• admin@ataxiatelangiectasia.es
Ataxia Telangiectasia
  • Inicio
  • ¿Qué es?
  • Bibliografía
  • Enlaces
  • Noticias

    Bibliography

    • NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated.
      Visto: 161
      • Canada
      • Germany
      • J Biol Chem
      • 2019
      • ATM structure
      • Abd Rahim MS
      • Cherniavskyi YK
      • Tieleman DP
      • Dames SA
      J Biol Chem. 2019 Mar 13. pii: jbc.RA119.007653. doi: 10.1074/jbc.RA119.007653. [Epub ahead of print]

      NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated.

      Abd Rahim MS1, Cherniavskyi YK2, Tieleman DP3, Dames SA4.

      Author information

      1
      Technische Universität München, Germany.
      2
      University of Calgary, Canada.
      3
      Biological Sciences, University of Calgary, Canada.
      4
      Department of Chemistry, Biomolecular NMR spectroscopy, Technische Universität München, Germany.

      Abstract

      The Ser/Thr protein kinase ataxia telangiectasia mutated (ATM) plays an important role in the DNA damage response, signaling in response to redox signals, the control of metabolic processes, and mitochondrial homeostasis. ATM localizes to the nucleus and at the plasma membrane, mitochondria, peroxisomes, and other cytoplasmic vesicular structures. It has been shown that the C-terminal FATC domain of human ATM (hATMfatc) can interact with a range of membrane mimetics and may thereby act as a membrane-anchoring unit. Here, NMR structural and 15N-relaxation data, NMR data using spin-labeled micelles, and MD simulations of micelle-associated hATMfatc revealed that it binds the micelle by a dynamic assembly of three helices with many residues of hATMfatc located in the head-group region. We observed that none of the three helices penetrates the micelle deeply or makes significant tertiary contacts to the other helices. NMR-monitored interaction experiments with hATMfatc variants in which two conserved aromatic residues (Phe-93 and Trp-96) were either individually or both replaced by alanine disclosed that the double substitution does not abrogate the interaction with micelles and bicelles at the high concentrations these aggregates are typically used, but impairs interactions with small unilamellar vesicles (SUVs), usually used at much lower lipid concentrations and considered a better mimetic for natural membranes. We conclude that the observed dynamic structure of micelle-associated hATMfatc may enable it to interact with differently composed membranes or membrane-associated interaction partners and thereby regulate ATM's kinase activity. Moreover, the FATC domain of ATM maybe function as membrane-anchoring unit for other biomolecules.

      Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

      KEYWORDS:

      ataxia telangiectasia mutated; membrane; molecular dynamics; nuclear magnetic resonance (NMR); protein kinase; signal transduction

      PMID:
       
      30867195
       
      DOI:
       
      10.1074/jbc.RA119.007653
    • Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation.
      Visto: 823
      • ATM
      • 2019
      • Sci Rep
      • mitochondrial
      • South Africa
      Sci Rep. 2019 Mar 18;9(1):4782. doi: 10.1038/s41598-019-41108-1.

      Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation.

      Blignaut M1, Loos B2, Botchway SW3,4, Parker AW3,5, Huisamen B6,7.

      Author information

      1
      Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa. 13813412@sun.ac.za.
      2
      Department of Physiological Sciences, Faculty of Sciences, Stellenbosch University, Stellenbosch, 7602, South Africa.
      3
      Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory, Harwell Campus, Didcot, OX11 0QX, UK.
      4
      Oxford Brookes University, Department of Biological and Medical Sciences, Oxford, OX3 0BP, UK.
      5
      Department of Physics, Faculty of Science, Stellenbosch University, Private Bag X1, Matieland, 7602, South Africa.
      6
      Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
      7
      Biomedical, Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa.

      Abstract

      The absence of Ataxia-Telangiectasia mutated protein kinase (ATM) is associated with neurological, metabolic and cardiovascular defects. The protein has been associated with mitochondria and its absence results in mitochondrial dysfunction. Furthermore, it can be activated in the cytosol by mitochondrial oxidative stress and mediates a cellular anti-oxidant response through the pentose phosphate pathway (PPP). However, the precise location and function of ATM within mitochondria and its role in oxidative phosphorylation is still unknown. We show that ATM is found endogenously within cardiac myocyte mitochondria under normoxic conditions and is consistently associated with the inner mitochondrial membrane. Acute ex vivo inhibition of ATM protein kinase significantly decreased mitochondrial electron transfer chain complex I-mediated oxidative phosphorylation rate but did not decrease coupling efficiency or oxygen consumption rate during β-oxidation. Chemical inhibition of ATM in rat cardiomyoblast cells (H9c2) significantly decreased the excited-state autofluorescence lifetime of enzyme-bound reduced NADH and its phosphorylated form, NADPH (NAD(P)H; 2.77 ± 0.26 ns compared to 2.57 ± 0.14 ns in KU60019-treated cells). This suggests an interaction between ATM and the electron transfer chain in the mitochondria, and hence may have an important role in oxidative phosphorylation in terminally differentiated cells such as cardiomyocytes.

      PMID:
       
      30886180
       
      DOI:
       
      10.1038/s41598-019-41108-1
    • Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation.
      Visto: 165
      • Spain
      • case
      • ATM mutations
      • Ann Hum Genet
      • 2019
      • Martin-Rodriguez S
      • Bernardo-Gonzalez I
      Ann Hum Genet. 2019 Mar 19. doi: 10.1111/ahg.12312. [Epub ahead of print]

      Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation.

      Martin-Rodriguez S1, Calvo-Ferrer A1, Ortega-Unanue N1, Samaniego-Jimenez L1, Sanz-Izquierdo MP1, Bernardo-Gonzalez I1.

