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    • Audiological findings in children with ataxia-telangiectasia (A-T) syndrome.
      Zugriffe: 179
      • ataxia telangiectasia
      • 2017
      • Int J Pediatr Otorhinolaryngol
      • Egypt
      • Afifi PO
      • Elsanadiky HH
      • ABR findings
      • Audiological assessment
      Int J Pediatr Otorhinolaryngol. 2017 Jan;92:94-98. doi: 10.1016/j.ijporl.2016.11.012. Epub 2016 Nov 15.
      Afifi PO1, Elsanadiky HH2.

      Author information

      1
      Lecturer of Audiology, Otorhinolaryngology Department, Ain Shams University, Cairo, Egypt. Electronic address: pretty_afifi@hotmail.com.
      2
      Assistant Professor of Audiology, Otorhinolaryngology Department, Faculty of Medicine, Tanta University, Egypt.

      Abstract

      AIM:

      To assess peripheral and central hearing in children with A-T.

      METHOD:

      3 children diagnosed with A-T according to the diagnostic criteria for A-T of the European Society for Immunodeficiencies. Involuntary movements were seen in the form of chorea-athetosis together with tremors. They were examined to assess both peripheral and central hearing was assessed (hearing thresholds). Sound-field testing, tympanometry, acoustic reflexes, Otoacoustic Emissions (OAEs) and Auditory Brainstem Responses (ABR) were done for all of them.

      RESULTS:

      Basic Audiological evaluation is of a limited value as the children are not co-operative. Sound field testing could not be done. Bilateral normal middle ear functions as reflected by Tympanometry and Acoustic Reflexes. Advanced Audiological evaluation including OAEs and ABR are more valuable in assessing hearing in children with A-T. Bilateral pass response at all test frequencies in DPOAEs. Abnormal ABR findings were obtained in the form of a delay in wave V latency more than 2 SD with subsequent increased in I-V interpeak latency with no significant interaural latency difference.

      CONCLUSION:

      Consistent with bilateral normal peripheral hearing sensitivity with central hearing affection.

      LIMITATIONS:

      The rarity of the disease, make it difficult to be applied on many cases.

      Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

      KEYWORDS:

      ABR findings; Ataxia-telangiectasia; Audiological assessment

      PMID:
       
      28012542
       
      DOI:
       
      10.1016/j.ijporl.2016.11.012
      [Indexed for MEDLINE]
    • A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype.
      Zugriffe: 328
      • Japan
      • Lavin MF
      • Australia
      • Wolvetang EJ
      • Hum Mol Genet
      • Quek H
      • Luff J
      • Cheung K
      • Kozlov S
      • Gatei M
      • Lee CS
      • Bellingham MC
      • Noakes PG
      • Lim YC
      • Barnett NL
      • Dingwall S
      • Mashimo T
      • Roberts TL
      • ratmodel
      Hum Mol Genet. 2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371.
      Quek H1,2, Luff J1, Cheung K1,2, Kozlov S1, Gatei M1, Lee CS3, Bellingham MC4, Noakes PG4, Lim YC2, Barnett NL1,5,6, Dingwall S1,2,7, Wolvetang E7, Mashimo T8, Roberts TL1,2,3, Lavin MF1.

      Author information

      1
      The University of Queensland Centre for Clinical Research, Herston, Qld, Australia.
      2
      QIMR Berghofer Medical Research Institute, Herston, Qld, Australia.
      3
      The Ingham Institute for Applied Medical Research and School of Medicine, Western Sydney University, Liverpool, NSW, Australia.
      4
      School of Biomedical Sciences, The University of Queensland, St Lucia, Qld, Australia.
      5
      Queensland Eye Institute, South Brisbane, Qld, Australia.
      6
      School of Biomedical Sciences, Queensland University of Technology, Brisbane, Qld, Australia.
      7
      Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Qld, Australia.
      8
      Graduate School of Medicine, Osaka University, Osaka, Japan.

      Abstract

      Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.

      PMID:
       
      28007901
       
      DOI:
       
      10.1093/hmg/ddw371
      [Indexed for MEDLINE]
    • Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone.
      Zugriffe: 191
      • ataxia telangiectasia
      • Italy
      • 2017
      • Menotta M
      • Biagiotti S
      • Chessa L
      • Magnani M
      • dexamethasone
      • Orazi S
      • Cell Biochem Biophys
      • Bartolini G
      • Marzia B
      • Germani A
      • Atomic force microscopy
      • Young’s modulus
      Cell Biochem Biophys. 2017 Mar;75(1):95-102. doi: 10.1007/s12013-016-0775-0. Epub 2016 Dec 8.
      Menotta M1, Biagiotti S2, Bartolini G2, Marzia B2, Orazi S2, Germani A3, Chessa L3, Magnani M2.

