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Familial dysautonomia

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https://www.readbyqxmd.com/read/29929962/retina-specific-loss-of-ikbkap-elp1-causes-mitochondrial-dysfunction-that-leads-to-selective-retinal-ganglion-cell-degeneration-in-a-mouse-model-of-familial-dysautonomia
#1
Yumi Ueki, Veronika Shchepetkina, Frances Lefcort
Familial dysautonomia (FD) is an autosomal recessive disorder marked by developmental and progressive neuropathies. It is caused by an intronic point mutation in the inhibitor of kappa B kinase complex-associated protein (IKAP, also called ELP1) gene IKBKAP/ELP1 , a component of the Elongator complex. Due to variation in tissue-specific splicing, the mutation primarily affects the nervous system. One of the most debilitating hallmarks of FD that affects patients' quality of life is progressive blindness. To determine the pathophysiological mechanisms that are triggered by the absence of IKAP in the retina, we generated retina-specific Ikbkap conditional knockout (CKO) mice using a Pax6-Cre , which abolished Ikbkap expression in all the cell types of the retina...
June 21, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29907605/transthyretin-amyloid-polyneuropathies-mimicking-a-demyelinating-polyneuropathy
#2
Pierre Lozeron, Louise-Laure Mariani, Pauline Dodet, Guillemette Beaudonnet, Marie Théaudin, Clovis Adam, Bertrand Arnulf, David Adams
OBJECTIVE: To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome...
June 15, 2018: Neurology
https://www.readbyqxmd.com/read/29762696/blocking-of-an-intronic-splicing-silencer-completely-rescues-ikbkap-exon-20-splicing-in-familial-dysautonomia-patient-cells
#3
Gitte H Bruun, Jeanne Mv Bang, Lise L Christensen, Sabrina Brøner, Ulrika Ss Petersen, Barbara Guerra, Alexander Gb Grønning, Thomas K Doktor, Brage S Andresen
Familial dysautonomia (FD) is a severe genetic disorder causing sensory and autonomic dysfunction. It is predominantly caused by a c.2204+6T>C mutation in the IKBKAP gene. This mutation decreases the 5' splice site strength of IKBKAP exon 20 leading to exon 20 skipping and decreased amounts of full-length IKAP protein. We identified a binding site for the splicing regulatory protein hnRNP A1 downstream of the IKBKAP exon 20 5'-splice site. We show that hnRNP A1 binds to this splicing regulatory element (SRE) and that two previously described inhibitory SREs inside IKBKAP exon 20 are also bound by hnRNP A1...
May 14, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29716616/stability-of-the-htlv-1-glycoprotein-46-gp46-gene-in-an-endemic-region-of-the-brazilian-amazon-and-the-presence-of-a-significant-mutation-n93d-in-symptomatic-patients
#4
Maria de Nazaré do Socorro de Almeida Viana, Akim Felipe Santos Nobre, Edivaldo Costa, Ingrid Christiane Silva, Bruna Teles Pinheiro, Cássia Cristine Costa Pereira, Louise de Souza Canto Ferreira, Danilo Souza de Almeida, Marcos William Leão de Araújo, Mariza da Silva Borges, Carlos Araujo da Costa, Edna Aoba Yassui Ishikawa, Stephen Francis Ferrari, Maísa Silva de Sousa
BACKGROUND: The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies...
May 2, 2018: Virology Journal
https://www.readbyqxmd.com/read/29701768/exon-specific-u1-snrnas-improve-elp1-exon-20-definition-and-rescue-elp1-protein-expression-in-a-familial-dysautonomia-mouse-model
#5
Irving Donadon, Mirko Pinotti, Katarzyna Rajkowska, Giulia Pianigiani, Elena Barbon, Elisabetta Morini, Helena Motaln, Boris Rogelj, Federico Mingozzi, Susan A Slaugenhaupt, Franco Pagani
Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204 + 6T>C) that negatively affects the definition of exon 20 in the Elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5' splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, Exon-Specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition...
April 25, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29698477/characteristics-of-ataxic-gait-in-familial-dysautonomia-patients
#6
Sigal Portnoy, Channa Maayan, Jeanna Tsenter, Yonah Ofran, Vladimir Goldman, Nurit Hiller, Naama Karniel, Isabella Schwartz
INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25...