      Author information

      1
      Department of Biomedical Diagnostics, Hospital San Pedro, Logroño, Spain.

      Abstract

      Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition. Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair. Atypical presentations can be found in A-T-like disease or in Nijmegen breakage syndrome, caused by deficiency of mre11 or nibrin proteins, respectively. In this report, we present the genetic characterization of a 4-year-old female with clinical diagnosis of A-T. Next-generation sequencing (NGS) revealed two novel heterozygous mutations in the ATM gene: a single-nucleotide variant (SNV) at exon 47 (NM_000051.3:c.6899G > C; p.Trp2300Ser) and ∼90 kb genomic duplication spanning exons 17-61, NG_009830.1:g.(41245_49339)_(137044_147250)dup. These findings were validated by Sanger sequencing and MLPA (multiplex ligation-dependent probe amplification) analysis respectively. Familial segregation study confirmed that the two variants are inherited, and the infant is a compound heterozygote. Thus, our study expands the spectrum of ATM pathogenic variants and demonstrates the utility of targeted NGS in the detection of copy number variation.

      © 2019 John Wiley & Sons Ltd/University College London.

      KEYWORDS:

      ataxia-telangiectasia; copy number variation; duplication; next-generation sequencing; novel pathogenic variant

      PMID:
       
      30888062
       
      DOI:
       
      10.1111/ahg.12312
    • Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy.
      Visto: 604
      • China
      • ATM
      • Autophagy
      • 2019
      • Cell Biochem Funct
      • Liang N
      • He Q
      • Sun H
      • lipophagy
      • pexophagy
      • selective autophagy
      Cell Biochem Funct. 2019 Mar 8. doi: 10.1002/cbf.3385. [Epub ahead of print]

      Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy.

      Liang N1, He Q1, Liu X2, Sun H1.

      Author information

      1
      Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Jilin Provincial Precision Medicine Laboratory of Molecular Biology and Translational Medicine on Differentiated Thyroid Carcinoma, Changchun City, Jilin Province, China.
      2
      School of Public Health and Management, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China.

      Abstract

      The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its critical nuclear roles in the DNA damage response (DDR), cell cycle checkpoints, and the maintenance of gene stability. In this review, we highlight the multifaceted cytoplasmic functions of ATM in autophagy. We focused on the functions of ATM in nonselective autophagy in cancer. An Oncomine database analysis showed a tight association between ATM and autophagy in various cancers. In particular, its mechanisms in nonselective autophagy, those induced by ionizing radiation (IR), are illustrated in detail and involve the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. Recently, an increasing number of studies revealed that autophagy could also be highly selective. We additionally emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. The regulation of these processes mainly involves ATM-PEX5, ATM-AMPK-TSC2-mTORC1-ULK1, PPM1D-ATM-MTOR, PINK I/Parkin, and NAD+/SIRT1. We aimed to provide new perspectives on the importance of ATM in the diverse field of autophagy. The intricate regulation of ATM in autophagy still requires further investigation, which would enhance our understanding of its role in cell dynamics and homeostasis. SIGNIFICANCE OF THE STUDY: Our review highlighted the multifaceted cytoplasmic functions of ATM on autophagy. First, we focused on the functions of ATM in nonselective autophagy within cancer especially those induced by IR, involving the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. These provided a theoretical understanding of tumour radiosensitivity and chemosensitivity. In addition, we emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. This review provides new perspectives on the importance of ATM in the diverse field of autophagy, which would provide more information on its role in whole cell dynamics and homeostasis.

      © 2019 John Wiley & Sons, Ltd.

      KEYWORDS:

      ATM; autophagy; lipophagy; mitophagy; pexophagy; selective autophagy

      PMID:
       
      30847960
       
      DOI:
       
      10.1002/cbf.3385
    • Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model.
      Visto: 136
      • Japan
      • J Hum Genet
      • Awaya T
      • 2019
      • Seckel syndrome
      • Ichisima J
      • Suzuki NM
      • Samata B
      • Takahashi J
      • Hagiwara M
      • Nakahata T
      • Saito MK
      J Hum Genet. 2019 Mar 8. doi: 10.1038/s10038-019-0574-8. [Epub ahead of print]

      Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model.

      Ichisima J1, Suzuki NM1, Samata B1, Awaya T2, Takahashi J1, Hagiwara M2, Nakahata T1,3, Saito MK4.

      Author information

      1
      Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
      2
      Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
      3
      Department of Fundamental Cell Technology, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
      4
      Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan. msaito@cira.kyoto-u.ac.jp.

      Abstract

      Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasiaand Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect. This mutation is considered the cause of an impaired response to DNA replication stress, the main function of ATR, contributing to the pathogenesis of microcephaly. However, the precise behavior and impact of this splicing defect in human neural progenitor cells (NPCs) is unclear. To address this, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone. SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs with negative enrichment of neuronal genesis-related gene sets. In SS-NPCs, abnormal mitotic spindles occurred more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that TG003, a CLK1 inhibitor, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Treatment with TG003 restored the ATR kinase activity in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model revealed a novel effect of the ATR mutation in mitotic processes of NPCs and NPC-specific missplicing, accompanied by the recovery of neuronal defects using a splicing rectifier.

      PMID:
       
      30846821
       
      DOI:
       
      10.1038/s10038-019-0574-8
    • Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.
      Visto: 158
      • France
      • 2019
      • J Eur Acad Dermatol Venereol
      • Leclerc-Mercier S
      • Bodemer C
      J Eur Acad Dermatol Venereol. 2019 Mar 14. doi: 10.1111/jdv.15568. [Epub ahead of print]

      Leclerc-Mercier S1,2,3, Moshous D4,5, Neven B4,5, Mahlaoui N4,6, Martin L7, Pellier I8, Blanche S4,5,6, Picard C4,5,6,9, Fischer A4,5,6,10, Perot P11, Eloit M11,12, Fraitag S1,2, Bodemer C2,3,5.