      Author information

      1
      Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy. michele.menotta@uniurb.it.
      2
      Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
      3
      Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

      Abstract

      Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. The cells were subsequently investigated for membrane and whole cell mechanical properties by atomic force microscopy. In addition, cytoskeleton protein dynamics and nuclear shapes were assayed by fluorescence microscopy, while western blots were used to assess actin and tubulin content. At the macro level, dexamethasone directly modified the cell shape, Young's modulus and cytoskeleton protein dynamics. At the nano level, the roughness of the cell surface and the local nano-mechanical proprieties were found to be affected by Dexa. Our results show that ataxia telangiectasia and wild type cells are affected by Dexa, although there are dissimilarities in some macro-level and nano-level features between the tested cell lines. The Young's modulus of the cells appears to depend mainly on nuclear shape, with a slight contribution from the tested cytoskeleton proteins. The current study proposes that dexamethasone influences ataxia telangiectasia cell membranes contents, cell components and cell shape.

      KEYWORDS:

      Ataxia telangiectasia; Atomic force microscopy; Dexamethasone; Young’s modulus

      PMID:
       
      27933465
       
      DOI:
       
      10.1007/s12013-016-0775-0
      [Indexed for MEDLINE]
    • Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with Dexamethasone.
      Zugriffe: 187
      • 2018
      • Italy
      • Menotta M
      • Chessa L
      • Magnani M
      • dexamethasone
      • Orazi S
      • Spapperi C
      • PLoS One
      • Gioacchini AM
      • Ricci A
      • proteomics
      • transcriptomics
      PLoS One. 2018 Apr 2;13(4):e0195388. doi: 10.1371/journal.pone.0195388. eCollection 2018.
      Menotta M1, Orazi S1, Gioacchini AM1, Spapperi C1, Ricci A1, Chessa L2, Magnani M1.

      Author information

       

      Abstract

      Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. We used 2DE and tandem MS to identify proteins that were influenced by the drug in A-T cells but not in healthy cells. Thirty-four proteins were defined out of a total of 746±63. Transcriptome analysis was performed by microarray and showed the differential expression of 599 A-T and 362 wild type (WT) genes and a healthy un-matching between protein abundance and the corresponding gene expression variation. The proteomic and transcriptomic profiles allowed the network pathway analysis to pinpoint the biological and molecular functions affected by Dexamethasone in Dexa-treated cells. The present integrated study provides evidence of the molecular mechanism of action of Dexamethasone in an A-T cellular model but also the broader effects of the drug in other tested cell lines.

      PMID:
       
      29608596
       
      PMCID:
       
      PMC5880408
       
      DOI:
       
      10.1371/journal.pone.0195388
      [Indexed for MEDLINE] 
      Free PMC Article
    • Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response.
      Zugriffe: 224
      • ataxia telangiectasia
      • Italy
      • 2016
      • Menotta M
      • Biagiotti S
      • Bianchi M
      • Chessa L
      • Magnani M
      • Glucocorticoids
      • Orazi S
      • Rossi L
      • Spapperi C
      • oxidative stress
      • FEBS J
      • Brundu S
      • Fraternale A
      • molecular cell biology
      • nuclear factor 2
      FEBS J. 2016 Nov;283(21):3962-3978. doi: 10.1111/febs.13901. Epub 2016 Oct 12.
      Biagiotti S1, Menotta M1, Orazi S1, Spapperi C1, Brundu S1, Fraternale A1, Bianchi M1, Rossi L1, Chessa L2, Magnani M1.

      Author information

      1
      Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
      2
      Department of Clinical and Molecular Medicine, University 'La Sapienza', Roma, Italy.

      Abstract

      Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity.

      KEYWORDS:

      ataxia telangiectasia; glucocorticoids; molecular cell biology; nuclear factor 2; oxidative stress

      PMID:
       
      27636396
       
      DOI:
       
      10.1111/febs.13901
      [Indexed for MEDLINE] 
      Free full text
    • Novel compound heterozygous mutations in a child with Ataxia-Telangiectasia showing unrelated cerebellar disorders.
      Zugriffe: 186
      • ataxia telangiectasia
      • Italy
      • 2016
      • Micheli R
      • Soresina A
      • Plebani A
      • Chessa L
      • ATM gene
      • Molinaro A
      • Pinelli L
      • J Neurol Sci
      • Germani A
      • Piane M
      • Costa S
      • Maffeis M
      • Meschini R
      • Ischemic stroke
      • Low-grade cerebellar astrocytoma
      J Neurol Sci. 2016 Dec 15;371:48-53. doi: 10.1016/j.jns.2016.10.014. Epub 2016 Oct 13.

