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  • Treatment of Granulomas in Patients With Ataxia Telangiectasia.
    Visto: 3364
    • TNF inhibitors
    • ataxia telangiectasia
    • granulomas
    • granulomatous inflammation
    • primary immunodeficiency
    • 2018
    • Woelke S
    • Valesky E
    • Bakhtiar S
    • Pommerening H
    • Pfeffermann LM
    • Schubert R
    • Zielen S
    • Front Immunol
    • Germany
    Front Immunol. 2018 Sep 18;9:2000. doi: 10.3389/fimmu.2018.02000. eCollection 2018.
    Woelke S1, Valesky E2, Bakhtiar S3, Pommerening H1, Pfeffermann LM3, Schubert R1, Zielen S1.

    Abstract

    Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported. Methods: From our cohort of 44 classical A-T patients, eight patients aged 2-11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT). Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again. Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients. What This Study Adds to the Field: Granulomas in A-Tprogress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients. AT A GLANCE COMMENTARY: Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T. What This Study Adds to the Field: Granulomas in A-Tprogress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.

    KEYWORDS:

    TNF inhibitors; ataxia telangiectasia; granulomas; granulomatous inflammation; primary immunodeficiency

    PMCFullTextFree

  • Ataxia-telangiectasia: A review of movement disorders, clinical features and genotype correlations - Addendum.
    Visto: 2616
    • ataxia telangiectasia
    • 2018
    • Levy A
    • Lang AE
    • Mov Disord
    • ataxia
    • choreoathetosis
    • dystonia
    • myoclonus
    • parkinsonism
    • phenomenology
    • Canada
    Mov Disord. 2018 Aug;33(8):1372. doi: 10.1002/mds.27449. Epub 2018 Jul 30.
    Levy A1,2, Lang AE1.

    Author information

    1
    Morton and Gloria Shulman Movement Disorders Clinic, and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.
    2
    Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

    Erratum for

    • Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations. [Mov Disord. 2018]
    PMID:
     
    30230625
     
    DOI:
     
    10.1002/mds.27449
    ataxia; ataxia-telangiectasia; choreoathetosis; dystonia; myoclonus; parkinsonism; phenomenology
  • Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations.
    Visto: 3729
    • ataxia telangiectasia
    • Levy A
    • Lang AE
    • ataxia
    • choreoathetosis
    • dystonia
    • myoclonus
    • parkinsonism
    • phenomenology
    • Canada
    Mov Disord. 2018 Aug;33(8):1238-1247. doi: 10.1002/mds.27319. Epub 2018 Feb 13.
    Levy A1,2,3, Lang AE1,2.

    Author information

     

    Erratum in

    • Ataxia-telangiectasia: A review of movement disorders, clinical features and genotype correlations - Addendum. [Mov Disord. 2018]

    Abstract

    Ataxia-telangiectasia is an autosomal recessive neurodegenerative disorder that was initially thought to present exclusively in childhood. With the discovery of the ATM gene, the phenotypic spectrum of the condition has expanded. This review elaborates the expanded phenomenology, including oculomotor apraxia and immunodeficiency, and estimates the presence of each movement disorder feature from previously reported literature. Initial manifestations of Ataxia-telangiectasia include cerebellar symptoms (67%), dystonia (18%), choreoathetosis (10%), and tremor (4%), with parkinsonism and myoclonus not reported as initial features. The prevalence of movement disorders during the course of the disease includes cerebellar symptoms (96%), dystonia (89%), parkinsonism (41%), choreoathetosis (89%), myoclonus (92%), and tremor (74%). Phenomenology and age of onset is modulated by presence of residual ATM kinase activity, with genotypes heavily truncating the ATM protein associated with the most severe phenotypes. Ataxia-telangiectasia commonly results in a spectrum of movement disordersbeyond ataxia and telangiectasias.

    © 2018 International Parkinson and Movement Disorder Society.

    KEYWORDS:

    ataxia; ataxia-telangiectasia; choreoathetosis; dystonia; myoclonus; parkinsonism; phenomenology

  • Secondary enuresis and urological manifestations in children with ataxia telangiectasia.
    Visto: 2649
    • ataxia telangiectasia
    • 2018
    • Israel
    • Eur J Paediatr Neurol
    • ATM
    • Incontinence
    • Neurogenic bladder
    • Urinary tract
    • Nissenkorn A
    • Erlich T
    • Zilberman DE
    • Sarouk I
    • Krauthammer A
    • Kitrey ND
    • Heimer G
    • BenZeev B
    • Mor Y
    Eur J Paediatr Neurol. 2018 Jul 26. pii: S1090-3798(18)30214-9. doi: 10.1016/j.ejpn.2018.07.006. [Epub ahead of print]
    Nissenkorn A1, Erlich T2, Zilberman DE2, Sarouk I3, Krauthammer A4, Kitrey ND2, Heimer G5, BenZeev B5, Mor Y6.

