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Open Access 01-12-2018 | Research article

Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia

Authors: Alexander Krauthammer, Avishay Lahad, Lior Goldberg, Ifat Sarouk, Batia Weiss, Raz Somech, Michalle Soudack, Itai M. Pessach

Published in: BMC Pediatrics | Issue 1/2018

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.

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McKinnon PJ. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol. 2012;7:303–21. https://doi.org/10.1146/annurev-pathol-011811-132509.CrossRefPubMed

Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14(4):197–210. https://doi.org/10.1038/nrm3546.CrossRef

Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in Ataxia telangiectasia. J Pediatr. 2004;144(4):505–11. https://doi.org/10.1016/j.jpeds.2003.12.046.CrossRefPubMed

Crawford TO. Ataxia telangiectasia. Semin Pediatr Neurol. 1998;5(4):287–94. https://doi.org/10.1016/S1071-9091(98)80007-7.CrossRefPubMed

Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P, McDermott EM. Immune deficiency in Ataxia-telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol. 2014;176(2):275–82. https://doi.org/10.1111/cei.12262.CrossRefPubMedPubMedCentral

McConville CM, Stankovic T, Byrd PJ, McGuire GM, Yao QY, Lennox GG, Taylor MR. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996;59(2):320–30.PubMedPubMedCentral

Staples ER, McDermott EM, Reiman A, Byrd PJ, Ritchie S, Taylor AM, Davies EG. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene. Clin Exp Immunol. 2008;153(2):214–20. https://doi.org/10.1111/j.1365-2249.2008.03684.x.CrossRefPubMedPubMedCentral

Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, Berkun Y, Efrati O, Amariglio N, Rechavi G, Somech R. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol. 2014;34(5):561–72. https://doi.org/10.1007/s10875-014-0044-1.CrossRefPubMed

Vacchio MS, Olaru A, Livak F, Hodes RJ. ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks. Proc Natl Acad Sci U S A. 2007;104(15):6323–8. https://doi.org/10.1073/pnas.0611222104.CrossRefPubMedPubMedCentral

10.

Ersoy F, Berkel AI, Sanal O, Oktay H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia. Turk J Pediatr. 1991;33(4):205–15.PubMed

11.

Schroeder SA, Zielen S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2014;49(4):389–99. https://doi.org/10.1002/ppul.22817.CrossRefPubMed

12.

Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):159. https://doi.org/10.1186/s13023-016-0543-7.CrossRefPubMedPubMedCentral

13.

Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood. 2013;121(20):4036–45. https://doi.org/10.1182/blood-2012-09-456897.CrossRefPubMedPubMedCentral

14.

Weiss B, Krauthammer A, Soudack M, Lahad A, Sarouk I, Somech R, Heimer G, Ben-Zeev B, Nissenkorn A. Liver Disease in Pediatric Patients with Ataxia Telangiectasia: A Novel Report. J Pediatr Gastroenterol Nutr. 2016;62(4):550–5. https://doi.org/10.1097/MPG.0000000000001036.CrossRefPubMed

15.

Noordzij JG, Wulffraat NM, Haraldsson A, Meyts I, Van't Veer LJ, Hogervorst FB, Warris A, Weemaes CM. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child. 2009;94(6):448–9. https://doi.org/10.1136/adc.2008.149351.CrossRefPubMed

16.

Aghamohammadi A, Imai K, Moazzami K, Abolhassani H, Tabatabaeiyan M, Parvaneh N, Nasiri Kalmarzi R, Nakagawa N, Oshima K, Ohara O, Nonoyama S, Rezaei N. Ataxia-telangiectasia in a patient presenting with hyper-immunoglobulin M syndrome. J Investig Allergol Clin Immunol. 2010;20(5):442–5.PubMed

17.

Rawat A, Imai K, Suri D, Gupta A, Bhisikar S, Saikia B, Minz RW, Sehgal S, Singh S. Ataxia telangiectasia masquerading as hyper IgM syndrome. Indian J Pediatr. 2016;83(3):270–1. https://doi.org/10.1007/s12098-015-1852-x.CrossRefPubMed

18.