2018: PloS One
https://www.readbyqxmd.com/read/29680425/prevalence-and-characteristics-of-sleep-disordered-breathing-in-familial-dysautonomia
#7
Kanwaljit Singh, Jose-Alberto Palma, Horacio Kaufmann, Nataliya Tkachenko, Lucy Norcliffe-Kaufmann, Christy Spalink, Mikhail Kazachkov, Sanjeev V Kothare
OBJECTIVE: Familial dysautonomia (FD) is an autosomal recessive disorder characterized by impaired development of sensory and afferent autonomic nerves. Untreated sleep-disordered breathing (SDB) has been reported to increase the risk of sudden unexpected death in FD. We aimed to describe the prevalence and characteristics of SDB in FD. PATIENTS/METHODS: Seventy-five patients with FD (20 adults and 55 children) underwent in-lab polysomnography, including peripheral capillary oxygen saturation (SpO2 ) and end-tidal capnography (EtCO2 ) measurements...
May 2018: Sleep Medicine
https://www.readbyqxmd.com/read/29672717/antisense-oligonucleotides-correct-the-familial-dysautonomia-splicing-defect-in-ikbkap-transgenic-mice
#8
Rahul Sinha, Young Jin Kim, Tomoki Nomakuchi, Kentaro Sahashi, Yimin Hua, Frank Rigo, C Frank Bennett, Adrian R Krainer
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic...
June 1, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29626450/female-specific-association-between-variants-on-chromosome-9-and-self-reported-diagnosis-of-irritable-bowel-syndrome
#9
Ferdinando Bonfiglio, Tenghao Zheng, Koldo Garcia-Etxebarria, Fatemeh Hadizadeh, Luis Bujanda, Francesca Bresso, Lars Agreus, Anna Andreasson, Aldona Dlugosz, Greger Lindberg, Peter T Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero Portincasa, Massimo Bellini, Giovanni Barbara, Anna Latiano, Matthias Hübenthal, Vincent Thijs, Mihai G Netea, Daisy Jonkers, Lin Chang, Emeran A Mayer, Mira M Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Alexandra Zhernakova, Mauro D'Amato
BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years)...
April 5, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29552666/improvement-of-chronic-corneal-opacity-in-ocular-surface-disease-with-prosthetic-replacement-of-the-ocular-surface-ecosystem-prose-treatment
#10
Anna Cressey, Deborah S Jacobs, Crystal Remington, Karen G Carrasquillo
Purpose: To demonstrate clearing of chronic corneal opacities and improvement of visual acuity with the use of BostonSight prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in ocular surface disease. Observations: We undertook retrospective analysis of the medical records of a series of patients who underwent PROSE treatment from August 2006 to December 2014. Patients were referred for ocular surface disease of various etiologies. Primary inclusion criterion was corneal opacity that improved with PROSE treatment...
June 2018: American Journal of Ophthalmology Case Reports
https://www.readbyqxmd.com/read/29545390/elongator-complex-is-required-for-long-term-olfactory-memory-formation-in-drosophila
#11
Dinghui Yu, Ying Tan, Molee Chakraborty, Seth Tomchik, Ronald L Davis
The evolutionarily conserved Elongator Complex associates with RNA polymerase II for transcriptional elongation. Elp3 is the catalytic subunit, contains histone acetyltransferase activity, and is associated with neurodegeneration in humans. Elp1 is a scaffolding subunit and when mutated causes familial dysautonomia. Here, we show that elp3 and elp1 are required for aversive long-term olfactory memory in Drosophila RNAi knockdown of elp3 in adult mushroom bodies impairs long-term memory (LTM) without affecting earlier forms of memory...
April 2018: Learning & Memory
https://www.readbyqxmd.com/read/29511897/autonomic-involvement-in-hereditary-transthyretin-amyloidosis-hattr-amyloidosis
#12
REVIEW
Alejandra Gonzalez-Duarte
PURPOSE: Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a progressive disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy. In this article, we discuss the pathophysiology and principal findings of autonomic neuropathy in hATTR amyloidosis, the most common methods of assessment and progression, and its relation as a predictive risk factor or a measure of progression in the natural history of the disease. METHODS: A literature search was performed using the terms "autonomic neuropathy," "dysautonomia," and "autonomic symptoms" in patients with hereditary transthyretin amyloidosis and familial amyloid polyneuropathy...