      Piane M1, Molinaro A2, Soresina A3, Costa S2, Maffeis M3, Germani A4, Pinelli L5, Meschini R6, Plebani A3, Chessa L4, Micheli R2.

      Author information

      1
      Department of Clinical and Molecular Medicine, "Sapienza" University of Roma, Italy. Electronic address: maria.piane@uniroma1.it.
      2
      Unit of Child Neurology and Psychiatry, Spedali Civili and University of Brescia, Brescia, Italy.
      3
      Department of Pediatrics, Spedali Civili and University of Brescia, Brescia, Italy.
      4
      Department of Clinical and Molecular Medicine, "Sapienza" University of Roma, Italy.
      5
      Department of Neuroradiology, Spedali Civili, Brescia, Italy.
      6
      Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.

      Abstract

      We report the case of a 6-year-old female patient with Ataxia Telangiectasia, an extremely rare condition, who developed in addition a left cerebellar astrocytoma and a right cerebellar infarction, considered as two independent events. Children with AT have an increased risk of developing cancer, but only few cases of glioma are reported and, at our knowledge, no other case of unrelated cerebellar glioma and cerebellar infarction in with the same AT patient have been described. The molecular analysis of ATM (Ataxia Telangiectasia Mutated) gene showed that the patient is compound heterozygote for two previously unreported mutations: c.3291delC (p.Phe1097fs) at exon 25 and c.8198A>C (p.Gln2733Pro) at exon 58. The role of the identified ATM gene mutations in the pathogenesis of Ataxia Telangiectasia and the coexisting cerebellar disorders is discussed.

      KEYWORDS:

      ATM gene; Ataxia-Telangiectasia; Ischemic stroke; Low-grade cerebellar astrocytoma

      PMID:
       
      27871447
       
      DOI:
       
      10.1016/j.jns.2016.10.014
      [Indexed for MEDLINE]
    • Integration-free erythroblast-derived human induced pluripotent stem cells (iPSCs) from an individual with Ataxia-Telangiectasia (A-T).
      Zugriffe: 232
      • United States of America
      • 2016
      • Stem Cell Res
      • Bhatt N
      • Ghosh R
      • Roy S
      • Gao Y
      • Armanios M
      • Cheng L
      • Franco S
      • induced pluripotent stem cells (iPSCs)
      • Blood erythroid cells
      Stem Cell Res. 2016 Sep;17(2):205-207. doi: 10.1016/j.scr.2016.08.003. Epub 2016 Aug 5.
      Bhatt N1, Ghosh R1, Roy S1, Gao Y2, Armanios M3, Cheng L2, Franco S4.

      Author information

      1
      Department of Radiation Oncology and Molecular Radiation Sciences, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      2
      Division of Hematology, Department of Medicine, and the Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      3
      Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center and the McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      4
      Department of Radiation Oncology and Molecular Radiation Sciences, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sfranco2@jhmi.edu.

      Abstract

      Peripheral blood was obtained from a 12-year old male carrying bialleleic inactivating mutations at the ATM locus, causing Ataxia-Telangiectasia (A-T). Blood erythroid cells were briefly expanded in vitro and induced pluripotent stem cells (iPSCs) were generated via transfection with episomal vectors carrying hOCT4, hSOX2, hKLF4, hMYC and hBCL2L1. SF-003 iPSCs were free of genomically integrated reprogramming genes, had the specific compound heterozygous mutations, stable karyotype, expressed pluripotency markers and formed teratomas in immunodeficient (NOD scid gamma; NGS) mice. The SF-003 iPSC line may be a useful resource for in vitro modeling of A-T.

      PMID:
       
      27879207
       
      DOI:
       
      10.1016/j.scr.2016.08.003
      [Indexed for MEDLINE] 
      Free full text
    • Ataxia telangiectasia: presentation and diagnostic delay.
      Zugriffe: 174
      • United Kingdom
      • 2017
      • Suri M
      • Arch Dis Child
      • Devaney R
      • Pasalodos S
      • Bush A
      • Bhatt JM
      Arch Dis Child. 2017 Apr;102(4):328-330. doi: 10.1136/archdischild-2016-310477. Epub 2016 Oct 31.
      Devaney R1, Pasalodos S2, Suri M2, Bush A3, Bhatt JM1.