Tangsinmankong N, Wayne AS, Howenstine MS, Washington KR, Langston C, Gatti RA, Good RA, Nelson RP Jr. Lymphocytic interstitial pneumonitis, elevated IgM concentration, and hepatosplenomegaly in ataxia-telangiectasia. J Pediatr. 2001;138(6):939–41. https://doi.org/10.1067/mpd.2001.113356.CrossRefPubMed

19.

Azarsiz E, Karaca NE, Gunaydin NC, Gulez N, Ozturk C, Aksu G, Genel F, Kutukculer N. Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia? Int J Immunopathol Pharmacol. 2014;27(3):421–7. https://doi.org/10.1177/039463201402700312.CrossRefPubMed

20.

van Os NJH, Jansen AFM, et al. Ataxia-telangiectasia: immunodeficiency and survival. Clin Immunol. 2017;178:45–55. https://doi.org/10.1016/j.clim.2017.01.009.CrossRefPubMed

21.

Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82(6):373–84. https://doi.org/10.1097/01.md.0000100046.06009.b0.

22.

de la Morena MT. Clinical Phenotypes of Hyper-IgM Syndromes. J Allergy Clin Immunol Pract. 2016;4(6):1023–36. https://doi.og/10.1016/j.jaip.2016.09.013.

23.

Ammann AJ. Respiratory complications of ataxia-telangiectasia. N Engl J Med. 1969;281(18):1019.CrossRefPubMed

24.

Lev A, Simon AJ, Broides A, Levi J, Garty BZ, Rosenthal E, et al. Thymic function in MHC class II-deficient patients. J Allergy Clin Immunol. 2013;131(3):831–9. https://doi.org/10.1016/j.jaci.2012.10.040.CrossRefPubMed

25.

Lev A, Simon AJ, Bareket M, Bielorai B, Hutt D, Amariglio N, et al. The kinetics of early T and B cell immune recovery after bone marrow transplantation in RAG-2-deficient SCID patients. PLoS One. 2012;7(1) https://doi.org/10.1371/journal.pone.0030494.

26.

Suarez F, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol. 2015;33(2):202–8. https://doi.org/10.1200/JCO.2014.56.5101.CrossRefPubMed

27.

McFarlin DE, Strober W, Waldmann TA. Ataxia Telangiectasia. Medicine (Baltimore). 1972;51:281–314.CrossRef

28.

Ghiasy S, Parvaneh L, Azizi G, Sadri G, Zaki Dizaji M, Abolhassani H, Aghamohammadi A. The clinical significance of complete class switching defect in Ataxia telangiectasia patients. Expert Rev Clin Immunol. 2017;13(5):499–505. https://doi.org/10.1080/1744666X.2017.1292131.CrossRefPubMed

29.

Leven EA, et al. Hyper IgM syndrome: a report from the USIDNET registry. J Clin Immunol. 2016;36(5):490–501. https://doi.org/10.1007/s10875-016-0291-4.CrossRefPubMedPubMedCentral

30.

Paulino TL, Rafael MN, Hix S, Shigueoka DC, Ajzen SA, Kochi C, Suano-Souza FI, da Silva R, Costa-Carvalho BT, Sarni ROS. Is age a risk factor for liver disease and metabolic alterations in ataxia telangiectasia patients? Orphanet J Rare Dis. 2017;12:1–7. https://doi.org/10.1186/s13023-017-0689-y.CrossRef

31.

Reiman A, et al. Lymphoid tumors and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011;105(4):586–91. https://doi.org/10.1038/bjc.2011.266.CrossRefPubMedPubMedCentral

32.

Mohammadinejad P, Abolhassani H, Aghamohammadi A, Pourhamdi S, Ghosh S, Sadeghi B, Nasiri Kalmarzi R, Durandy A, Borkhardt A. Class switch recombination process in ataxia telangiectasia patients with elevated serum levels of IgM. J Immunoassay Immunochem. 2015;36(1):16–26. https://doi.org/10.1080/15321819.2014.891525.CrossRefPubMed

Title: Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia
Authors: Alexander Krauthammer
Avishay Lahad
Lior Goldberg
Ifat Sarouk
Batia Weiss
Raz Somech
Michalle Soudack
Itai M. Pessach
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Pediatrics / Issue 1/2018
Electronic ISSN: 1471-2431
DOI: https://doi.org/10.1186/s12887-018-1156-1

At a glance: The STEP trials

Springer Medicine

Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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