      Author information

      1
      Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
      2
      National Reference Centre for Genodermatosis and Rare Diseases of the Skin (MAGEC), Necker-Enfants Malades Hospital, APHP, Paris, France.
      3
      Department of Dermatology, Necker-Enfants Malades Hospital, APHP, Paris, France.
      4
      Department of Immunohematology, Necker-Enfants Malades Hospital, APHP, Paris, France.
      5
      Imagine Institute, Inserm U 1163, Descartes University, Paris Sorbonne Cité, France.
      6
      National Reference Centre for Primary Immune Deficiency (CEREDIH), Necker-Enfants Malades Hospital, APHP, Paris, France.
      7
      Department of Dermatology, UNAM University, Angers University Hospital, Angers, France.
      8
      Departments of Pediatric Hematology, UNAM University, Angers University Hospital, Angers, France.
      9
      Study center of primary immunodeficiency, Necker-Enfants Malades Hospital, APHP, Paris, France.
      10
      Collège de France, Paris, France.
      11
      Institut Pasteur, Biology of Infection Unit, Inserm U1117 Laboratory of Pathogen Discovery, 28 rue du Docteur Roux, F-75724, Paris, France.
      12
      Ecole Nationale Vétérinaire d'Alfort Virologie, 7 avenue Général de Gaulle, F-94704, Maisons Alfort, France.

      Abstract

      BACKGROUND:

      Pediatric cutaneous granulomas with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 pediatric cases and review the literature.

      OBJECTIVES:

      To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in pediatric PID.

      METHODS:

      We collected data on 17 patients with cutaneous granulomas and PID registered with us, and also reviewed 33 cases from the literature.

      RESULTS:

      Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%), and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus.

      CONCLUSION:

      Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histologic subtypes in a single patient is suggestive of a PID. This article is protected by copyright. All rights reserved.

      This article is protected by copyright. All rights reserved.

      KEYWORDS:

      cutaneous granuloma; pediatric dermatology; primary immunodeficiency

      PMID:
       
      30869812
       
      DOI:
       
      10.1111/jdv.15568
    • ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells.
      Visto: 163
      • Japan
      • ATM expression
      • 2019
      • Mol Hum Reprod
      • Hirakawa T
      • Narahara H
      • hypermethylation
      • DNA demethylating agent
      • DNA methylation
      • cell cycle arrest
      • endometriosis
      Mol Hum Reprod. 2019 Mar 14. pii: gaz016. doi: 10.1093/molehr/gaz016. [Epub ahead of print]

      ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells.

      Hirakawa T1, Nasu K1,2, Aoyagi Y1, Takebayashi K1, Zhu R1, Narahara H1.

      Author information

      1
      Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
      2
      Division of Obstetrics and Gynecology, Support System for Community Medicine, Faculty of Medicine, Oita University, Oita 879-5593, Japan.

      Abstract

      A number of genes involved in the pathogenesis of endometriosis are silenced by the hypermethylation of their promoter regions. We assessed the effect and mechanism of the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) (10 μM) on the cell cycle in human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) by flow cytometry. The DNA methylation status of G2/M checkpoint regulators were investigated by methylation-specific polymerase chain reaction (PCR). The expression of ATM and the effect of 5-aza-dC on its expression were also evaluated by quantitative reverse transcription-PCR and western blotting analysis. 5-aza-dC treatment resulted in the cell cycle arrest of ECSCs at the G2/M phase. In contrast, 5-aza-dC did not affect the cell cycle of NESCs. The promoter region of the ataxia telangiectasia mutated (ATM) gene was hypermethylated in ECSCs, but not in NESCs. ATM mRNA expression was attenuated in ECSCs compared to that in NESCs. Further, 5-aza-dC was found to restore ATM expression of in ECSCs by its promoter demethylation. Our findings indicate that ATM promoter hypermethylation occurs in endometriosis, and that ATM silencing is involved in tumorigenesis during this disease; moreover, selective DNA demethylating agents and molecular target drugs against ATM silencing are promising for the treatment of endometriosis.

      © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

      KEYWORDS:

      DNA demethylating agent; DNA methylation; ataxia telangiectasia mutated (ATM); cell cycle arrest; endometriosis

      PMID:
       
      30869775
       
      DOI:
       
      10.1093/molehr/gaz016
    • Dermatofibrosarcoma protuberans in a pediatric patient with ataxia telangiectasia syndrome.
      Visto: 185
      • United States of America
      • case
      • Pediatr Dermatol
      • 2019
      • dermatofibrosarcoma protuberans
      • Duffy R
      • Liagat M
      • Lawrence N
      • Manders S
      Pediatr Dermatol. 2019 Mar 10. doi: 10.1111/pde.13779. [Epub ahead of print]

      Dermatofibrosarcoma protuberans in a pediatric patient with ataxia telangiectasia syndrome.

      Duffy R1, Liaqat M2, Lawrence N2, Manders S1.

      Author information

      1
      Cooper Medical School of Rowan University, Camden, NJ.
      2
      Division of Dermatology, Cooper University Hospital, Camden, NJ.

      Abstract

      Ataxia telangiectasia (AT) is a rare autosomal recessive neurodegenerative disorder caused by a mutation in the ATM gene. An impaired immune response due to the gene mutation leads to an increased risk of infection and malignancy. We present a rare case of dermatofibrosarcoma protuberans arising in a patient with AT.

      © 2019 Wiley Periodicals, Inc.

      KEYWORDS:

      ataxia telangiectasia syndrome; dermatofibrosarcoma protuberans

      PMID:
       
      30854690
       
      DOI:
       
      10.1111/pde.13779
    • Bladder Artery Embolization for Massive Hematuria Treatment in a Patient With Ataxia-Telangiectasia Acute Lymphoblastic Leukemia.
      Visto: 162
      • Turkey
      • J Pediatr Hematol Oncol
      • 2019
      • Bahadir A
      • Kaya G
      J Pediatr Hematol Oncol. 2019 Mar 29. doi: 10.1097/MPH.0000000000001471. [Epub ahead of print]

      Bahadir A1, Oguz Ş2, Erduran E1, Dinç H2, Yalçin Cömert HS3, Bahat Özdogan E4, Kaya G5.

      Author information

      1
      Division of Pediatric Hematology-Oncology.
      2
      Division of Radiology.
      3
      Division of Pediatric Surgery.
      4
      Division of Pediatric Nephrology.
      5
      Division of Pediatric Intensive Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.