      Author information

      1
      Nottingham Children's Hospital, National Paediatric Ataxia Telangiectasia Clinic, QMC, Nottingham, UK.
      2
      Nottingham Clinical Genetics Service, National Paediatric Ataxia Telangiectasia Clinic, Nottingham, UK.
      3
      Imperial College, National Heart and Lung Institute, Royal Brompton & Harefield NHS Foundation Trust, London, UK.

      Abstract

      BACKGROUND AND AIMS:

      Ataxia telangiectasia (A-T) is a rare progressive, multisystem genetic disease. Families of children with ultra-rare diseases often experience significant diagnostic delays. We reviewed the diagnostic process for A-T in order to identify causes of delay in an attempt to facilitate earlier identification of A-T in the future.

      METHODS:

      A retrospective case note review of 79 children at the National Paediatric A-T clinic seen since May 2009. Data were collected on the nature and age of initial symptoms, the age at first presentation, measurement of alpha feto-protein (AFP) and age of genetic diagnostic confirmation.

      RESULTS:

      At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0-118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1-109 months).

      CONCLUSIONS:

      There are significant delays in presentation and diagnostic confirmation of A-T. A greater awareness of A-T and early measurement of AFP may help to improve this.

      Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

      KEYWORDS:

      Alpha Fetoprotein; Ataxia Telangiectasia; diagnostic delay; presentation delay

      PMID:
       
      27799156
       
      DOI:
       
      10.1136/archdischild-2016-310477
      [Indexed for MEDLINE]
    • Robust reprogramming of Ataxia-Telangiectasia patient and carrier erythroid cells to induced pluripotent stem cells.
      Zugriffe: 219
      • ataxia telangiectasia
      • United States of America
      • ATM
      • 2016
      • Telomere length
      • Ionizing radiation
      • Stem Cell Res
      • Bhatt N
      • Ghosh R
      • Roy S
      • Gao Y
      • Armanios M
      • Cheng L
      • Franco S
      • induced pluripotent stem cells (iPSCs)
      • teratoma
      Stem Cell Res. 2016 Sep;17(2):296-305. doi: 10.1016/j.scr.2016.08.006. Epub 2016 Aug 12.
      Bhatt N1, Ghosh R1, Roy S1, Gao Y2, Armanios M3, Cheng L2, Franco S4.

      Author information

      1
      Department of Radiation Oncology and Molecular Radiation Sciences, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      2
      Division of Hematology, Department of Medicine, and the Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      3
      Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center and the McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
      4
      Department of Radiation Oncology and Molecular Radiation Sciences, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sfranco2@jhmi.edu.

      Abstract

      Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse.

      KEYWORDS:

      ATM; Ataxia-Telangiectasia; induced pluripotent stem cells; radiation; telomere; teratoma

      PMID:
       
      27596957
       
      DOI:
       
      10.1016/j.scr.2016.08.006
      [Indexed for MEDLINE] 
      Free full text
    • Ataxia telangiectasia associated with nodular regenerative hyperplasia.
      Zugriffe: 175
      • United States of America
      • 2016
      • J Clin Immunol
      • Milligan KL
      • Schirm K
      • Leonard S
      • Hussey AA
      • Agharahimi A
      • Kleiner DE
      • Fuss I
      • Lingala S
      • Heller T
      • Rosenzweig SD
      • nodular regenerative hyperplasia
      J Clin Immunol. 2016 Nov;36(8):739-742. Epub 2016 Sep 26.
      Milligan KL1,2, Schirm K1, Leonard S3, Hussey AA2, Agharahimi A2, Kleiner DE4, Fuss I5, Lingala S6, Heller T6, Rosenzweig SD7,8.

      Author information

      1
      Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
      2
      Primary Immunodeficiency Clinic, NIAID, NIH, Building 10, Room 2C410, 10 Center Drive, Bethesda, MD, 20892, USA.
      3
      Division of Allergy and Immunology, University of California, San Diego, Rady Children's Hospital, San Diego, CA, USA.
      4
      Laboratory of Pathology, NCI, NIH, Bethesda, MD, USA.
      5
      Mucosal Immunity Section, NIAID NIH, Bethesda, MD, USA.
      6
      Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA.
      7
      Primary Immunodeficiency Clinic, NIAID, NIH, Building 10, Room 2C410, 10 Center Drive, Bethesda, MD, 20892, USA. srosenzweig@cc.nih.gov.
      8
      Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Building 10, Room 2C410, 10 Center Drive, Bethesda, MD, 20892, USA. srosenzweig@cc.nih.gov.
      PMID:
       
