NEMO is a complicated disease caused by a genetic mutations in the IKBKG gene. The official name of this gene is “inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma.” NEMO can involve many different cells of the body, and it often manifests in different ways in different individuals depending on the location of the mutation inside the gene. The most common clinical finding are skin and dental issues and susceptibility to specific bacterial, viral infections It’s considered an immunodeficiency that affects multiple facets of the immune system. Patients often have severe infections that can affect virtually any part of the body.
Definition of NEMO
NEMO originated as a clinical association between ectodermal dysplasia (ED) and susceptibility to infections. Such patients had the constellation of findings consistent with ectodermal dysplasia (thickened skin, conical teeth, absence of sweat glands, as well as thin and sparse hair). In addition to the dry, flaky skin of ectodermal dysplasia, patients had a range of infections with pyogenic organisms (S. pneumoniae and S. aureus) being the most prevalent. Infections were found in a range of tissues including the lungs, skin, central nervous system, liver, abdomen, urinary tract, bones, and gastrointestinal tract. Almost all cases occur in boys.
The early description of these patients indicated a range of severity and infections. Many patients exhibited B cell problems with a complete lack of response against bacteria such as S. pneumoniae. Other patients exhibited defects in other arms of the immune system with susceptibility to mycobacteria and skin infections.
In 2001, research uncovered the genetics of the large majority of these cases, and in these patients, the disease was renamed NEMO to reflect the genetic mutation. NEMO is a protein, it stands for the NF-κB Essential Modulator and is also known as the Inhibitor of Kappa Kinase γ (IKKγ). The protein acts as a scaffold for two other proteins to form a protein kinase complex. This complex is required for the downstream activation of the NF-κB family of transcription factors, which further regulate gene expression. This family of proteins regulates the development of a number of organ systems, including the immune system. Indeed, in the complete absence of NEMO activity, the effects cause embryonic lethality.
In patients with NEMO, the NEMO protein retains residual activity, but the activity is blunted. These “hypomorphic” proteins allow an embryo to develop, but many organ systems fail to develop normally, including the immune system. In the NEMO syndrome, B cells, T cells, neutrophils, macrophages, and dendritic cells respond poorly to bacterial and fungal invasion. This leads to problems in the engagement of the innate immune system as well as the formation of protective antibodies against microbes. The discovery of the genetics helped explain why patients showed such a wide-range of infectious susceptibilities.
There is at least one additional genetic cause of NEMO with defects in a similar pathway. While this form can affect both males and females, the disease is extremely rare.