      Abstract

      Ataxia-telangiectasia (AT) is a hereditary recessive autosomal disorder following a course of progressive cerebellar ataxia, and oculocutaneous telangiectasia. Disease-specific telangiectasias are generally localized in the oculocutaneous region, while telangiectasias located within the bladder are rarely seen in patients with AT. The patient who had been followed-up with a diagnosis of AT since the age of 3 years was later diagnosed with acute lymphoblastic leukemia at the age of 8 years. The patient developed hematuria approximately in the 29th month of treatment. The cystoscopy revealed regions of extensive hemorrhagic telangiectasis, which was interpreted as the bladder involvement of AT. The case presented here underwent several cycles of intravesical steroid and tranexamic acid treatments and intravesical cauterization procedures, but the patient was unresponsive to all medical treatment approaches. The patient was consequently evaluated by an interventional radiology unit for a selective arterial embolization. The patient's hematuria resolved after embolization. Bladder wall telangiectasia may, on rare occasions, develop in patients with AT, and can result in life-threatening hemorrhages. We also suggest that a selective arterial embolectomy can be safely carried out in pediatric patients with treatment-resistant intravesical bleeding.

      PMID:
       
      30933018
       
      DOI:
       
      10.1097/MPH.0000000000001471
    • Functional classification of ATM variants in Ataxia-Telangiectasia patients.
      Visto: 139
      • Germany
      • France
      • Phenotype
      • ATM mutations
      • Splice site
      • Fievet A
      • Stern MH
      • Hum Mutat
      • 2019
      Hum Mutat. 2019 May 3. doi: 10.1002/humu.23778. [Epub ahead of print]

      Functional classification of ATM variants in Ataxia-Telangiectasia patients.

      Fievet A1,2, Bellanger D1, Rieunier G1, Dubois d'Enghien C2, Sophie J3, Calvas P3, Carriere JP4, Anheim M5, Castrioto A6, Flabeau O7, Degos B8, Ewenczyk C9, Mahlaoui N10, Touzot F10, Suarez F11, Hully M12, Roubertie A13, Aladjidi N14, Tison F15, Antoine-Poirel H16, Dahan K16, Doummar D17, Nougues MC18, Ioos C19, Rougeot C20, Masurel A21, Bourjault C22, Ginglinger E23, Prieur F24, Siri A25, Bordigoni P26, Nguyen K27, Philippe N28, Bellesme C29, Demeocq F30, Altuzarra C31, Mathieu-Dramard M32, Couderc F33, Dörk T34, Auger N35, Parfait B36, Abidallah K2, Moncoutier V2, Collet A2, Stoppa-Lyonnet D1,2,37, Stern MH1,2.

      Author information

      1
      Institut Curie, PSL Research University, INSERM U830, Paris, France.
      2
      Institut Curie, Hôpital, Service de Génétique, Paris, France.
      3
      CHU de Toulouse, Service de Génétique Médicale, Toulouse, France.
      4
      Hopital des enfants de Toulouse, Unité de Neuropédiatrie, Toulouse, France.
      5
      CHU de Strasbourg, Service de neurologie, Strasbourg, France.
      6
      CHU de Grenoble, Pole de psychiatrie et de neurologie, Grenoble, France.
      7
      CH de la côte Basque, Service de neurologie, Bayonne, France.
      8
      Hôpitaux universitaires Pitié Salpêtrière - Charles Foix, Département des maladies du système nerveux, Paris, France.
      9
      Hôpitaux universitaires Pitié Salpêtrière - Charles Foix, Service de génétique, Paris, France.
      10
      Hôpital Necker Enfants Malades, Service d'Immunologie, d'Hématologie et de Rhumatologie Pédiatriques, Paris, France.
      11
      Hôpital Necker Enfants Malades, Service d'Hématologie Adulte, Paris, France.
      12
      Hôpital Necker Enfants Malades, Service de Neurologie Pédiatrique, Paris, France.
      13
      CHU de Montpellier, Service de Neuropédiatrie, Montpellier, France.
      14
      CHU de Bordeaux, Service de Pédiatrie, Bordeaux, France.
      15
      CHU de Bordeaux, Département de Neurologie, Bordeaux, France.
      16
      Cliniques universitaires Saint-Luc & Université Catholique de Louvain, Centre de Génétique Humaine, Brussels, Belgium.
      17
      Hopital Armand Trousseau, Service de Neurologie Pédiatrique, Paris, France.
      18
      CH intercommunal de Créteil, Service de Pédiatrie, Créteil, France.
      19
      Hôpital Raymond Poincaré, Pôle de Pédiatrie, Garches, France.
      20
      Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France.
      21
      Hopital d'Enfants de Dijon, Service de Génétique, Dijon, France.
      22
      CH de Bretagne sud, Site du Scorff, Service de Pédiatrie, Lorient, France.
      23
      CH de Mulhouse, Service de Génétique, Mulhouse, France.
      24
      CHU de St Etienne, Hôpital Nord, Service de Génétique Médicale, Saint Etienne, France.
      25
      CHU de Nancy, Service de Neurologie, Nancy, France.
      26
      CHU Nancy, Hôpitaux de Brabois, Service de Pédiatrie II, Vandoeuvre, France.
      27
      Hopital de la Timone, Département de Génétique Médicale, Marseille, France.
      28
      Hopital Debrousse, Service d'Hématologie Pédiatrique, Lyon, France.
      29
      GH Cochin-saint-Vincent de Paul, Service d'Endocrinologie et de Neurologie Pédiatrique, Paris, France.
      30
      CHU de Clermont-Ferrand, Hôtel Dieu, Service de Pédiatrie B, Clermont-Ferrand, France.
      31
      CHU Besançon, Service de Pédiatrie, Besançon, France.
      32
      Hopital d'Amiens-Nord, Unité de Génétique Clinique Pédiatrique, Amiens, France.
      33
      CH d'Aix en Provence - du Pays d'Aix, Service de Pédiatrie, Aix en Provence, France.
      34
      Hannover Medical School, Gynecology Research Unit, Hannover, Germany.
      35
      Gustave Roussy, Service Génétique des Tumeurs, Villejuif, France.
      36
      Centre de ressources Biologiques, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
      37
      University Paris Descartes, Sorbonne Paris Cité.

