Bibliography

  • Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.
    الزيارات: 140
     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.
    الزيارات: 145
     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.
    الزيارات: 170
     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.
    الزيارات: 145
     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.
    الزيارات: 121
     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.
    الزيارات: 171
     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
    الزيارات: 99

    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)
    الزيارات: 331
    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,
     

    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
    الزيارات: 314
    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.
    الزيارات: 136
     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
    الزيارات: 144
     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.
    الزيارات: 136
     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.
    الزيارات: 125
     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.
    الزيارات: 117
     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
    الزيارات: 143
    . 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.
    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
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      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
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      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
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      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.
  • [Two cases of T lymphocyte malignant tumor secondary to ataxia telangiectasia syndrome]
    الزيارات: 146
    . 2021 Nov 2;59(11):973-975.
     doi: 10.3760/cma.j.cn112140-20210406-00294.

    [Two cases of T lymphocyte malignant tumor secondary to ataxia telangiectasia syndrome]

    [Article in Chinese]
    X H Huang1, Y J Gao1, C C Chen1, Y L Han1, Z Wang1, S H Shen1, W T Hu1
    Affiliations 

    Affiliation

    • 1Department of Hematology Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Key Laboratory of Children's Hematology Oncology, National Health Commission, Shanghai 200125, China.

    Abstract

    2例患儿均于1岁左右出现进行性神经发育倒退及共济失调，并于学龄期罹患T淋巴细胞恶性肿瘤，同时经基因检测确诊毛细血管扩张共济失调综合征。本病自婴幼儿期发病，以神经系统症状为主要表现，伴毛细血管扩张及免疫缺陷，极易误诊。合并恶性肿瘤后对常规剂量化疗尤其是甲氨蝶呤及环磷酰胺敏感，极易出现严重化疗相关不良反应，需行个体化治疗。.

    Both children developed progressive neurodevelopmental regression and ataxia around 1 year old, and developed T lymphocyte malignancies at school age. At the same time, the telangiectasia ataxia syndrome was diagnosed by genetic testing. The disease begins in infants and young children. It is mainly manifested by neurological symptoms, accompanied by telangiectasia and immunodeficiency, which is easy to be misdiagnosed. Malignant tumors are sensitive to conventional dose chemotherapy, especially methotrexate and cyclophosphamide, and are prone to severe chemotherapy-related adverse reactions, requiring individualized treatment. 

    Ambos niños desarrollaron regresión progresiva del neurodesarrollo y ataxia alrededor del año de edad, y desarrollaron tumores malignos de linfocitos T. Al mismo tiempo, el síndrome de telangiectasia ataxia fue diagnosticado mediante pruebas genéticas. La enfermedad comienza en lactantes y niños pequeños y se manifiesta principalmente por síntomas neurológicos, acompañados de telangiectasia e inmunodeficiencia, que es fácil de diagnosticar erróneamente. Los tumores malignos son sensibles a la quimioterapia de dosis convencional, especialmente metotrexato y ciclofosfamida, y son propensos a reacciones adversas graves relacionadas con la quimioterapia, que requieren un tratamiento individualizado.

     

    MeSH terms

  • X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia
    الزيارات: 175
    . 2021 Oct 23;1-9.
     doi: 10.1007/s10875-021-01151-y. Online ahead of print.

    X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

    Hassan Abolhassani12, Ahmad Vosughimotlagh3, Takaki Asano4, Nils Landegren56, Bertrand Boisson478, Samaneh Delavari2, Paul Bastard78, Maribel Aranda-Guillén6, Yating Wang1, Fanglei Zuo1, Fabian Sardh56, Harold Marcotte9, Likun Du1, Shen-Ying Zhang4, Qian Zhang4, Nima Rezaei2, Olle Kämpe610, Jean-Laurent Casanova47811, Lennart Hammarström1, Qiang Pan-Hammarströmqiang.pan-hammarstrom@ki.se." href="https://pubmed.ncbi.nlm.nih.gov/34686943/#affiliation-12" ref="linksrc=author_aff" style="box-sizing: inherit; background-color: rgb(241, 241, 241); color: rgb(50, 58, 69); text-decoration: none; font-size: inherit; display: inline-block; line-height: 1; padding: 0.1rem 0.3rem; border-radius: 2px; transition: color 0.3s ease 0s; margin-right: 0px;">12
    Affiliations 

    Affiliations

    • 1Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden.
    • 2Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
    • 3Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
    • 4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
    • 5Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    • 6Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
    • 7Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
    • 8University of Paris, Imagine Institute, Paris, France.
    • 9Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    • 10Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
    • 11Howard Hughes Medical Institute, New York, NY, USA.
    • 12Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden. qiang.pan-hammarstrom@ki.se.
    Free PMC article

    Abstract

    Background: Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.