      27671921
       
      PMCID:
       
      PMC5097878
       
      DOI:
       
      10.1007/s10875-016-0334-x
      Free PMC Article
    • Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia.
      Zugriffe: 172
      • ataxia telangiectasia
      • Spain
      • 2017
      • Next-generation sequencing
      • Neuromolecular Med
      • Carranza D
      • Vega AK
      • Torres-Rusillo S
      • Montero E
      • Martinez LJ
      • Santamaría M
      • Santos JL
      • Molina IJ
      • ATM expression
      • ATM mutations
      • Founder effect
      • Spanish patients
      • T cell lines
      Neuromolecular Med. 2017 Mar;19(1):161-174. doi: 10.1007/s12017-016-8440-8. Epub 2016 Sep 23.
      Carranza D1, Vega AK1, Torres-Rusillo S1, Montero E1, Martinez LJ2, Santamaría M3, Santos JL4, Molina IJ5,6.

      Author information

      1
      Institute of Biopathology and Regenerative Medicine, Center for Biomedical Research, University of Granada, Health Sciences Technology Park, Avda. del Conocimiento s/n, 18016, Armilla, Granada, Spain.
      2
      Genomic Unit, Center Pfizer-University of Granada-Junta de Andalucia for Genomics and Oncological Research (GENYO), Health Sciences Technology Park, Granada, Spain.
      3
      Service of Immunology and Department of Cell Biology and Immunology, "Reina Sofia" University Hospital, University of Córdoba, Córdoba, Spain.
      4
      Service of Pediatrics, "Virgen de las Nieves" University Hospital, University of Granada, Granada, Spain.
      5
      Institute of Biopathology and Regenerative Medicine, Center for Biomedical Research, University of Granada, Health Sciences Technology Park, Avda. del Conocimiento s/n, 18016, Armilla, Granada, Spain. imolina@ugr.es.
      6
      Instituto de Investigación Biosanitaria ibs.GRANADA, Granada University Hospitals, University of Granada, Granada, Spain. imolina@ugr.es.

      Abstract

      Ataxia-telangiectasia is a multisystemic disease with severe neurological affectation, immunodeficiency and telangiectasia. The disorder is caused by alterations in the ATM gene, whose size and complexity make molecular diagnosis difficult. We designed a target-enrichment next-generation sequencing strategy to characterize 28 patients from several regions of Spain. This approach allowed us to identify gene variants affecting function in 54 out of the 56 alleles analyzed, although the two unresolved alleles belong to brothers. We found 28 ATM gene mutations, of which 10 have not been reported. A total of 171 gene variants not affecting function were also found, of which 22 are reported to predispose to disease. Interestingly, all Roma (Spanish Gypsies) patients are homozygous for the same mutation and share the H3 ATM haplotype, which is strong evidence of a founder effect in this population. In addition, we generated a panel of 27 primary T cell lines from A-T patients, which revealed significant expression of ATM in two patients and traces of the protein in nine more. None of them retained residual ATM activity, and almost all T cell lines show increased or intermediate radiosensitivity.

      KEYWORDS:

      ATM expression; ATM mutations; Ataxia-telangiectasia; Founder effect; Next-generation sequencing; Spanish patients; T cell lines

      PMID:
       
      27664052
       
      DOI:
       
      10.1007/s12017-016-8440-8
      [Indexed for MEDLINE]
    • Ataxia telangiectasia presenting as hyper IgM syndrome without neurologic signs.
      Zugriffe: 228
      • United States of America
      • 2016
      • hyper IgM syndrome
      • Milligan KL
      • Leonard S
      • Rosenzweig SD
      • Ann Allergy Asthma Immunol
      • Doshi A
      • Ryu J
      • Thornburg CD
      • Hershey D
      • Cherry R
      Ann Allergy Asthma Immunol. 2016 Sep;117(3):221-6. doi: 10.1016/j.anai.2016.07.028.
      Doshi A1, Ryu J2, Thornburg CD3, Hershey D4, Cherry R5, Milligan K6, Rosenzweig S6, Leonard S7.

