Immunodeficiency with Multiple Intestinal Atresias (TTC7A)
Multiple intestinal atresia and combined immunodeficiency MIA-CID (MIM 243150) is an autosomal recessive disorder caused by mutations in the TTC7A gene (MIM 609332).
Tetratricopeptide repeat domain 7A (TTC7A) is a gene encoding for the TTC7A protein, characterized by the tetratricopeptide repeat (TPR) region. This domain is known to be involved in protein-protein interaction in the assembly of multiprotein complexes. Proteins containing TPR domains are involved in multiple crucial biological processes, such as cell cycle regulation and transcriptional control.
TTC7A has been shown to interact with EFR3 and phosphatidylinositol 4-kinase (PI4KA-PI4KIIIα), which in turn catalyzes the conversion of phosphatidylinositol to phosphatidylinositol 4-phospate (PI4P), primary blocks of phosphoinositides involved in plasma membrane functions, polarity, and homeostasis (Avitzur et al. 2014; Lees et al. 2017; Chen et al. 2013). Lack of TTC7A diminished transport of the PI4KIIIα enzyme from the Golgi to the plasma membrane blocking phosphatidylinositol phosphorylation, which is crucial in cell polarity maintenance (Kammermeier et al. 2016).
TTC7A protein is mainly expressed in thymocytes and enterocytes, thus its crucial role in these cell types’ homeostasis. Its lack is known to lead to a reduction in thymocytes and enterocytes, as TTC7A depletion affects actin cytoskeleton rearrangements enhancing RhoA signaling, being required in its regulated form for all the major cellular functions, such as polarization, proliferation, and migration (Lemoine et al. 2014).
Lack of TTC7A leads to different degrees of intestinal epithelial disruption. In the most severe form, multiple intestinal atresias (MIA) are evident even in the antenatal period, requiring immediate surgical interventions soon after birth. These cases are usually associated with different forms of immunodeficiency, usually lacking T-lymphocytes (Samuels et al. 2013; Chen et al. 2013; Bigorgne et al. 2014; Notarangelo 2014). More recently TTC7A deficiency has been described in association with early-onset IBD (Avitzur et al. 2014), but also isolates MIA or isolated CID were described (Lien et al. 2017), extensive enteropathy or apoptotic enterocolitis, a clinical phenotype resembling CVID (Lawless et al. 2017), enteropathy-lymphocytopenia-alopecia (Lemoine et al. 2014), or tricho-hepato-enteric syndrome (SD/THE) (Neves et al. 2017). In this broad spectrum of clinical phenotypes involving at the moment less than 50 cases (Lien et al. 2017), some intermediate cases with mild immunological and intestinal involvement have also been published, such as one case resembling CVID (Lawless et al. 2017).
Autoimmune manifestations (hemolysis, thyroiditis, alopecia, diabetes, psoriasis, and onychomycosis) are frequently associated with the different forms of TTC7A deficiency (Lien et al. 2017) as well as different dermatological features, in particular ichthyosis (Leclerc-Mercier et al. 2016). The CID/SCID phenotype is mainly caused by the not-organized thymus in which lymphocytes could not develop properly. Early fatal outcome is usually related to sepsis or intestinal obstructions, underlying the impairment of both epithelial cells and lymphocytes, which cooperatively causes the disorder (Lemoine et al. 2014).
The high heterogeneity of the clinical presentations does not allow depicting a single laboratory protocol for the diagnosis of the disease, but in the most severe cases, MIA is evident soon after birth. In those cases usually, the immunological phenotype displays severe T cell lymphopenia in all the subsets, with variably reduced number of B and NK cells and low TRECs number consistent with thymopoiesis impairment leading to a CID phenotype (Fullerton et al. 2018); moreover proliferative T cell response to PHA and anti-CD3 is markedly reduced as is reduced immunoglobulin production. All these laboratory findings are consistent with high occurrence of severe bacterial and viral infections in the patients.
These CID-MIA patients are often hypogammaglobulinemic, requiring IVIG administration, and do not respond to vaccinations displaying lymphoid depletion.
Thymus biopsies in multiple observations showed different abnormalities: small size and depleted organization, with few and small Hassall’s corpuscles and a not-defined cortico-medullary organization (Chen et al. 2013; Bigorgne et al. 2014).
The gut in MIA is characterized by severe villous atrophy, with evidences of apoptosis and abolition of epithelial organization probably due to the in vitro demonstrated inversion of the apicobasal polarity (Bigorgne et al. 2014; Avitzur et al. 2014).
A final diagnosis is achieved by gene sequencing of the TTC7A gene. Mutations have been described on all the length of the gene and include all the possible kind of mutations, with a possible founder effect for a 4nucleotide deletion in exon 7 found in multiple French-Canadian patients with MIA-CID (Samuels et al. 2013). There not seems to exist a genotype-phenotype correlation, as the same mutation could give the complete MIA-CID phenotype, or only the MIA one, but it seems clear that the more severe cases usually do not express TTC7A protein, while cases with a phenotype limited to bowel with no MIA usually express protein at low levels as a result of double missense mutations (Samuels et al. 2013). What is not yet clear is if a partial defect due to hypomorphic mutations could affect only the expression in the intestinal epithelium, while more severe mutations could affect also the thymus giving the more complex clinical phenotype.
Due to the broad range of clinical presentation, no standardized protocol for TTC7A deficiency treatment is actually in use. The kind of treatment is usually dictated by the clinical phenotype. The soon after birth bowel resection is the needed intervention to remove atresias, and liver and small bowel transplantation could be an option (Gilroy et al. 2004; Lien et al. 2017). In the MIA cases with CID phenotype, hematopoietic stem cell transplantation has been attempted to correct the thymus defect. Treatment demonstrated efficacy and safeness from the immunological point of view, but the persistent lack of TTC7A in the enterocytes hesitates in HSCT as a non-definitive curative measure with refractory diarrhea and fatal outcome in the need for intestinal transplantation (Lien et al. 2017) Anyhow longer follow-up data on HSCT in TTC7A deficiency will help to understand whether the treatment will be at least partially efficient (Kammermeier et al. 2016).
In cases characterized by isolated enteropathy, usually total parenteral nutrition (TPN) is required for life, while in cases with mild immune involvement, IVIG and antibiotic prophylaxis will be added. Refractory diarrhea seen in apoptotic enteropathy usually does not respond to immunosuppression with steroids, azathioprine, methotrexate, cyclosporine, sirolimus, tacrolimus, and anti-TNF-α agonists (Lien et al. 2017).
Due to TTC7A involvement in modulation of Rho kinase activity and effective use in vitro of Rho kinase (ROCK) inhibitors to revert enterocytes apoptosis in patients’ organoids, it has been suggested that the use of ROCK inhibitors could become a possible therapeutic option (Bigorgne et al. 2014).
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