March 6, 2018: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/29508456/autonomic-dysfunction-in-genetic-forms-of-synucleinopathies
#13
REVIEW
Viorica Chelban, Ekawat Vichayanrat, Lucia Schottlaende, Valeria Iodice, Henry Houlden
The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia...
March 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29497044/elongator-and-codon-bias-regulate-protein-levels-in-mammalian-peripheral-neurons
#14
Joy Goffena, Frances Lefcort, Yongqing Zhang, Elin Lehrmann, Marta Chaverra, Jehremy Felig, Joseph Walters, Richard Buksch, Kevin G Becker, Lynn George
Familial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the translation of codon-biased genes in lower organisms. Here we investigate whether Elongator serves a similar function in mammalian peripheral neurons, the population devastated in FD. Using codon-biased eGFP sensors, and multiplexing of codon usage with transcriptome and proteome analyses of over 6,000 genes, we identify two categories of genes, as well as specific gene identities that depend on Elongator for normal expression...
March 1, 2018: Nature Communications
https://www.readbyqxmd.com/read/29435868/ambulatory-blood-pressure-profiles-in-familial-dysautonomia
#15
Lior Goldberg, Bat-El Bar-Aluma, Alex Krauthammer, Ori Efrati, Yehonatan Sharabi
OBJECTIVE: Familial dysautonomia (FD) is a rare genetic disease that involves extreme blood pressure fluctuations secondary to afferent baroreflex failure. The diurnal blood pressure profile, including the average, variability, and day-night difference, may have implications for long-term end organ damage. The purpose of this study was to describe the circadian pattern of blood pressure in the FD population and relationships with renal and pulmonary function, use of medications, and overall disability...
February 12, 2018: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/29332244/structural-insights-into-the-function-of-elongator
#16
REVIEW
Udit Dalwadi, Calvin K Yip
Conserved from yeast to humans, Elongator is a protein complex implicated in multiple processes including transcription regulation, α-tubulin acetylation, and tRNA modification, and its defects have been shown to cause human diseases such as familial dysautonomia. Elongator consists of two copies of six core subunits (Elp1, Elp2, Elp3, Elp4, Elp5, and Elp6) that are organized into two subcomplexes: Elp1/2/3 and Elp4/5/6 and form a stable assembly of ~ 850 kDa in size. Although the catalytic subunit of Elongator is Elp3, which contains a radical S-adenosyl-L-methionine (SAM) domain and a putative histone acetyltransferase domain, the Elp4/5/6 subcomplex also possesses ATP-modulated tRNA binding activity...
May 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29289840/founder-mutation-in-ikbkap-gene-causes-vestibular-impairment-in-familial-dysautonomia
#17
Joel V Gutiérrez, Horacio Kaufmann, Jose-Alberto Palma, Carlos Mendoza-Santiesteban, Vaughan G Macefield, Lucy Norcliffe-Kaufmann
OBJECTIVE: To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia. METHODS: Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead...
November 26, 2017: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/29234869/a-controlled-trial-of-inhaled-bronchodilators-in-familial-dysautonomia
#18
Bat-El Bar-Aluma, Ori Efrati, Horacio Kaufmann, Jose-Alberto Palma, Lucy Norcliffe-Kaufmann
BACKGROUND: Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS: We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation...
February 2018: Lung
https://www.readbyqxmd.com/read/28906019/response-letter-to-optimising-physiology-for-adolescents-with-dysautonomia
#19
LETTER
K R Armstrong, A M De Souza, P L Sneddon, J E Potts, V E Claydon, S Sanatani
No abstract text is available yet for this article.
December 2017: Acta Paediatrica
https://www.readbyqxmd.com/read/28717942/erratum-to-animal-and-cellular-models-of-familial-dysautonomia
#20
Frances Lefcort, Marc Mergy, Sarah B Ohlen, Yumi Ueki, Lynn George
No abstract text is available yet for this article.
August 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
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