    Author information

    Abstract

    BACKGROUND:

    Ataxia telangiectasia (AT) is a neurodegenerative cerebellar disorder, caused by mutations in the ATM gene, involved in DNA repair. Radiosensitivity, progressive ataxia, immune deficiency and malignancies, are well known symptoms, but urological manifestations are scarcely described.

    OBJECTIVE:

    To characterize urologic manifestations in a large cohort of AT patients.

    METHODS:

    Retrospective cross-sectional chart study comprising 52 AT patients followed at a National AT Center.

    RESULTS:

    25% of the cohort (13 patients/8 males) had urologic symptoms, which presented at 11 ± 4.3 years. The most common symptom was secondary enuresis affecting 15% of the patients (8 children/4 males). Incontinence appeared at 8 ± 6.2 years of age, and resolved spontaneously within 15 ± 8.3 months in 6 patients. It preceded loss of ambulatory capacity by 1-2 years in 7 patients. Lumbosacral MRI were normal (4 children) and urine cultures (all) were negative. Urodynamic evaluation that was performed in only one patient revealed overactive bladder. Additional manifestations were macroscopic hematuria due to bladder telangiectasia in a 12-year-old, and renal cell carcinoma in a 22-year-old. Other manifestations unrelated to AT were neprolithiasis, vesico-ureteral reflux and scrotal pain, each in 1 patient.

    DISCUSSION:

    Transient secondary enuresis is a frequent finding in AT patients, heralding loss of ambulatory capacity, tough it's pathophysiological mechanism is largely no understood.

    Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

    KEYWORDS:

    ATM; Ataxia telangiectasia; Incontinence; Neurogenic bladder; Urinary tract

  • P 111 - Rehabilitation results in children with ataxia telengiectasia: three case reports.
    Visto: 2573
    • 2018
    • rehabilitation
    • Turkey
    • Cankaya O
    • Seyhan K
    • Günel MK
    • Gait Posture
    Gait Posture. 2018 Sep;65 Suppl 1:421. doi: 10.1016/j.gaitpost.2018.07.034. Epub 2018 Jul 24.

    P 111 - Rehabilitation results in children with ataxia telengiectasia: three case reports.

    Cankaya O1, Seyhan K2, Günel MK3.

    Author information

    1
    Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: ozgemuezzinoglu@gmail.com.
    2
    Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: kubra.seyhan@yahoo.com.
    3
    Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Turkey.

    KEYWORDS:

    Ataxia telangiectasia; Physical therapy

  • Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia.
    Visto: 2609
    • 2018
    • Israel
    • Sarouk I
    • Krauthammer A
    • BMC Pediatr
    • Lahad A
    • Goldberg L
    • Weiss B
    • Somech R
    • Soudack M
    • Pessach IM
    • Class switching
    • Complications
    • Elevated IgM
    • Immunoglobulins
    • Lung functions
    • Phenotype
    BMC Pediatr. 2018 Jun 4;18(1):185. doi: 10.1186/s12887-018-1156-1.
    Krauthammer A1,2, Lahad A3,4, Goldberg L3,5, Sarouk I3,6, Weiss B4,5, Somech R3,5, Soudack M3,7, Pessach IM8,5.

    Author information

    1
    Department of Pediatrics, The Edmond and Lily Safra Children's Hospital, 52625, Tel- Hashomer, Israel. krautalex@gmail.com.
    2
    Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. krautalex@gmail.com.
    3
    Department of Pediatrics, The Edmond and Lily Safra Children's Hospital, 52625, Tel- Hashomer, Israel.
    4
    Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Tel- Hashomer, Israel.
    5
    Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    6
    Pediatric Pulmonary Unit, The Edmond and Lily Safra Children's Hospital, Tel- Hashomer, Israel.
    7
    Pediatric Radiology Unit, The Edmond and Lily Safra Children's Hospital, Tel- Hashomer, Israel.
    8
    The Claudio Cohen Department of Pediatric Intensive Care, The Edmond and Lily Safra Children's Hospital, Tel- Hashomer, Israel.

    Abstract

    BACKGROUND:

    Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. In the current study we aimed to better characterize this group of patients.

    METHODS:

    We performed a retrospective review of 46 patient records, followed from January 1986 to January 2015 at the Israeli National AT Center. Demographic, clinical, radiological, laboratory data was reviewed and compared between AT patients with elevated IgM levels (EIgM) and patients with normal IgM levels (NIgM).

    RESULTS:

    15/46(32.6%) patients had significantly elevated IgM levels. This group had a unique phenotype characterized mainly by increased risk of infection and early mortality. Colonization of lower respiratory tract with Mycobacterium gordonae and Pseudomonas aeruginosa as well as viral skin infections were more frequent in EIgM patients. Patients with NIgM had a significantly longer survival as compared to patients with EIgM but had an increased incidence of fatty liver or cirrhosis. T-cell recombination excision circles and kappa-deleting element recombination circle levels were significantly lower in the EIgM group, suggesting an abnormal class switching in this group.

