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Human Genetics of Tuberculosis of the Nervous System

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Tuberculosis of the Central Nervous System

Abstract

Central nervous system (CNS) disease caused by Mycobacterium tuberculosis is a devastating manifestation of tuberculosis (TB) in children. CNS TB accounts for 10% of all cases of extrapulmonary TB, with high neurological morbidity and mortality rates. The diagnosis of CNS TB remains challenging, in particular in children, as clinical features are nonspecific, bacteriological confirmation is commonly missing, and laboratory tests are insensitive. The resulting treatment delay is often the strongest risk factor for poor outcomes. While the pathogenesis of CNS TB remains poorly understood, recent findings showed that some cases of severe childhood TB could be explained by single-gene inborn errors of immunity involving the IL-12/IL-23-IFN-γ pathway. In the present study, we describe the first cases of such genetic defects in two Moroccan patients with clearly documented CNS TB. The first patient presented an autosomal recessive TYK2 deficiency leading to an impaired response to IL-12 and a resulting impaired IFN-γ production. The second patient had an autosomal dominant STAT1 deficiency affecting the response to IFN-γ. These observations also provide further support to the hypothesis that severe TB of childhood is not only an infectious disease but also a genetic disorder at least in some instances. They also pave the way for the development of new treatments based on pathophysiology such as the administration of recombinant IFN-γ in patients who have an impaired production of this cytokine.

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Abbreviations

BCG:

Bacillus Calmette-Guérin vaccine

CADD:

Combined Annotation-Dependent Depletion is a tool for scoring the deleteriousness of single-nucleotide variants as well as insertion/deletion variants in the human genome (http://cadd.gs.washington.edu)

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CT scan:

Computed tomography scan

DNA:

Deoxyribonucleic acid

EBV:

Epstein-Barr virus

EMSA:

Electrophoretic mobility shift assay

GAF:

Gamma-activating factor

GAS:

Gamma-activating sequences

GOF:

Gain of function

HIES:

Hyper IgE syndrome

IFN-γ:

Interferon gamma

IL-12:

Interleukin 12

INH:

Isoniazid

ISGF3:

Interferon-stimulated gene factor 3

LIF:

Leukemia inhibitory factor

LOF:

Loss of function

MRI:

Magnetic resonance imaging

MSMD:

Syndrome of Mendelian susceptibility to mycobacterial diseases

NK:

Natural killer cell

rh :

Recombinant human

RIF:

Rifampin

SNP:

Single-nucleotide polymorphism

TB:

Tuberculosis

TBM:

Tuberculous meningitis

WES:

Whole exome sequencing

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Author information

Authors and Affiliations

  1. Genetics Unit, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco

    Jamila El Baghdadi PhD, Safa El Azbaoui PhD student & Ayoub Sabri PhD student

  2. Faculty of Sciences – Kenitra, IbnTofail University, Kenitra, Morocco

    Safa El Azbaoui PhD student & Ayoub Sabri PhD student

  3. Department of Pediatrics P1, Clinical Immmunology Unit, Casablanca Children Hospital, Medical and Pharmacy School of Casablanca, King Hassan II University, Casablanca, Morocco

    Fatima Ailal MD

  4. Department of Neurosurgery, Avicenne Military Hospital, Marrakech, Morocco

    Ali Akhaddar MD, IFAANS

  5. Mohammed V University, Rabat, Morocco

    Ali Akhaddar MD, IFAANS

  6. St. Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller Branch, Rockefeller University Hospital, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Xiao-Fei Kong MD, PhD, Jean Laurent Casanova MD, PhD, Laurent Abel MD, PhD & Stéphanie Boisson-Dupuis PhD

  7. Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco

    Ahmed Aziz Bousfiha MD

  8. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France

    Jean Laurent Casanova MD, PhD, Laurent Abel MD, PhD & Stéphanie Boisson-Dupuis PhD

  9. Paris Descartes University, Imagine Institute, Paris, France

    Jean Laurent Casanova MD, PhD, Laurent Abel MD, PhD & Stéphanie Boisson-Dupuis PhD

  10. Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France

    Jean Laurent Casanova MD, PhD

  11. Howard Hughes Medical Institute, New York, NY, USA

    Jean Laurent Casanova MD, PhD

Authors
  1. Jamila El Baghdadi PhD
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  2. Safa El Azbaoui PhD student
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  3. Fatima Ailal MD
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  4. Ali Akhaddar MD, IFAANS
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  5. Ayoub Sabri PhD student
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  6. Xiao-Fei Kong MD, PhD
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  7. Ahmed Aziz Bousfiha MD
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  8. Jean Laurent Casanova MD, PhD
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  9. Laurent Abel MD, PhD
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  10. Stéphanie Boisson-Dupuis PhD
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Corresponding author

Correspondence to Jamila El Baghdadi PhD .

Editor information

Editors and Affiliations

  1. Adnan Menderes University, School of Medicine, Aydın, Turkey

    Mehmet Turgut

  2. Mohammed V University in Rabat, Avicenne Military Hospital of Marrakech, Rabat, Morocco

    Ali Akhaddar

  3. Hacettepe University, School of Medicine, Ankara, Turkey

    Ahmet T. Turgut

  4. King George Medical University, Lucknow, Uttar Pradesh, India

    Ravindra K. Garg

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El Baghdadi, J. et al. (2017). Human Genetics of Tuberculosis of the Nervous System. In: Turgut, M., Akhaddar, A., Turgut, A., Garg, R. (eds) Tuberculosis of the Central Nervous System. Springer, Cham. https://doi.org/10.1007/978-3-319-50712-5_2

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  • DOI: https://doi.org/10.1007/978-3-319-50712-5_2

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