      Author information

      1
      Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, Rady Children's Hospital, San Diego, California. Electronic address: ashmi.doshi@gmail.com.
      2
      Division of Pulmonary Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, California.
      3
      Division of Hematology and Oncology, University of California, San Diego, Rady Children's Hospital, San Diego, California.
      4
      Division of Hospital Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, California.
      5
      Division of Gastroenterology Hepatology and Nutrition, University of California, San Diego, Rady Children's Hospital, San Diego, California.
      6
      National Institutes of Health Primary Immunodeficiency Clinic, National Institute of Health, Bethesda, Maryland.
      7
      Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, Rady Children's Hospital, San Diego, California.
      PMID:
       
      27613453
       
      DOI:
       
      10.1016/j.anai.2016.07.028
      [Indexed for MEDLINE]
    • Cerebral microbleeds and iron depletion of dentate nuclei in ataxia-telangiectasia.
      Zugriffe: 156
      • 2018
      • Neurology
      • Taiwan
      • Liu HS
      • Chen YC
      • Chen CY
      Neurology. 2016 Sep 6;87(10):1062-3. doi: 10.1212/WNL.0000000000003066.
      Liu HS1, Chen YC2, Chen CY1.

      Author information

      1
      From the School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University (H.-S.L., C.-Y.C.); Department of Medical Imaging, Taipei Medical University Hospital (H.-S.L., C.-Y.C.); Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University (C.-Y.C.); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University (H.-S.L., C.-Y.C.); Translational Imaging Research Center, College of Medicine, Taipei Medical University (H.-S.L.,C.-Y.C.); Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University (Y.-C.C.), Taipei, Taiwan.
      2
      From the School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University (H.-S.L., C.-Y.C.); Department of Medical Imaging, Taipei Medical University Hospital (H.-S.L., C.-Y.C.); Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University (C.-Y.C.); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University (H.-S.L., C.-Y.C.); Translational Imaging Research Center, College of Medicine, Taipei Medical University (H.-S.L.,C.-Y.C.); Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University (Y.-C.C.), Taipei, Taiwan. sandy0928@seed.net.tw.
      PMID:
       
      27597554
       
      DOI:
       
      10.1212/WNL.0000000000003066
      [Indexed for MEDLINE]
    • Growth and nutrition in children with ataxia telangiectasia.
      Zugriffe: 189
      • ataxia telangiectasia
      • 2018
      • United Kingdom
      • Nutritional
      • Suri M
      • immunodeficiency
      • Arch Dis Child
      • Pasalodos S
      • Bush A
      • Bhatt JM
      • Growth
      • Stewart E
      • Prayle AP
      • Tooke A
      • Respiratory infections
      Arch Dis Child. 2016 Dec;101(12):1137-1141. doi: 10.1136/archdischild-2015-310373. Epub 2016 Aug 29.
      Stewart E1, Prayle AP2, Tooke A1, Pasalodos S3, Suri M3, Bush A4,5,6, Bhatt JM1.

      Author information

      1
      Nottingham Children's Hospital, National Paediatric Ataxia Telangiectasia Clinic, QMC, Nottingham, UK.
      2
      University of Nottingham, School of Clinical Science, Queens Medical Centre, Child Health, Nottingham, UK.
      3
      Nottingham Clinical Genetics Service, National Paediatric Ataxia Telangiectasia Clinic, Clinical Genetics Service, City Hospital Campus, Nottingham, UK.
      4
      Imperial College, London, UK.
      5
      National Heart and Lung Institute, London, UK.
      6
      Royal Brompton & Harefield NHS Foundation Trust, London, UK.

      Abstract

      BACKGROUND:

      Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer. Nutritional failure adversely impacts outcomes in many respiratory diseases. Several factors influence nutrition in children with A-T. We hypothesised that children with A-T have progressive growth failure and that early gastrostomy tube feeding (percutaneous endoscopic gastrostomy, PEG) is a favourable management option with good nutritional outcomes.

      METHODS:

      Data were collected prospectively on weight, height and body mass index (BMI) at the national paediatric A-T clinic. Adequacy and safety of oral intake was assessed. Nutritional advice was given at each multidisciplinary review.

      RESULTS:

      101 children (51 girls) had 222 measurements (32 once, 32 twice, 24 thrice) between 2009 and 2016. Median (IQR) age was 9.3 (6.4 to 13.1) years. Mean (SD) weight, height and BMI Z-scores were respectively -1 (1.6), -1.2 (1.2) and -0.4 (1.4). 35/101 children had weight Z-scores below -2 on at least one occasion. Weight, height and BMI Z-scores declined over time. Decline was most obvious after 8 years of age. 14/101 (14%) children had a PEG, with longitudinal data available for 12. In a nested case control study, there was a trend for improvement in weight in those with a PEG (p=0.10).