      Abstract

      Ataxia-Telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ATM. This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines (LCL) from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score (ATLAS) to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification. This article is protected by copyright. All rights reserved.

      This article is protected by copyright. All rights reserved.

      KEYWORDS:

      ATM; Ataxia-Telangiectasia; checkpoint; mutation; phenotype; splice

      PMID:
       
      31050087
       
      DOI:
       
      10.1002/humu.23778
    • Three new cases of Ataxia-Telangiectasia-Like Disorder: no impairment of the ATM pathway, but S-phase checkpoint defect.
      Visto: 185
      • France
      • ATM
      • Ataxia-Telangiectasia-Like Disorder
      • MRE11A gene
      • Fievet A
      • Stern MH
      • Hum Mutat
      • 2019
      Hum Mutat. 2019 Apr 29. doi: 10.1002/humu.23773. [Epub ahead of print]

      Three new cases of Ataxia-Telangiectasia-Like Disorder: no impairment of the ATM pathway, but S-phase checkpoint defect.

      Fiévet A1,2,3, Bellanger D1,2, Valence S4,5,6,7, Mobuchon L1,2, Afenjar A8, Giuliano F9, Dubois d'Enghien C3, Parfait B10, Pedespan JM11, Auger N12, Rieunier G1,2, Collet A3, Burglen L5,6,7,13, Stoppa-Lyonnet D2,3,14, Stern MH1,2,3.

      Author information

      1
      Institut Curie, PSL Research University, Paris, France.
      2
      INSERM U830, D.R.U.M. team, Paris, France.
      3
      Institut Curie, Hôpital, Service de Génétique, Paris, France.
      4
      APHP, GHUEP, Hôpital Armand Trousseau, Service de Neurologie Pédiatrique, Paris, France.
      5
      Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", Paris-Lyon-Lille, France.
      6
      Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, APHP, Hôpital Armand Trousseau, Paris, France.
      7
      INSERM U1141, Université Paris Diderot, Paris, France.
      8
      Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", APHP, Hôpital Armand Trousseau, Paris, France.
      9
      Service de génétique médicale, CHU de Nice, Hôpital l'Archet 2, Nice, France.
      10
      Centre de ressources Biologiques, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
      11
      Unité de Neuropédiatrie, CHU Pellegrin, Bordeaux, France.
      12
      Department of Biopathology, Gustave Roussy, Villejuif, France.
      13
      Département de Génétique Médicale, APHP, GHUEP, Hôpital Armand Trousseau, Paris, France.
      14
      Faculté de médecine, Université Paris-Descartes, Paris, France.

      Abstract

      Ataxia-Telangiectasia-Like Disorder (ATLD) is a rare genomic instability syndrome caused by bi-allelic variants of MRE11 characterized by progressive cerebellar ataxia and typical karyotype abnormalities. These symptoms are common to those of Ataxia-Telangiectasia, which is consistent with the key role of MRE11 in ATM activation after DNA double-strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported bi-allelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these ATLD patients. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S-phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants. This article is protected by copyright. All rights reserved.

      This article is protected by copyright. All rights reserved.

      KEYWORDS:

      ATLD; ATM; MRE11; MRN; ataxia; checkpoint

      PMID:
       
      31033087
       
      DOI:
       
      10.1002/humu.23773
    • Anti-peptide Antibody Responses in Patients with Ataxia-telangiectasia
      Visto: 117
      • primary immunodeficiency
      • Iran
      • 2019
      • Immunology and Genetics Journal
      • Jamee M
      • Sharifi L

      Anti-peptide Antibody Responses in Patients with Ataxia-telangiectasia

      Mahnaz Jamee1, 2, Laleh Sharifi3 , Saleh Ghiasy

      Corresponding author: Saleh Ghiasy E-mail: saleh.ghiasy@yahoo.com 1. Student Research Committee, Alborz University of Medical Sciences, Alborz, Iran 2. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran 3. Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran 4. Cancer Research Center, Sha

      Article 3, Volume 2, Issue 1, Winter 2019, Page 28-36 XML PDF (808.47 K) Document Type: Original Article DOI: 10.22034/IGJ.2019.85745 Abstract Background/Objectives: Ataxia-telangiectasia (AT) is a rare inherited disorder caused by mutations in the ATM (Ataxia Telangiectasia Mutated) gene. Antibody response to diphtheria and tetanus toxoid vaccines may reveal indirect information about both cellular and humoral arms of the immune system in these patients. This study, therefore, set out to assess the specific antibody responses against tetanus and diphtheria vaccination among AT patients. Methods: Thirty-eight AT patients were entered the study and an appropriate questionnaire was completed for all of them. Laboratory findings including alpha fetoprotein, lymphocyte subsets, serum immunoglobulin levels of IgG, IgG subsets, IgA, IgM, IgE and antibody response against diphtheria and tetanus toxoids were measured. Results: Thirty-eight A-T patients were enrolled in this study. Based on the anti-tetanus and anti-diphtheria antibody production, 24 and 14 patients were categorized in responder (R) and non-responder (NR) groups, respectively. Respiratory tract infection was the most common infectious complication reported more frequently in the R comparing to NR group. Within the non-infectious manifestations, after cerebellar ataxia, ocular telangiectasia (52.6%) and FTT (26.3%) were the most frequent. 34.8% of individuals in R group but none of the NR patients had normal serum immunoglobulin profile (P=0.015). Contrarily, HIGM phenotype was found more frequent in NR group comparing to R group (50% vs. 17.4%, p= 0.063). Conclusions: In accordance with the previous studies, we observed sufficient antibody response to diphtheria and tetanus vaccines in most of the AT patients. Keywords Ataxia telangiectasia; immune deficiency; specific antibody response; anti-peptide antibody; polypeptide vaccine; humoral immune defect

