+919G>A GLA deep intronic mutations have been described to cause Fabry disease by inducing overexpression of the alternatively spliced mRNA, along with a dramatic decrease in the major one...
October 25, 2016: Molecular Therapy. Nucleic Acids
Yosep Chong, Minyoung Kim, Eun Sil Koh, Seok Joon Shin, Ho-Shik Kim, Sungjin Chung
BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in α-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease. CASE PRESENTATION: A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated...
October 24, 2016: BMC Medical Genetics
Khaled El Cheikh, Ilaria Basile, Afitz Da Silva, Coralie Bernon, Pierre Cérutti, Frédéric Salgues, Marc Perez, Marie Maynadier, Magali Gary-Bobo, Catherine Caillaud, Martine Cérutti, Marcel Garcia, Alain Morère
Improving therapeutics delivery in enzyme replacement therapy (ERT) for lysosomal storage disorders is a challenge. Herein, we present the synthesis of novel analogues of mannose 6-phosphate (M6P), known as AMFAs and functionalized at the anomeric position for enzyme grafting. AMFAs are non-phosphate serum-resistant derivatives that efficiently bind the cation-independent mannose 6-phosphate receptor (CI-M6PR), which is the main pathway to address enzymes to lysosomes. One of the AMFAs was used to improve the treatment of the lysosomal myopathy Pompe disease, in which acid α-glucosidase (GAA) is defective...
October 24, 2016: Angewandte Chemie
Albina Nowak, Thomas P Mechtler, Robert J Desnick, David C Kasper
BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities...
October 19, 2016: Molecular Genetics and Metabolism
Catherine Breen, Jean Mercer, Simon A Jones, Amir Jahic, Lesley Heptinstall, Karen Tylee, William G Newman, Christian Beetz
Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder.
2016: Human Genome Variation
Matthias Boentert, Hélène Prigent, Katalin Várdi, Harrison N Jones, Uwe Mellies, Anita K Simonds, Stephan Wenninger, Emilia Barrot Cortés, Marco Confalonieri
Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. Sleep-disordered breathing, daytime hypercapnia, and the need for nocturnal ventilation eventually evolve in most patients. Additionally, respiratory muscle weakness leads to decreased cough and impaired airway clearance, increasing the risk of acute respiratory illness...
October 17, 2016: International Journal of Molecular Sciences
Luba Nalysnyk, Philip Rotella, Jason C Simeone, Alaa Hamed, Neal Weinreb
OBJECTIVES: The objectives of this research were: (1) to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and; (2) to summarize the published evidence on GD epidemiology which is essential to accurately depict the total societal burden of this rare worldwide disorder. METHODS: A comprehensive literature review was undertaken to summarize the published evidence on the epidemiology of GD...
October 20, 2016: Hematology (Amsterdam, Netherlands)
Takeshi Funakoshi, Toshihiko Aki, Masateru Tajiri, Kana Unuma, Koichi Uemura
Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure...
October 18, 2016: Journal of Biological Chemistry
K V Firsov, A S Kotov
Fabry disease (Anderson-Fabry disease) is an X-linked recessive lysosomal storage disorder resulting from deficient activity of lysosomal hydrolase, alpha-galactosidase A (alpha-Gal A), which leads to progressive accumulation of globotriaosylceramide (Gb3) in various cells, predominantly endothelial and vascular smooth muscle cells, with clinical manifestations affecting major organs including the central nervous system. Manifestations of Fabry disease include progressive renal and cardiac insufficiency, neuropathic pain, stroke and cerebral disease, skin and gastrointestinal symptoms...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Monika Dyczko, Anna Grzywa-Celińska, Wojciech Barud, Rafał Celiński, Wojciech Dworzański, Katarzyna Szmygin-Milanowska, Jerzy Mosiewicz
: Gaucher's disease if one of the most frequent, among extremely rare, lysosomal storage diseases. It is the autosomal recessive inherited metabolic disorder, which can present in three main clinical forms. Type 1 - the most benign, in a not-neuropathic form, and types 2 and 3, both in neuropathic form, which manifest serious neurological symptoms. AIM: The aim of the study was to draw attention to the late diagnosing of Gaucher's disease in the Polish population and to popularize the knowledge about this ultra-rare disease...
July 29, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Mona Abaoui, Michel Boutin, Pamela Lavoie, Christiane Auray-Blais
Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and resulting in the accumulation of glycosphingolipids in different tissues and biological fluids. Glycosphingolipid biomarkers, such as globotriaosylceramide (Gb3 ) isoforms, globotriaosylsphingosine (lyso-Gb3 ) and related analogs, and galabiosylceramide (Ga2 ) isoforms and analogs, are found to be abnormally increased in urine and in plasma of Fabry patients and have the potential to be used as specific biomarkers of the disease...
