Human Genetics of Tuberculosis of the Nervous System

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.