      Doi: 10.22034/igj.2019.166485.1008

    • Diagnostic Value of Next Generation Sequencing Ataxia Panel as a Part of Multistep Investigation Approach in Sporadic and Autosomal Recessive Cerebellar Ataxias in Russia (P1.8-013)
      Visto: 347
      • Russia
      • Next-generation sequencing
      • Neurology
      • 2019
      • Seliverstov Y
      April 09, 2019; 92 (15 Supplement) MAY 5, 2019
       
      Yury Seliverstov, Evgenii Nuzhnyi, Sergey Klyushnikov, Natalia Abramycheva, Anna Vetchinova, Sergei Illarioshkin
      First published April 9, 2019,
       
       CITATION

      Objective: To investigate the spectrum of sporadic and autosomal recessive cerebellar ataxias (SARCAs) in patients under 50 years of age in the Russian population using a multistep diagnostic approach with a next generation sequencing ataxia panel (NGSAP).

      Background: Due to a high variability in clinical presentation, SARCAs often represent a diagnostic challenge for a clinician.

      Design/Methods: During the period of September 2016–July 2018, we analyzed 52 patients under 50 years of age who were referred to our centre with SARCAs. First step implied thorough exclusion (including brain MRI) of acquired cerebellar ataxia and multiple system atrophy (MSA). Second step included tests for SCA types 1, 2, 3, 6, 8, and 17 along with Friedreich’s ataxia (FA). At the third step, certain laboratory tests along with biochemical screening for NP-C, Gaucher’s disease, and GM2-gangliosidoses were done. Third step also included ophthalmic exam, electromyography, and abdominal ultrasound. The final step implied a NGSAP with further interpretation based on (but not limited to) data obtained at the third step.

      Results: At the first step, 6 patients were found to have acquired cerebellar ataxia and 2 patients was diagnosed with MSA. At the second step, 3 patients turned to be positive for SCA types 1, 2, and 17 along with 9 patients positive for FA. After the third step, 32 patients underwent NGSAP (136 genes) based on Illumina MiSeq platform. NGSAP allowed to diagnose ataxia-telangiectasia (n=5), ataxia with oculomotor apraxia type 1 (n=1) and type 2 (n=1), SANDO syndrome (n=2), Krabbe disease (n=1), ARCA3 (n=1), SCAR16 (n=1), and NBIA2A (n=1). In 19 patients NGSAP was negative for clinically significant mutations.

      Conclusions: Non-hereditary cerebellar ataxias represented 15.4% of SARCAs. FA was the most frequent (17.3%) hereditary SARCA. Being a part of the multistep approach, NGSAP provides a positive diagnostic yield in 40.6% of undiagnosed patients with SARCAs in Russian population.

      Disclosure: Dr. Seliverstov has nothing to disclose. Dr. Nuzhnyi has nothing to disclose. Dr. Klyushnikov has nothing to disclose. Dr. Abramycheva has nothing to disclose. Dr. Vetchinova has nothing to disclose. Dr. Illarioshkin has nothing to disclose.

    • Odalisque's position as a geste antagoniste in a variant phenotype of Ataxia‐Telangiectasia
      Visto: 330
      • Movement disorders
      • case
      • Belgium
      • 2019
      • Barrea C
      • Movement Diorders
      Christophe Barrea MD 
       
      Frederique Depierreux MD 
       
      Laurent Servais MD, PhD
      First published: 16 April 2019
       
      https://doi.org/10.1002/mdc3.12771
       
      A 15-year-old patient exhibits abnormal movements with dystonic-myoclonic jerks focused mainly on the neck and upper limbs. These manifestations are invasive and can be exacerbated by movement and above all slightest touch. The symptoms started when he was 2-year-old with mild transient ataxia, followed by myoclonus and finally dystonia that quickly became the prominent symptom. Dystonic movements mainly appear in orthostatic position and induce left torticollis combined with severe ipsilateral laterocollis. The boy has developed spontaneously a particular geste antagoniste1 combining lateral decubitus and the application of his left hand on the ipsilateral temple, leading to a caricatured posture reminiscent of the “Odalisques” (figure 1 and 2). The patient is homozygous for ATM c.3149T>C (p.(Leu1050Pro)), leading to a variant form of Ataxia-Telangiectasia2 .
    • Identification of aberrantly methylated differentially expressed genes in breast cancer by integrated bioinformatics analysis.
      Visto: 149
      • China
      • breast cancer
      • biomarker
      • 2019
      • DNA methylation
      • Yi L
      • Luo P
      • Zhang J
      • bioinformatics analysis
      • gene expression
      J Cell Biochem. 2019 Sep;120(9):16229-16243. doi: 10.1002/jcb.28904. Epub 2019 May 12.

      Identification of aberrantly methylated differentially expressed genes in breast cancer by integrated bioinformatics analysis.

      Yi L1, Luo P1, Zhang J1.

      Author information

      1
      Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.

      Abstract

      BACKGROUND:

      Abnormal DNA methylation has been demonstrated to drive breast cancer tumorigenesis. Thus, this study aimed to explore differentially expressed biomarkers driven by aberrant methylation in breast cancer and explore potential pathological mechanisms using comprehensive bioinformatics analysis.

      METHODS:

      Gene microarray datasets of expression (GSE45827) and methylation (GSE32393) were extracted from the Gene Expression Omnibus database. Abnormally methylated differentially expressed genes (DEGs) were obtained by overlapping datasets. Functional enrichment analysis of screened genes and protein-protein interaction (PPI) networks were executed with the Search Tool for the Retrieval of Interacting Genes database. PPI networks were visualized, and hub genes were screened using Cytoscape software. The results were further verified using Oncomine and The Cancer Genome Atlas (TCGA) databases. Finally, the genetic alterations and prognostic roles of hub genes were analyzed.