    CONCLUSIONS:

    EIgM in AT patients are indicative of a more severe phenotype that probably results from a specific immune dysfunction. EIgM in AT should be considered a unique AT phenotype that may require different management.

    KEYWORDS:

    AT; Class switching; Complications; Elevated IgM; Immunoglobulins; Lung functions; Phenotype

    PMID:
     
    29866155
     
    PMCID:
     
    PMC5987459
     
    DOI:
     
    10.1186/s12887-018-1156-1
  • B-cell subsets imbalance and reduced expression of CD40 in ataxia-telangiectasia patients.
    Visto: 2647
    • ataxia telangiectasia
    • 2018
    • Brazil
    • Allergol Immunopathol (Madr)
    • Pereira CTM
    • Bichuetti-Silva DC
    • da Mota NVF
    • Salomão R
    • Brunialti MKC
    • Costa-Carvalho BT
    • B cells
    • Cd21low
    • CD40
    • CD40L
    • IgM memory B cells
    • Switched memory B cells
    Allergol Immunopathol (Madr). 2018 Sep - Oct;46(5):438-446. doi: 10.1016/j.aller.2017.09.031. Epub 2018 May 5.
    Pereira CTM1, Bichuetti-Silva DC1, da Mota NVF2, Salomão R2, Brunialti MKC2, Costa-Carvalho BT3.

    Author information

    1
    Department of Pediatrics, Federal University of Sao Paulo Medical School, 598, Botucatu Street, Vila Clementino, São Paulo, SP 04023-062, Brazil.
    2
    Division of Infectious Diseases, Federal University of Sao Paulo Medical School, 669, Pedro de Toledo Street, Vila Clementino, São Paulo, SP 04039-032, Brazil.
    3
    Department of Pediatrics, Federal University of Sao Paulo Medical School, 598, Botucatu Street, Vila Clementino, São Paulo, SP 04023-062, Brazil. Electronic address: beacarvalho@terra.com.br.

    Abstract

    BACKGROUND:

    Ataxia-telangiectasia (AT) is a well-known primary immunodeficiency with recurrent sinopulmonary infections and variable abnormalities in both the humoral and cellular immune system. Dysfunctions in immunoglobulin production, reduced number of B cells, and B-cell receptor excision circles copies have been reported. We aimed to understand the immunological mechanisms involving the humoral compartment in AT patients by analysing peripheral blood B cells subsets, B-T lymphocyte cooperation through the expression of CD40 and CD40 ligand (CD40L), and cytokines involved in class-switch recombination production.

    METHODS:

    We compared the proportion of B-cell subsets, the expression of CD40/CD40L, and the plasma levels of IL-6 and IFN-γ of 18 AT patients and 15 healthy age-sex-matched controls using flow cytometry.

    RESULTS:

    We found that some steps in peripheral B cell development were altered in AT with a pronounced reduction of cell-surface CD40 expression. The proportions of transitional and naïve-mature B cells were reduced, whereas CD21-low, natural effector memory, IgM-only memory, and IgG atypical memory B cells were present in a higher proportion.

    CONCLUSIONS:

    These findings revealed a disturbed B-cell homeostasis with unconventional maturation of B lymphocyte memory cells, which can explain the consequent impairment of humoral immunity.

    Copyright © 2018 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

    KEYWORDS:

    Ataxia-telangiectasia; B cells; CD21low; CD40; CD40L; IgM memory B cells; Switched memory B cells

    PMID:
     
    29739685
     
    DOI:
     
    10.1016/j.aller.2017.09.031
     
     
  • A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing.
    Visto: 2508
    • 2018
    • ATM
    • Alonazi NA
    • Hundallah KJ
    • Al Hashem AM
    • Mohamed S
    • Genetic
    • mutation
    • Saudi Arabia
    • case
    Neurosciences (Riyadh). 2018 Apr;23(2):162-164. doi: 10.17712/nsj.2018.2.20170463.
    Alonazi NA1, Hundallah KJ, Al Hashem AM, Mohamed S.

    Author information

    1
    Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail: dralonazi@gmail.com.

    Abstract

    Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder caused by variants in ATM gene and characterized by progressive neurologic impairment, cerebellar ataxia, and oculo-cutaneous telangiectasia. Immunodeficiency with a recurrent sinopulmonary infections are observed in patients with A-T. Here, we report a novel stop codon variant, c.5944 C>T (p.Gln1982*), revealed by whole-exome sequencing in a 9-year old boy. He presented with recurrent upper respiratory tract infections, failure to thrive, developmental delay, ataxic gait, and bulbar telangiectasia.

    PMID:
     
    29664460
  • A Case of Ataxia-telangiectasia Presented With Hemophagocytic Syndrome.
    Visto: 2547
    • 2018
    • Turkey
    • Genetic
    • Celiksoy MH
    • Ozyavuz Cubuk P
    • Guner SN
    • Yildiran A
    • J Pediatr Hematol Oncol
    • hemophagocytic syndrome
    • case
    J Pediatr Hematol Oncol. 2018 Apr 3. doi: 10.1097/MPH.0000000000001134. [Epub ahead of print]
    Celiksoy MH1, Ozyavuz Cubuk P2, Guner SN1, Yildiran A1.