    Objectives: We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).

    Methods: Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.

    Results: We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.

    Conclusions: We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

    Keywords: ATM; COVID-19; TLR7; antibody deficiency; ataxia-telangiectasia; critical COVID-19; inborn errors of immunity; primary immunodeficiency.

  • Effects of Acetyl-DL-Leucine on Ataxia and Downbeat-Nystagmus in Six Patients With Ataxia Telangiectasia
    الزيارات: 129
    . 2021 Oct 7;8830738211028394.
     doi: 10.1177/08830738211028394. Online ahead of print.

    Effects of Acetyl-DL-Leucine on Ataxia and Downbeat-Nystagmus in Six Patients With Ataxia Telangiectasia

    Adriana Brueggemann12, Antonela Bicvic32, Martina Goeldlin3, Roger Kalla3, Hassen Kerkeni3, Georgios Mantokoudis4, Mathias Abegg5, Miriam Kolníková6, Markus Mohaupt13, Tatiana Bremova-Ertl1378
    Affiliations 

    Affiliations

    • 1Department of Internal Medicine, Sonnenhofspital, Lindenhofgruppe, Bern, Switzerland.
    • 2Shares the first author place.
    • 3Department of Neurology, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland.
    • 4Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland.
    • 5Department of Ophthalmology, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland.
    • 6Comenius University Children's Hospital, Department of Child Neurology, Bratislava, Slovak Republic.
    • 7Center for Rare Diseases, Institute for Clinical Chemistry, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland.
    • 8German Center for Vertigo and Balance Disorders, Ludwig-Maximilians University Hospital, Campus Grosshadern, Munich, Germany.

    Abstract

    Background: There is no authorized treatment for ataxia telangiectasia (AT). As cerebellar symptoms of storage diseases were improved by acetyl-DL-leucine (ADLL), the authors hypothesized a symptomatic and disease-modifying effect in AT upon supplementation with ADLL.

    Methods: Six patients were treated with ADLL 3 g/day for 1 week followed by 5g/day for 3 weeks to 1 year. Cerebellar ataxia was evaluated by validated scales. Gaze-holding, saccades and smooth pursuit were examined by video-oculography. Measurements took place at baseline, at 1 month of therapy in 5 patients, and after 6 and 12 months in 1 patient.

    Results: The Scale for Assessment and Rating of Ataxia changed from the baseline, mean, (SD, min-max) of 22.1 (5.88, 11-28.5) to 18 points (5.39, 8.5-23.5) after 1 month on medication (P = .0028). All patients demonstrated gaze-holding deficits; 3 patients had central-position downbeat-nystagmus. Mean slow-phase velocity of this nystagmus with the gaze straight-ahead changed from 5.57°/s (1.8, 3.53-6.99) to 4.7°/s (0.79, 3.97-5.56) after 1 month on treatment (1.35, -2.56-4.17) (P = .046).

    Interpretation: ADLL may improve ataxia and ocular stability in AT patients, while the molecular basis still remains to be elucidated. A multicentric, rater-blinded, phase II trial currently investigates the effects of acetyl-L-leucine in AT (NCT03759678).

    Keywords: ataxia; cerebellum; neurodevelopment; pediatric; quality of life.

  • Novel Compound Heterozygous Mutation c.3955_3958dup and c.5825C>T in the ATM Gene: Clinical Evidence of Ataxia-Telangiectasia and Cancer in a Peruvian Family
    الزيارات: 138
    . 2021 Aug;12(5):289-293.
     doi: 10.1159/000515696. Epub 2021 Jun 17.