      RESULTS:

      In total, we found 18 hypomethylated upregulated oncogenes and 21 hypermethylated downregulated tumor suppressor genes (TSGs). These genes were mainly linked to the biological process categories of cellular component movement and cellular metabolism as well as nuclear factor-κB (NF-κB) and ataxia telangiectasia mutated (ATM) signaling pathways. Six hub genes were identified: three hypomethylated upregulated oncogenes (BCL2, KIT, and RARA) and three hypermethylated downregulated TSGs (ATM, DICER1, and DNMT1). The expression and methylation status of hub genes validated in Oncomine and TCGA databases were significantly altered and were consistent with our findings. Downregulation of BCL2, KIT, ATM, and DICER1 was closely associated with shorter overall survival in breast cancer patients. In addition, the expression levels of ATM and DICER1 were significantly distinct among different subgroups of clinical stages, molecular subtypes, and histological types.

      CONCLUSIONS:

      Our study reveals possible methylation-based DEGs and involved pathways in breast cancer, which could provide novel insights into underlying pathogenesis mechanisms. Abnormally methylated oncogenes and TSGs, especially ATM and DICER1, may emerge as novel biomarkers and therapeutic targets for breast cancer in the future.

      © 2019 Wiley Periodicals, Inc.

      KEYWORDS:

      bioinformatics analysis; biomarker; breast cancer; gene expression; methylation

      PMID:
       
      31081184
       
      DOI:
       
      10.1002/jcb.28904
    • Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related
      Visto: 163
      • 2019
      J Med Chem. 2019 Jun 13;62(11):5547-5561. doi: 10.1021/acs.jmedchem.9b00426. Epub 2019 May 16.

      Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor.

      Knegtel R1, Charrier JD1, Durrant S1, Davis C1, O'Donnell M1, Storck P1, MacCormick S1, Kay D1, Pinder J1, Virani A1, Twin H1, Griffiths M1, Reaper P1, Littlewood P1, Young S1, Golec J1, Pollard J1.

      Author information

      1
      Vertex Pharmaceuticals (Europe) Ltd. , 86-88 Jubilee Avenue, Milton Park , Abingdon , Oxfordshire OX14 4RW , United Kingdom.

      Abstract

      The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

      PMID:
       
      31074988
       
      DOI:
       
      10.1021/acs.jmedchem.9b00426
    • The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper.
      Visto: 151
      • Cerebellum
      • Schmahmann JD
      • cerebellar cognitive affective syndrome
      • 2019
      • Argyropoulos GPD
      • van Dun K
      • Adamaszek M
      • Leggio M
      • Manto M
      • Masciullo M
      • Molinari M
      • Stoodley CJ
      • Van Overwalle F
      • Ivry RB
      Cerebellum. 2019 Sep 14. doi: 10.1007/s12311-019-01068-8. [Epub ahead of print]

      The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper.

      Argyropoulos GPD1, van Dun K2, Adamaszek M3, Leggio M4,5, Manto M6,7, Masciullo M8, Molinari M9, Stoodley CJ10, Van Overwalle F11, Ivry RB12, Schmahmann JD13.

      Author information

      1
      Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. georgios.argyropoulos@ndcn.ox.ac.uk.
      2
      Rehabilitation Research Center REVAL, UHasselt, Hasselt, Belgium.
      3
      Clinical and Cognitive Neurorehabilitation, Center of Neurology and Neurorehabilitation, Klinik Bavaria Kreischa, An der Wolfsschlucht 1-2, 01703, Kreischa, Germany.
      4
      Department of Psychology, Sapienza University of Rome, Rome, Italy.
      5
      Ataxia Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.
      6
      Department of Neurology, CHU-Charleroi, 6000, Charleroi, Belgium.
      7
      Department of Neurosciences, University of Mons, 7000, Mons, Belgium.
      8
      SPInal REhabilitation Lab (SPIRE), IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy.
      9
      Neuro-Robot Rehabilitation Lab, IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy.
      10
      Department of Psychology, American University, Washington, DC, 20016, USA.
      11
      Department of Psychology, Vrije Universiteit Brussel, Brussels, Belgium.
      12
      Department of Psychology, University of California, Berkeley, CA, USA.
      13
      Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

      Abstract

      Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the "cerebellar cognitive affective syndrome" ("CCAS") or "Schmahmann syndrome." Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion-affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.

      KEYWORDS:

      Affect; Cerebellar cognitive affective syndrome; Cerebellum; Cognition; Emotion; Schmahmann syndrome

      PMID:
       
      31522332
       
      DOI:
       
      10.1007/s12311-019-01068-8
    • Antioxidant Defense, Redox Homeostasis, and Oxidative Damage in Children With Ataxia Telangiectasia and Nijmegen Breakage Syndrome.
      Visto: 143
      • Poland
      • Pietrucha B
      • Heropolitanska-Pliszka E
      • Maciejczyk M
      • Car H
      • Sawicka-Powierza J
      • Zalewska A
      • Pac M
      • Wolska-Kusnierz B
      • Bernatowska E
      • redox homeostasis
      • Mikoluc B
      • 2019
      Front Immunol. 2019 Sep 27;10:2322. doi: 10.3389/fimmu.2019.02322. eCollection 2019.
      Maciejczyk M1, Heropolitanska-Pliszka E2, Pietrucha B2, Sawicka-Powierza J3, Bernatowska E2, Wolska-Kusnierz B2, Pac M2, Car H4, Zalewska A5, Mikoluc B6.

      Author information

      1
      Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland.
      2
      Clinical Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
      3
      Department of Family Medicine, Medical University of Bialystok, Bialystok, Poland.
      4
      Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland.
      5
      Department of Conservative Dentistry, Medical University of Bialystok, Bialystok, Poland.
      6
      Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, Bialystok, Poland.

      Abstract

      Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

      Copyright © 2019 Maciejczyk, Heropolitanska-Pliszka, Pietrucha, Sawicka-Powierza, Bernatowska, Wolska-Kusnierz, Pac, Car, Zalewska and Mikoluc.