    Author information

    1
    Department of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun.
    2
    Haseki Training and Research Hospital, Genetic Diseases Diagnosis Center, Istanbul, Turkey.

    Abstract

    Ataxia-telangiectasia (A-T) is a multisystem disease caused by a genetic defect located on the long arm of chromosome 11 (11p22-23). The gene defect results in the loss of A-T-mutated protein, subsequently leading to unrepaired DNA fractures and defects in the signal transduction pathway. As a result, characteristic findings arise, including recurrent sinopulmonary infections, hypersensitivity against ionized radiation with the tendency to develop cancer related to progressive cerebellar ataxia, pathognomonic oculocutaneous telangiectasias, varying degrees of humoral and cellular immunodeficiency, and infertility. This case report presents a 3-year-old male patient with A-T who developed hemophagocytic syndrome. To the best of our knowledge, no such case has been previously reported.

    PMID:
     
    29620677
     
    DOI:
     
    10.1097/MPH.0000000000001134
  • Inflammation, a significant player of Ataxia-Telangiectasia pathogenesis?
    Visto: 2603
    • ataxia telangiectasia
    • 2018
    • ATM
    • Iran
    • Zaki-Dizaji M
    • Akrami SM
    • Azizi G
    • Abolhassani H
    • Aghamohammadi A
    • Infammation
    • Neurodegeneration
    • Reactive oxygen species
    • Senescence
    • Sweden
    • Inflamm Res
    Inflamm Res. 2018 Jul;67(7):559-570. doi: 10.1007/s00011-018-1142-y. Epub 2018 Mar 26.
    Zaki-Dizaji M1,2, Akrami SM1, Azizi G3,4, Abolhassani H2,5, Aghamohammadi A6.

    Author information

    1
    Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
    2
    Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Science, 62 Qarib St., Keshavarz Blvd., Tehran, 14194, Iran.
    3
    Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
    4
    Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran.
    5
    Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    6
    Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Science, 62 Qarib St., Keshavarz Blvd., Tehran, 14194, Iran. aghamohammadi@tums.ac.ir.

    Abstract

    INTRODUCTION:

    Ataxia-Telangiectasia (A-T) syndrome is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, chromosome instability, radiosensitivity, and predisposition to malignancy. There is growing evidence that A-T patients suffer from pathologic inflammation that is responsible for many symptoms of this syndrome, including neurodegeneration, autoimmunity, cardiovascular disease, accelerated aging, and insulin resistance. In addition, epidemiological studies have shown A-T heterozygotes, somewhat like deficient patients, are susceptible to ionizing irradiation and have a higher risk of cancers and metabolic disorders.

    AREA COVERED:

    This review summarizes clinical and molecular findings of inflammation in A-Tsyndrome.

    CONCLUSION:

    Ataxia-Telangiectasia Mutated (ATM), a master regulator of the DNA damage response is the protein known to be associated with A-T and has a complex nuclear and cytoplasmic role. Loss of ATM function may induce immune deregulation and systemic inflammation.

    KEYWORDS:

    ATM; Ataxia–Telangiectasia; Inflammation; Neurodegeneration; Reactive oxygen species; Senescence

    PMID:
     
    29582093
     
    DOI:
     
    10.1007/s00011-018-1142-y
  • Minimum effective betamethasone dosage on the neurological phenotype in patients with ataxia-telangiectasia: a multicenter observer-blind study.
    Visto: 2563
    • ataxia telangiectasia
    • primary immunodeficiency
    • 2018
    • Italy
    • Eur J Neurol
    • Pignata C
    • Cirillo E
    • Del Giudice E
    • Micheli R
    • Cappellari AM
    • Soresina A
    • Dellepiane RM
    • Pietrogrande MC
    • Dell'Era L
    • Specchia F
    • Pession A
    • Plebani A
    • SARA scale
    • ataxia and gait disorders
    • betamethasone
    Eur J Neurol. 2018 Jun;25(6):833-840. doi: 10.1111/ene.13606. Epub 2018 Mar 26.
    Cirillo E1, Del Giudice E1, Micheli R2, Cappellari AM3, Soresina A4, Dellepiane RM5, Pietrogrande MC5, Dell'Era L5, Specchia F6, Pession A6, Plebani A4, Pignata C1.

    Author information

    1
    Department of Translational Medical Sciences, Pediatrics Section, Federico II University of Naples, Naples, Italy.
    2
    Unit of Child Neurology and Psychiatry, ASST Spedali Civili Brescia, Brescia, Italy.
    3
    Department of Neuroscience and Mental Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
    4
    Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, University of Brescia, Brescia, Italy.
    5
    Department of Pediatrics, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
    6
    Department of Pediatrics, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy.