      CONCLUSIONS:

      Patients with A-T decline in growth over time. There is an urgent need for new strategies, including an understanding of why growth falters. We suggest early proactive consideration of PEG from age 8 years onwards to prevent progressive growth failure.

      Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

      KEYWORDS:

      Ataxia Telangiectasia; Growth; Immunodeficiency; Nutrition; Respiratory infections

      PMID:
       
      27573920
       
      DOI:
       
      10.1136/archdischild-2015-310373
      [Indexed for MEDLINE] 
      Free full text
    • More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes.
      Zugriffe: 168
      • ataxia telangiectasia
      • choreoathetosis
      • United States of America
      • 2016
      • Pearson TS
      • Tremor Other Hyperkinet Mov (N Y)
      • ataxia with oculomotor apraxia
      • ataxia with vitamin E deficiency
      Tremor Other Hyperkinet Mov (N Y). 2016 Jul 16;6:368. doi: 10.7916/D8H70FSS. eCollection 2016.
      Pearson TS1.

      Author information

      1
      Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

      Abstract

      BACKGROUND:

      The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized.

      METHODS:

      A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus).

      RESULTS:

      Involuntary movements occur in the majority of patients with ataxia-telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia-telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia).

      DISCUSSION:

      An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment.

      KEYWORDS:

      Choreoathetosis; ataxia with oculomotor apraxia; ataxia with vitamin E deficiency

      PMID:
       
      27536460
       
      PMCID:
       
      PMC4950223
       
      DOI:
       
      10.7916/D8H70FSS
      Free PMC Article
    • Ataxia telangiectasia: a syndrome deserving attention and study.
      Zugriffe: 189
      • 2016
      • Australia
      • Dev Med Child Neurol
      Dev Med Child Neurol. 2016 Oct;58(10):999-1000. doi: 10.1111/dmcn.13178. Epub 2016 Jun 6.
      Capra S1.

      Author information

      1
      School of Human Movement and Nutrition Sciences, University of Queensland, St Lucia, Qld, Australia.

      Comment on

      • Assessment of impaired coordination between respiration and deglutition in children and young adults with ataxia telangiectasia. [Dev Med Child Neurol. 2016]
      PMID:
       
      27265211
       
      DOI:
       
      10.1111/dmcn.13178
      [Indexed for MEDLINE] 
      Free full text
    • Treatment of acute leukemia in children with ataxia telangiectasia (A-T).
      Zugriffe: 196
      • ataxia telangiectasia
      • The Netherlands
      • Poland
      • France
      • Eur J Med Genet
      • cancer
      • Schoenaker MH
      • Suarez F
      • Szczepanski T
      • Mahlaoui N
      • Loeffen JL
      • Children
      • Leukemia
      • Malignancy
      Eur J Med Genet. 2016 Dec;59(12):641-646. doi: 10.1016/j.ejmg.2016.05.012. Epub 2016 May 27.
      Schoenaker MH1, Suarez F2, Szczepanski T3, Mahlaoui N4, Loeffen JL5.

      Author information

      1
      Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.
      2
      Department of Hematology and French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implication, INSERM UMR 1163 & CNRS ERL 8254, France; Institut Imagine, Sorbonne Paris Cité, Paris Descartes University, France.
      3
      Department of Pediatric Hematology and Oncology, Zabrze, Medical University of Silesia, Katowice, Poland.
      4
      Pediatric Immuno-Haematology and Rheumatology Unit and French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
      5
      Department of Pediatric Oncology and Hematology, Sophia Children's Hospital, Erasmus MC, Postbox 2040, 3000CA Rotterdam, Netherlands. Electronic address: j.loeffen@erasmusmc.nl.

      Abstract

      Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy.

      KEYWORDS:

      Ataxia telangiectasia; Cancer; Children; Leukemia; Malignancy

      PMID:
       
      27238889
       
      DOI:
       
      10.1016/j.ejmg.2016.05.012
      [Indexed for MEDLINE]
    • Assessment of impaired coordination between respiration and deglutition in children and young adults with ataxia telangiectasia.
      Zugriffe: 201
      • United States of America
      • 2016
      • Lederman HM
      • Dev Med Child Neurol
      • Lefton-Greif MA
      • Perlman AL
      • He X
      • Crawford TO
      • deglutition
      • respiration
      Dev Med Child Neurol. 2016 Oct;58(10):1069-75. doi: 10.1111/dmcn.13156. Epub 2016 May 23.

