Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds

Errami, Abderrahmane; Baghdadi, Jamila El; Ailal, Fatima; Bakkouri, Jalila El; Jeddane, Leïla; Rada, Noureddine; Benajiba, Noufissa; Mokhantar, Khaoula; Ouazahrou, Kaoutar; Zaidi, Sanae; Abel, Laurent; Casanova, Jean‐Laurent; Boisson–Dupuis, Stéphanie; Bustamante, Jacinta; Bousfiha, Ahmed Aziz

doi:10.1007/s10875-022-01419-x

Cited by 6 publications

(7 citation statements)

References 50 publications

(56 reference statements)

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Section: Consanguinitymentioning

confidence: 99%

“…Several studies have noted that the prevalence of IEI is closely related to consanguineous marriages [51,60]. In populations with high rates of consanguinity, such as East Asian, North African, and Middle Eastern countries, MSMD was reported to be more frequent in childhood mycobacterial disease cases than in developed countries [51,60]. This resulted in MSMD initially being categorized as autosomal recessive due to the high frequency of multiple-case siblings, as well as consanguineous relatives [51]; however, contrary to North Africa and other countries with high rates of consanguinity (>60%), a study investigating an MSMD cohort in South Africa found that consanguinity was rare and occurred in less than 2% of patients [19,20].…”

Section: Consanguinitymentioning

confidence: 99%

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Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa

Scholtz,

Jooste,

Möller

et al. 2023

IJMS

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Inborn errors of immunity (IEI) are genetic disorders with extensive clinical presentations. They can range from increased susceptibility to infections to significant immune dysregulation that results in immune impairment. While IEI cases are individually rare, they collectively represent a significant burden of disease, especially in developing countries such as South Africa, where infectious diseases like tuberculosis (TB) are endemic. This is particularly alarming considering that certain high penetrance mutations that cause IEI, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), put individuals at higher risk for developing TB and other mycobacterial diseases. MSMD patients in South Africa often present with different clinical phenotypes than those from the developed world, therefore complicating the identification of disease-associated variants in this setting with a high burden of infectious diseases. The lack of available data, limited resources, as well as variability in clinical phenotype are the reasons many MSMD cases remain undetected or misdiagnosed. This article highlights the challenges in diagnosing MSMD in South Africa and proposes the use of transcriptomic analysis as a means of potentially identifying dysregulated pathways in affected African populations.

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Section: Consanguinitymentioning

confidence: 99%

Section: Consanguinitymentioning

confidence: 99%

Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa

Scholtz,

Jooste,

Möller

et al. 2023

IJMS

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“…AR STAT1 and IRF8 deficiencies also underlie susceptibility to viral disease [ 29 , 30 ]. AR complete IFN-γR1, IFN-γR2, IFN-γ, STAT1, IRF8, and IRF1 deficiencies underlie a complete absence of the IFN-γ-mediated antimycobacterial response [ 2 , 6 , 10 – 28 , 30 ]. AR complete IFN-γR1 and IFN-γR2 deficiencies have been reported in more than 100 kindreds [ 10 – 28 ]; the patients’ cells are unable to respond to IFN-γ and hematopoietic stem cell transplantation (HCST) is the only curative treatment available [ 10 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…AR complete IFN-γR1, IFN-γR2, IFN-γ, STAT1, IRF8, and IRF1 deficiencies underlie a complete absence of the IFN-γ-mediated antimycobacterial response [ 2 , 6 , 10 – 28 , 30 ]. AR complete IFN-γR1 and IFN-γR2 deficiencies have been reported in more than 100 kindreds [ 10 – 28 ]; the patients’ cells are unable to respond to IFN-γ and hematopoietic stem cell transplantation (HCST) is the only curative treatment available [ 10 – 28 ]. AR complete IRF1 deficiency has been reported in two unrelated patients and is probably another indication for HCST [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the commercial availability of recombinant IFN-γ (IFN-γ1b), its efficacy and safety were not assessed in these patients. Patients with MSMD due to other inborn errors impairing the production of IFN-γ, such as IL-12p40 and IL-12Rβ1 deficiencies, have been shown to benefit from IFN-γ1b therapy [ 28 , 34 – 40 ]. In this context, we describe a patient from Turkey with a novel form of AR complete IFN-γ deficiency who was treated for 30 months with recombinant IFN-γ1b.…”

Section: Introductionmentioning

confidence: 99%

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Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency

Rosain,

Kiykim,

Michev

et al. 2024

J Clin Immunol

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Purpose Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-γ and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-γ have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST). Methods We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings. Results The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Guérin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient’s cells, the mutant IFN-γ was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-γ1b plus two antimycobacterial drugs. Treatment with IFN-γ1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-γ. Conclusion We describe a patient with a new form of autosomal recessive IFN-γ deficiency, with intracellular, but not extracellular IFN-γ. IFN-γ1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-γ deficiency or at least an option to better control mycobacterial infection prior to HCST.

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