    Abstract

    BACKGROUND AND PURPOSE:

    Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease, due to A-T mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A-T severely affects patients' quality of life. Successful treatment options are still not available. The aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects.

    METHODS:

    Nine A-T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day. Neurological assessment and the evaluation of quality of life were performed through the Scale for the Assessment and Rating of Ataxia and the Italian version of the Childhood Health Assessment Questionnaire (CHAQ) at each time-point. The drug safety profile was evaluated. Patients were categorized as responders, partial responders and non-responders.

    RESULTS:

    Four of nine patients had a benefit at a dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only one additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective. A correlation between the serum adrenocorticotropic hormone levels and the clinical response was observed. Five of 30 CHAQ items improved in four patients.

    CONCLUSIONS:

    These data suggest that a short-term betamethasone oral treatment, at a daily dosage of 0.005 mg/kg, is effective in some patients. Pre-existing risk factors for side effects should be taken into account before therapy.

    © 2018 EAN.

    KEYWORDS:

    SARA scale; ataxia and gait disorders; ataxia-telangiectasia; betamethasone; primary immunodeficiency

  • Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity.
    Visto: 3389
    • ataxia
    • Italy
    • 2012
    • Menotta M
    • Biagiotti S
    • Bianchi M
    • Chessa L
    • Magnani M
    • J Biol Chem
    • dexamethasone
    • Alternative Splicing
    • Genetic Diseases
    • Glucocorticoids
    • Translation
    • SDR-mediated Splicing
    J Biol Chem. 2012 Nov 30;287(49):41352-63. doi: 10.1074/jbc.M112.344473. Epub 2012 Oct 10.

    Menotta M1, Biagiotti S, Bianchi M, Chessa L, Magnani M.

    Author information

    1
    Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy. michele.menotta@uniurb.it

    Abstract

    Ataxia telangiectasia (AT) is a rare genetic disease, still incurable, resulting from biallelic mutations in the ataxia telangiectasia-mutated (ATM) gene. Recently, short term treatment with glucocorticoid analogues improved neurological symptoms characteristic of this syndrome. Nevertheless, the molecular mechanism involved in glucocorticoid action in AT patients is not yet known. Here we describe, for the first time in mammalian cells, a short direct repeat-mediated noncanonical splicing event induced by dexamethasone, which leads to the skipping of mutations upstream of nucleotide residue 8450 of ATM coding sequence. The resulting transcript provides an alternative ORF translated in a new ATM variant with the complete kinase domain. This miniATM variant was also highlighted in lymphoblastoid cell lines from AT patients and was shown to be likely active. In conclusion, dexamethasone treatment may partly restore ATM activity in ataxia telangiectasia cells by a new molecular mechanism that overcomes most of the mutations so far described within this gene.

    PMID:
     
    23055520
     
    PMCID:
     
    PMC3510833
     
    DOI:
     
    10.1074/jbc.M112.344473
    [Indexed for MEDLINE] 
    Free PMC Article
  • Atm reactivation reverses ataxia telangiectasia phenotypes in vivo.
    Visto: 2505
    • ataxia telangiectasia
    • 2018
    • Italy
    • United States of America
    • Cell Death Dis
    • Di Siena S
    • Campolo F
    • Gimmelli R
    • Di Pietro C
    • Marazziti D
    • Dolci S
    • Lenzi A
    • Nussenzweig A
    • Pellegrini M
    • DNA double-strand break repair
    • ATM kinase
    • mouse model
    Cell Death Dis. 2018 Feb 22;9(3):314. doi: 10.1038/s41419-018-0357-8.
    Di Siena S1, Campolo F2, Gimmelli R3, Di Pietro C3, Marazziti D3, Dolci S2, Lenzi A4, Nussenzweig A5, Pellegrini M6,7,8.

    Author information

    1
    Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University, Rome, Italy.
    2
    Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
    3
    Institute of Cell Biology and Neurobiology, CNR, Monterotondo, Rome, Italy.
    4
    Department of Experimental Medicine, Sapienza University, Rome, Italy.
    5
    Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, 20893, USA.
    6
    Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University, Rome, Italy. manuela.pellegrini@cnr.it.
    7
    Institute of Cell Biology and Neurobiology, CNR, Monterotondo, Rome, Italy. manuela.pellegrini@cnr.it.
    8
    Department of Medicine and Health Science 'V. Tiberio', University of Molise, Campobasso, Italy. manuela.pellegrini@cnr.it.

    Abstract

    Hereditary deficiencies in DNA damage signaling are invariably associated with cancer predisposition, immunodeficiency, radiation sensitivity, gonadal abnormalities, premature aging, and tissue degeneration. ATM kinase has been established as a central player in DNA double-strand break repair and its deficiency causes ataxia telangiectasia, a rare, multi-system disease with no cure. So ATM represents a highly attractive target for the development of novel types of gene therapy or transplantation strategies. Atm tamoxifen-inducible mouse models were generated to explore whether Atm reconstitution is able to restore Atm function in an Atm-deficient background. Body weight, immunodeficiency, spermatogenesis, and radioresistance were recovered in transgenic mice within 1 month from Atm induction. Notably, life span was doubled after Atm restoration, mice were protected from thymoma and no cerebellar defects were observed. Atm signaling was functional after DNA damage in vivo and in vitro. In summary, we propose a new Atm mouse model to investigate novel therapeutic strategies for ATM activation in ataxia telangiectasia disease.