    Novel Compound Heterozygous Mutation c.3955_3958dup and c.5825C>T in the ATM Gene: Clinical Evidence of Ataxia-Telangiectasia and Cancer in a Peruvian Family

    Richard S Rodriguez123, Mario Cornejo-Olivas14, Jeny Bazalar-Montoya1, Elison Sarapura-Castro1, Mariela Torres-Loarte56, Andrea Rivera-Valdivia178, Yasser Sullcahuaman-Allende235
    Affiliations 

    Affiliations

    • 1Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, Lima, Peru.
    • 2Equipo funcional de Genética y Biología Molecular, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
    • 3Facultad de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru.
    • 4Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru.
    • 5IGENOMICA, Instituto de Investigación Genómica, Lima, Peru.
    • 6School of Medicine, Universidad Peruana de Ciencias Aplicadas, Lima, Peru.
    • 7Fogarty Interdisciplinary Cerebrovascular Diseases Training Program in South America, Lima, Peru.
    • 8Fogarty Northern Pacific Global Health Fellows Program, Seattle, Washington, USA.
    • PMID: 34602955
      •  
    • PMCID: PMC8436714 (available on )
      •  
    • DOI: 10.1159/000515696

    Abstract

    Pathogenic and likely pathogenic variants in the ATM gene are associated both with Ataxia-telangiectasia disease or ATM syndrome and an increased cancer risk for heterozygous carriers. We identified a novel compound heterozygous mutation c.3955_3958dup (p.Asp1320delinsValTer) and c.5825C>T (p.Ala1942Val) in the ATM gene in a Peruvian patient with progressive ataxia combined with other movement disorders, mild conjunctival telangiectasia and increased alpha-fetoprotein, without history of recurrent infection or immunodeficiency. We also determined the carrier status of the family members, and we were able to detect gastric and breast cancer at an early stage during the cancer risk assessment in the mother (c.3955_3958dup). Here, we describe clinical evidence for the novel compound heterozygous mutation and c.3955_3958dup not previously reported.

    Keywords: ATM; Ataxia-telangiectasia; c.3955_3958dup; c.5825C>T; rs1591646379; rs730881394.

  • Functions of NK and iNKT cells in pediatric and adult CVID, ataxia telangiectasia and agammaglobulinemia patients
    الزيارات: 121
    . 2021 Sep 30;240:46-55.
     doi: 10.1016/j.imlet.2021.09.008. Online ahead of print.

    Functions of NK and iNKT cells in pediatric and adult CVID, ataxia telangiectasia and agammaglobulinemia patients

    Suzan Adin-Cinar1, Metin Yusuf Gelmez1, Nilgun Akdeniz1, Gulce Ozcit-Gurel1, Ayca Kiykim2, Elif Karakoc-Aydiner3, Isil Barlan3, Gunnur Denizgdeniz@istanbul.edu.tr." href="https://pubmed.ncbi.nlm.nih.gov/34599947/#affiliation-4" ref="linksrc=author_aff" style="box-sizing: inherit; background-color: rgb(241, 241, 241); color: rgb(50, 58, 69); text-decoration: none; font-size: inherit; display: inline-block; line-height: 1; padding: 0.1rem 0.3rem; border-radius: 2px; transition: color 0.3s ease 0s; margin-right: 0px;">4
    Affiliations 

    Affiliations

    • 1Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
    • 2Division of Pediatric Allergy and Immunology, Istanbul Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.
    • 3Division of Pediatric Allergy and Immunology, Marmara Medical Faculty, Marmara University, Istanbul, Turkey.
    • 4Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey. Electronic address: gdeniz@istanbul.edu.tr.

    Abstract

    Primary immune deficiencies (PID) are known to be more than 400 genetic defects caused by the impairment in development and/or functions of the immune system. Common Variable Immunodeficiency (CVID), Ataxia Telangiectasia (AT) and Agammaglobulinemia (AG) are examples of the most common immunodeficiency syndrome. Natural killer (NK) cells are a component of innate immune system and play a major role in the host-rejection of both tumors and virally infected cells. iNKT cells have a role in autoimmune and infectious diseases and controlling of tumor rejection. In this study, NK and iNKT cells and their functions, and intracellular cytokine amount are aimed to determine in patients that suffer CVID, AT and AG. NKp30, NKp46, NKG2D, perforin and granzyme mRNA expression levels were analyzed using RT-PCR. Receptors, cytokine amount of NK cell subset and iNKT were analyzed by flow cytometry. Decreased CD3+ T and elevated NK cell subset in pediatric AT were found. Expression of NKp44 was decreased in adult AG, but not in pediatric patients. Low NKp44 expression in CD3-CD16+CD56dim NK cell subset was found in pediatric AT patients. High HLA-DR, perforin and granzyme expression were found in CD3-CD16+CD56dim NK cell subset of pediatric CVID and AT patients. Alteration of the number of NK subsets, NK receptor expression and cytokine production were observed in pediatric patients compared to healthy subjects.

    Keywords: NK; Natural killer cell subset; Primary immunodeficiency.

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