      KEYWORDS:

      antioxidants; ataxia-telangiectasia (AT); nijmegen breakage syndrome (NBS); oxidative damage; oxidative stress

      PMID:
       
      31611883
       
      PMCID:
       
      PMC6776633
       
      DOI:
       
      10.3389/fimmu.2019.02322
    • Microglial Self-Recognition STINGs in A-T Neurodegeneration.
      Visto: 136
      • United States of America
      • Neurodegeneration
      • Microglia
      • 2019
      • Ferro A
      • Sheeler C
      • Cvetanovic M
      • Trends Neurosci
      Trends Neurosci. 2019 Oct 14. pii: S0166-2236(19)30178-X. doi: 10.1016/j.tins.2019.09.005. [Epub ahead of print]

      Microglial Self-Recognition STINGs in A-T Neurodegeneration.

      Ferro A1, Sheeler C1, Cvetanovic M2.

      Author information

      1
      Department of Neuroscience, University of Minnesota, 2101 6th Street South East, Minneapolis, MN 55455, USA.
      2
      Department of Neuroscience, University of Minnesota, 2101 6th Street South East, Minneapolis, MN 55455, USA; Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street South East, Minneapolis, MN 55455, USA. Electronic address: mcvetano@umn.edu.

      Abstract

      Microglial inflammation is often seen as a secondary event in neurodegeneration. A recent study by Song et al. demonstrates that loss of ataxia telangiectasia mutated (ATM) activates microglia through the cytosolic DNA sensor STING. This highlights the ability of microglia to recognize and respond to self-DNA, with potentially neurotoxic consequences.

      Copyright © 2019 Elsevier Ltd. All rights reserved.

      KEYWORDS:

      ATM; NF-κB; ataxia telangiectasia; microglia

      PMID:
       
      31623867
       
      DOI:
       
      10.1016/j.tins.2019.09.005
    • Abnormal Saccades Differentiate Adolescent Onset Variant Ataxia Telangiectasia from Other Myoclonus Dystonia
      Visto: 167
      • Clinical
      • India
      • Neurol India
      • Saccades
      • Cherian A
      • 2021
      • Ann Indian Acad Neurol
       
      . Jul-Aug 2021;24(4):630-632.
       doi: 10.4103/aian.AIAN_619_20. Epub 2021 Apr 10.

      Abnormal Saccades Differentiate Adolescent Onset Variant Ataxia Telangiectasia from Other Myoclonus Dystonia

      Ajith Cherian1, Mitesh Chandarana1, Ashish Anand Susvirkar1, K P Divya1, Udit U Saraf1, Syam Krishnan1
      Affiliations 

      Affiliation

      • 1Department of Neurology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Kerala, India.
      • PMID: 34728979
      •  
      • PMCID: PMC8513963
      •  
      • DOI: 10.4103/aian.AIAN_619_20
      Free PMC article
      No abstract available

      Conflict of interest statement

      There are no conflicts of interest.

      References

        1. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749–53. - PubMed
        1. van Os NJH, Hensiek A, van Gaalen J, Taylor AMR, van Deuren M, Weemaes CMR, et al. Trajectories of motor abnormalities in milder phenotypes of ataxia telangiectasia. Neurology. 2019;92:e19–29. - PubMed
        1. Verhagen MMM, Abdo WF, Willemsen MAAP, Hogervorst FBL, Smeets DFCM, Hiel JAP, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009;73:430–7. - PubMed
        1. Saunders-Pullman RJ, Gatti R. Ataxia-telangiectasia: Without ataxia or telangiectasia? Neurology. 2009;73:414–5. - PubMed
        1. Chang FC, Westenberger A, Dale RC, Smith M, Pall HS, Perez-Dueñas B, et al. Phenotypic insights into ADCY5-associated disease. Mov Disord. 2016;31:1033–40. - PMC - PubMed
        1. Groen JL, Andrade A, Ritz K, Jalalzadeh H, Haagmans M, Bradley TE, et al. CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum Mol Genet. 2015;24:987–93. - PMC - PubMed
        1. Mencacci NE, R'bibo L, Bandres-Ciga S, Carecchio M, Zorzi G, Nardocci N, et al. The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort. Hum Mol Genet. 2015;24:5326–9. - PMC - PubMed
        1. Groen JL, Ritz K, Jalalzadeh H, van der Salm SMA, Jongejan A, Mook OR, et al. RELN rare variants in myoclonus-dystonia. Mov Disord. 2015;30:415–9. - PubMed
        1. Goyal V, Behari M. Dystonia as presenting manifestation of ataxia telangiectasia: A case report. Neurol India. 2002;50:187–9. - PubMed
        1. Mahadevappa M, Kamble N, Santhosh Kumar DV, Yadav R, Netravathi M, Pal PK. A clinical profile of 100 patients with ataxia telangiectasia seen at a tertiary care center. Ann Mov Disord. 2020;3:33–8.

    Página 16 de 21

    • 11
    • 12
    • 13
    • 14
    • 15
    • 16
    • 17
    • 18
    • 19
    • 20

    Language

      Español (España)
    • Hindi (India)
    • Hebrew
    • Arabic (اللغة العربية)
    • Turkish (Turkey)
    • 日本語 (Japan)
    • Russian (Russia)
    • Français (France)
    • Deutsch (Deutschland)
    • Español (España)
    • Nederlands (nl-NL)
    • Português Brasileiro (pt-BR)
    • Polski (PL)
    • Italiano (Italia)
    • English (United Kingdom)

    Idiomas

      Español (España)
    • Hindi (India)
    • Hebrew
    • Arabic (اللغة العربية)
    • Turkish (Turkey)
    • 日本語 (Japan)
    • Russian (Russia)
    • Français (France)
    • Deutsch (Deutschland)
    • Español (España)
    • Nederlands (nl-NL)
    • Português Brasileiro (pt-BR)
    • Polski (PL)
    • Italiano (Italia)
    • English (United Kingdom)

    Tweets by A_Tinfo

    Ataxia Telangiectasia
      • Inicio
      • ¿Qué es?
      • Bibliografía
      • Enlaces
      • Noticias
      • admin@ataxiatelangiectasia.es