    PMID:
     
    29472706
     
    PMCID:
     
    PMC5833483
     
    DOI:
     
    10.1038/s41419-018-0357-8
    Free PMC Article
  • Comparison of Selected Parameters of Redox Homeostasis in Patients with Ataxia-Telangiectasia and Nijmegen Breakage Syndrome.
    Visto: 2577
    • Poland
    • 2017
    • Oxid Med Cell Longev
    • Pietrucha B
    • Heropolitanska-Pliszka E
    • Maciejczyk M
    • Car H
    • Sawicka-Powierza J
    • Motkowski R
    • Karpinska J
    • Hryniewicka M
    • Zalewska A
    • Pac M
    • Wolska-Kusnierz B
    • Bernatowska E
    • redox homeostasis
    • coenzyme Q10 (CoQ10)
    • vitamin A
    • vitamin E
    • Nijmegen breakage syndrome (NBS)
    Oxid Med Cell Longev. 2017;2017:6745840. doi: 10.1155/2017/6745840. Epub 2017 Dec 31.
    Pietrucha B1, Heropolitanska-Pliszka E1, Maciejczyk M2, Car H2, Sawicka-Powierza J3, Motkowski R4, Karpinska J5, Hryniewicka M5, Zalewska A6, Pac M1, Wolska-Kusnierz B1, Bernatowska E1, Mikoluc B4.

    Author information

    1
    Clinical Immunology, The Children's Memorial Health Institute, Av. Dzieci Polskich 20, 04-730 Warsaw, Poland.
    2
    Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37 Str., 15-295 Bialystok, Poland.
    3
    Department of Family Medicine, Medical University of Bialystok, Bialystok, Poland.
    4
    Department of Pediatrics Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, Waszyngtona 17 Str., 15-274 Bialystok, Poland.
    5
    Institute of Chemistry, University of Bialystok, Bialystok, Poland.
    6
    Department of Conservative Dentistry, Medical University of Bialystok, Bialystok, Poland.

    Abstract

    This study compared the antioxidant status and major lipophilic antioxidants in patients with ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and concentrations of coenzyme Q10 (CoQ10) and vitamins A and E were estimated in the plasma of 22 patients with AT, 12 children with NBS, and the healthy controls. In AT patients, TAS (median 261.7 μmol/L) was statistically lower but TOS (496.8 μmol/L) was significantly elevated in comparison with the healthy group (312.7 μmol/L and 311.2 μmol/L, resp.). Tocopherol (0.8 μg/mL) and CoQ10 (0.1 μg/mL) were reduced in AT patients versus control (1.4 μg/mL and 0.3 μg/mL, resp.). NBS patients also displayed statistically lower TAS levels (290.3 μmol/L), while TOS (404.8 μmol/L) was comparable to the controls. We found that in NBS patients retinol concentration (0.1 μg/mL) was highly elevated and CoQ10 (0.1 μg/mL) was significantly lower in comparison with those in the healthy group. Our study confirms disturbances in redox homeostasis in AT and NBS patients and indicates a need for diagnosing oxidative stress in those cases as a potential disease biomarker. Decreased CoQ10 concentration found in NBS and AT indicates a need for possible supplementation.

    PMID:
     
    29456787
     
    PMCID:
     
    PMC5804414
     
    DOI:
     
    10.1155/2017/6745840
  • T-cell prolymphocytic leukemia in an adolescent with ataxia-telangiectasia: novel approach with a JAK3 inhibitor (tofacitinib).
    Visto: 2502
    • United States of America
    • 2017
    • Blood Adv
    • Li G
    • Waite E
    • Wolfson J
    • T-cell prolymphocytic leukemia
    • JAK3 inhibitor
    • tofacitinib
    • T-cell
    • chemotherapy
    Blood Adv. 2017 Dec 18;1(27):2724-2728. doi: 10.1182/bloodadvances.2017010470. eCollection 2017 Dec 26.
    Li G1, Waite E2, Wolfson J3.

    Author information

    1
    Department of Pathology and Laboratory Medicine and.
    2
    Department of Pharmacy, Children's of Alabama, Birmingham, AL; and.
    3
    Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, AL.

    Abstract

    A 19-year-old ataxia-telangiectasia patient with T-cell prolymphocytic leukemia harbored 2 JAK3-activating hotspot mutations.The patient suffered toxicities with chemotherapy, but demonstrated a clinical response to novel use of a JAK3 inhibitor (tofacitinib).