October 11, 2016: Current Protocols in Human Genetics
Jessica M Kelly, Allison Bradbury, Douglas R Martin, Mark E Byrne
Approximately 1 in 5000-8000 children are born annually with a lysosomal storage disease (LSD), which affects their cells' ability to break down naturally occurring substrates. Accumulation, or "storage," of undegraded substrates leads to a wide variety of clinical symptoms, and early mortality. Currently, for LSDs with central nervous system (CNS) involvement, there is no available treatment. Four methods of treatment are being explored in clinical trials and preclinical settings: enzyme replacement therapy, ex vivo gene therapy, in vivo gene therapy, and nanoparticle-based therapy...
October 7, 2016: Progress in Neurobiology
Alexander W M Hooper, Suleiman A Igdoura
Microgliosis and astrogliosis are known to be exacerbating factors in the progression of the lysosomal storage disorder Sandhoff disease. We have also found evidence for excitotoxicity via glutamate receptors in Sandhoff disease. To view the interaction of these cascades, we measured cerebellar expression of markers for gliosis, apoptosis, and excitatory synapses over the disease course in a Sandhoff disease mouse model. We observe a 2-stage model, with initial activation of microgliosis as early as 60days of age, followed by a later onset of astrogliosis, caspase-mediated apoptosis, and reduction in GluR1 at approximately 100days of age...
October 15, 2016: Journal of Neuroimmunology
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
L Kuchař, B Asfaw, J Rybová, J Ledvinová
In recent years, mass spectrometry (MS) has become the dominant technology in lipidomic analysis. It is widely used in diagnosis and research of lipid metabolism disorders including those characterized by impairment of lysosomal functions and storage of nondegraded-degraded substrates. These rare diseases, which include sphingolipidoses, have severe and often fatal clinical consequences. Modern MS methods have contributed significantly to achieve a definitive diagnosis, which is essential in clinical practice to begin properly targeted patient care...
2016: Advances in Clinical Chemistry
Maria Francisca Coutinho, Marisa Encarnação, Francisco Laranjeira, Lúcia Lacerda, Maria João Prata, Sandra Alves
While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase...
October 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Matheus Trovão de Queiroz, Vanessa Gonçalves Pereira, Cinthia Castro do Nascimento, Vânia D'Almeida
Non-coding RNAs (ncRNAs) are a functional class of RNA involved in the regulation of several cellular processes which may modulate disease onset, progression, and prognosis. Lysosomal storage diseases (LSD) are a group of rare disorders caused by mutations of genes encoding specific hydrolases or non-enzymatic proteins, characterized by a wide spectrum of manifestations. The alteration of ncRNA levels is well established in several human diseases such as cancer and auto-immune disorders; however, there is a lack of information focused on the role of ncRNA in rare diseases...
2016: Frontiers in Endocrinology
William I Wooten, Marianne S Muhlebach, Joseph Muenzer, Ceila E Loughlin, Bradley V Vaughn
Mucolipidosis II (Inclusion cell or I-cell disease) is an autosomal recessive lysosomal storage disorder clinically comparable to the mucopolysaccharidoses (MPS), characterized by progressive respiratory and neurologic deterioration. Sleep problems, especially obstructive sleep apnea (OSA) and disrupted sleep architecture, are observed in other lysosomal storage diseases but have not been described in mucolipidosis II. We report the progression of polysomnographic abnormalities in a child with mucolipidosis II, demonstrated by worsening sleep-related hypoventilation, OSA, and sleep state fragmentation despite advancing PAP therapy...
September 29, 2016: Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine
W Panmontha, P Amarinthnukrowh, P Damrongphol, T Desudchit, K Suphapeetiporn, V Shotelersuk
Fucosidosis is a rare lysosomal storage disorder inherited in an autosomal recessive manner. Its estimated frequency is below 1 in 200,000 live births. Its clinical phenotypes include progressive neurological and mental deterioration, coarse facial features, growth retardation, visceromegaly, angiokeratomas, and seizures. The disease is caused by mutations in the FUCA1 gene that lead to deficiency of a-L-fucosidase. Here, we describe the clinical and molecular features of a Thai boy with fucosidosis. Whole exome sequencing and array-based comparative genomic hybridization analysis revealed that the patient was compound heterozygous for a single base-pair deletion (c...
September 16, 2016: Genetics and Molecular Research: GMR
Devin Dersh, Yuichiro Iwamoto, Yair Argon
Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared to WT α...
September 28, 2016: Molecular Biology of the Cell
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