      Lefton-Greif MA1,2,3, Perlman AL4, He X5, Lederman HM1,3,6, Crawford TO1,3,7.

      Author information

      1
      Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
      2
      The Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
      3
      The Ataxia-Telangiectasia Clinical Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
      4
      University of Illinois at Urbana-Champaign, Champaign, IL, USA.
      5
      Department of Statistics, University of Michigan, Ann Arbor, MI, USA.
      6
      The Eudowood Division of Pediatric Allergy and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
      7
      Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

      Abstract

      AIM:

      This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing.

      METHOD:

      Twenty participants (11 males, 9 females; range 9-21y) with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA).

      RESULTS:

      Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger p<0.015 and older p<0.001). The frequency of an expiratory pattern of peri-deglutitive airflow increased with age in participants in the comparison group (p=0.006), but not in those with ataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (p<0.001) but was unchanged in participants with ataxia telangiectasia (p=0.164).

      INTERPRETATION:

      Non-invasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory-swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae.

      © 2016 Mac Keith Press.

      Comment in

      • Ataxia telangiectasia: a syndrome deserving attention and study. [Dev Med Child Neurol. 2016]
      PMID:
       
      27214374
       
      PMCID:
       
      PMC5010999
       
      DOI:
       
      10.1111/dmcn.13156
      [Indexed for MEDLINE] 
      Free PMC Article
    • Ataxia-telangiectasia (A-T): An emerging dimension of premature ageing.
      Zugriffe: 186
      • ataxia telangiectasia
      • Israel
      • United States of America
      • ATM
      • Lederman HM
      • DNA damage response
      • Ageing Res Rev
      • Shiloh Y
      • Protein kinase
      Ageing Res Rev. 2017 Jan;33:76-88. doi: 10.1016/j.arr.2016.05.002. Epub 2016 May 12.
      Shiloh Y1, Lederman HM2.

      Author information

      1
      The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yossih@post.tau.ac.il.
      2
      Division of Pediatric Allergy and Immunology, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD 21287, USA.

      Abstract

      A-T is a prototype genome instability syndrome and a multifaceted disease. A-T leads to neurodegeneration - primarily cerebellar atrophy, immunodeficiency, oculocutaneous telangiectasia (dilated blood vessels), vestigial thymus and gonads, endocrine abnormalities, cancer predisposition and varying sensitivity to DNA damaging agents, particularly those that induce DNA double-strand breaks. With the recent increase in life expectancy of A-T patients, the premature ageing component of this disease is gaining greater awareness. The complex A-T phenotype reflects the ever growing number of functions assigned to the protein encoded by the responsible gene - the homeostatic protein kinase, ATM. The quest to thoroughly understand the complex A-T phenotype may reveal yet elusive ATM functions.

      KEYWORDS:

      ATM; Ageing; Ataxia-telangiectasia; DNA damage response; Protein kinase

      PMID:
       
      27181190
       
      DOI:
       
      10.1016/j.arr.2016.05.002
      [Indexed for MEDLINE]
       
    • Allogeneic-matched sibling stem cell transplantation in a 13-year-old boy with ataxia telangiectasia and EBV-positive non-Hodgkin lymphoma.
      Zugriffe: 214
      • Germany
      • 2016
      • case
      • Bone Marrow Transplant
      • Beier R
      • Sykora KW
      • Woessmann W
      • Maecker-Kolhoff B
      • Sauer M
      • Kreipe HH
      • Dörk-Bousset T
      • Kratz C
      • Lauten M
      • non-Hodgkin lymphoma
      Bone Marrow Transplant. 2016 Sep;51(9):1271-4. doi: 10.1038/bmt.2016.93. Epub 2016 May 9.
      Beier R1, Sykora KW1, Woessmann W2, Maecker-Kolhoff B1, Sauer M1, Kreipe HH3, Dörk-Bousset T4, Kratz C1, Lauten M5.

      Author information

      1
      Hannover Medical School, Pediatric Hematology and Oncology, Hannover, Germany.
      2
      Justus Liebig University, Pediatric Hematology and Oncology, Giessen, Germany.
      3
      Hannover Medical School, Institute of Pathology, Hannover, Germany.
      4
      Hannover Medical School, University Women's Hospital, Hannover, Germany.
      5
      University of Lübeck, University Hospital Schleswig-Holstein, Department of Pediatrics, Hannover, Germany.
      PMID:
       
      27159176
       
      DOI:
       
      10.1038/bmt.2016.93
      [Indexed for MEDLINE]

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