    PMID:
     
    29296924
     
    PMCID:
     
    PMC5745136
     
    DOI:
     
    10.1182/bloodadvances.2017010470
    Free PMC Article
  • Long-term nutritional and gastrointestinal aspects in patients with ataxia telangiectasia.
    Visto: 2519
    • 2018
    • Israel
    • Nissenkorn A
    • Sarouk I
    • Krauthammer A
    • Lahad A
    • Weiss B
    • Somech R
    • Nutrition
    • Levi-Kidron H
    • Sadeh-Kon T
    • BMI-Z
    • Caloric intake
    • Percutaneous gastrostomy
    • Nutritional
    Nutrition. 2018 Feb;46:48-52. doi: 10.1016/j.nut.2017.08.008. Epub 2017 Aug 24.
    Krauthammer A1, Lahad A2, Sarouk Y3, Somech R4, Nissenkorn A5, Modan-Moses D6, Levi-Kidron H2, Sadeh-Kon T2, Weiss B7.

    Author information

    1
    Department of Pediatrics, and Immunology, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    2
    Pediatric Gastroenterology and Nutrition Unit, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    3
    Pediatric Pulmonology Unit and Ataxia Telangiectasia Center, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    4
    Department of Pediatrics, and Immunology, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    5
    Sackler Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    6
    Sackler Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    7
    Pediatric Gastroenterology and Nutrition Unit, The Edmond and Lily Safra Children's Faculty of Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: weissb@sheba.health.gov.il.

    Abstract

    OBJECTIVE:

    Ataxia telangiectasia (A-T) is a rare genetic disease involving multiple organs, but, to our knowledge, data on long-term gastrointestinal and nutritional involvement are scarce. The aim of this study was to longitudinally review the nutritional and gastrointestinal aspects of A-T.

    METHODS:

    This was a retrospective chart review of patients followed from 1986 to 2015 at one center. Demographic, laboratory, and nutritional data were retrieved. Body mass index (BMI) values were converted to BMI Z-score (BMI-Z). Caloric intake was estimated by food diaries and compared with estimated energy requirements for sex and age with a physical activity level factor for light physical activity.

    RESULTS:

    The study included 53 patients (28 males [53%], ages 14.6 ± 5.2 y). BMI-Z was inversely correlated with age (r = 0.48; P < 0.004). A decline below minimal BMI percentiles was observed after the age of 4 y in boys and 7 y in girls. The relative percentage of caloric intake decreased with age (r = -0.5; P < 0.002), and was positively correlated with BMI-Z (r = 0.35; P < 0.05). Presence of cough during meals was associated with recurrent lower respiratory tract infections (Fisher exact test, P < 0.01). Gastrostomy tubes were inserted in 12 patients, leading to improvement in BMI-Z from -5.1 ± 2.4 to -4 ± 2.9 (P < 0.05).

    CONCLUSIONS:

    There is a progressive growth failure and low nutritional intake with age in patients with A-T, starting in early childhood in males, and more prominent in patients with cough and choking during meals. A proactive approach and insertion of a percutaneous gastrostomy tube as soon as the BMI-Z starts to decrease should be considered.

    Copyright © 2017 Elsevier Inc. All rights reserved.

    KEYWORDS:

    BMI-Z; Caloric intake; Percutaneous gastrostomy

    PMID:
     
    29290356
     
    DOI:
     
    10.1016/j.nut.2017.08.008
  • Telangiectasias in Ataxia Telangiectasia: Clinical significance, role of ATM deficiency and potential pathophysiological mechanisms.
    Visto: 2572
    • 2018
    • United Kingdom
    • The Netherlands
    • ATM kinase
    • Eur J Med Genet
    • telangiectasias
    • angiogenesis
    • Schoenaker MHD
    • Van Os NJH
    • Van der Flier M
    • Van Deuren M
    • Seyger MM
    • Taylor AMR
    • Weemaes CMR
    • Willemsen MAAP
    Eur J Med Genet. 2018 May;61(5):284-287. doi: 10.1016/j.ejmg.2017.12.012. Epub 2017 Dec 26.
    Schoenaker MHD1, Van Os NJH2, Van der Flier M3, Van Deuren M4, Seyger MM5, Taylor AMR6, Weemaes CMR3, Willemsen MAAP2.

    Author information

    1
    Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: michiel.schoenaker@radboudumc.nl.
    2
    Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
    3
    Department of Pediatrics, Radboudumc Amalia Children's Hospital, and Radboudumc Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    4
    Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
    5
    Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands.
    6
    School of Cancer Sciences, University of Birmingham, Birmingham, UK.

    Abstract

    Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis.

    PMID:
     
    29288088
     
    DOI:
     
    10.1016/j.ejmg.2017.12.012
    [Indexed for MEDLINE]
  • More than ataxia - Movement disorders in ataxia-telangiectasia.
    Visto: 2596
    • 2018
    • ataxia
    • Canada
    • Brazil
    • ataxia and gait disorders
    • Parkinsonism Relat Disord
    • Teive HAG
    • Camargo CHF
    • Munhoz RP
    • Movement disorders
    Parkinsonism Relat Disord. 2018 Jan;46:3-8. doi: 10.1016/j.parkreldis.2017.12.009. Epub 2017 Dec 12.

    More than ataxia - Movement disorders in ataxia-telangiectasia.

    Teive HAG1, Camargo CHF2, Munhoz RP3.

    Author information

    1
    Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil. Electronic address: hagteive@mps.com.br.
    2
    Neurology Service, Hospital Universitário, State University of Ponta Grossa, Ponta Grossa, Brazil. Electronic address: chcamargo@uol.com.br.
    3
    Movement Disorders Centre, Toronto Western Hospital, Toronto University, Toronto, ON, Canada. Electronic address: renatopuppi@yahoo.com.

    Abstract

    Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative disease caused by mutations in the ATM gene with progressive neurological dysfunction, multisystem abnormalities and cancer predisposition. Classically, AT is associated with cerebellar ataxia, oculocutaneous telangiectasia and oculomotor apraxia. The aim of this review is to describe the movement disorders observed in patients with AT. Movement disorders in AT patients described in the literature are reviewed. The selected articles were analyzed with a focus on clinical presentation, presence of movement disorders, and atypical cases or variants of the syndrome. In AT patients, particularly adults, chorea and dystonia are the most common movement disorders, besides cerebellar ataxia. Myoclonus, tremor and parkinsonism have been described less frequently in patients with AT. Archetypal findings, such as oculocutaneous abnormalities may not be uniformly present. AT can present with different movement disorders, in isolation or combined, with or without cerebellar ataxia or oculocutaneous telangiectasias. Neurologists with expertise in movement disorders should be aware of AT when investigating patients with movement disorders of unknown etiology.

    KEYWORDS:

    Ataxia; Ataxia-telangiectasia; Movement disorders

    PMID:
     
    29249681
     
    DOI:
     
    10.1016/j.parkreldis.2017.12.009
  • Neurofibromatosis type-1 in a patient with ataxia-telangiectasia.
    Visto: 2571
    • Turkey
    • 2017
    • Neurofibromatosis type-1
    • J Cancer Res Ther
    • Kupeli S
    J Cancer Res Ther. 2017 Oct-Dec;13(6):1073-1074. doi: 10.4103/0973-1482.183212.

    Neurofibromatosis type-1 in a patient with ataxia-telangiectasia.

    Kupeli S1.

    Author information

    1
    Department of Pediatric Oncology and Pediatric Bone Marrow Transplantation Unit, Faculty of Medicine, Cukurova University, Adana, Turkey.
    PMID:
     
    29237983
     
    DOI:
     
    10.4103/0973-1482.183212
  • Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis.
    Visto: 2516
    • Italy
    • United States of America
    • 2017
    • Front Neurol
    • eye movements
    • Ataxia-Telangiectasia-Like Disorder
    • Federighi P
    • Ramat S
    • Pretegiani E
    • Federico A
    • Rufa A
    • Purkinje cells
    • granule cells
    • parallel fibers
    • saccade hypermetria
    Front Neurol. 2017 Nov 9;8:596. doi: 10.3389/fneur.2017.00596. eCollection 2017.
    Federighi P1, Ramat S2, Rosini F1, Pretegiani E3, Federico A4, Rufa A1.

    Author information

    1
    Eye Tracking and Visual Application Lab (EVA Lab), Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
    2
    Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
    3
    Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, MD, United States.
    4
    UOC Neurology and Neurometabolic Diseases, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.

    Abstract

    OBJECTIVE:

    To investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD), a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT) spectrum disorders.

    METHODS:

    Saccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD. Visually guided saccades were compared with those of 40 healthy subjects. Steady fixation was tested in primary and eccentric positions. Quantitative characterization of saccade parameters, saccadic intrusions (SI), and nystagmus was performed.

    RESULTS:

    Patients showed abnormally hypermetric and fast horizontal saccades to the left and greater inaccuracy than healthy subjects in all saccadic eye movements. Eye movement abnormalities included slow eye movements that preceded the initial saccade. Horizontal and vertical spontaneous jerk nystagmus, gaze-evoked, and rebound nystagmus were evident. Fixation was interrupted by large square-wave jerk SI and macrosaccadic oscillations.

    CONCLUSION:

    Slow eye movements accompanying saccades, SI, and cerebellar nystagmus are frequently seen in AT patients, additionally our ATLD patients showed the presence of fast and hypermetric saccades suggesting damage of granule cell-parallel fiber-Purkinje cell synapses of the cerebellar vermis. A dual pathogenetic mechanism involving neurodevelopmental and neurodegenerative changes is hypothesized to explain the peculiar phenotype of this disease.

    KEYWORDS:

    Purkinje cells; ataxia-telangiectasia-like disorder; granule cells; parallel fibers; saccade hypermetria

    PMID:
     
    29170652
     
    PMCID:
     
    PMC5684103
     
    DOI:
     
    10.3389/fneur.2017.00596

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