Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up

Kammermeier, Jochen; Lucchini, Giovanna; Worth, Austen; Rampling, Dyanne; Amrolia, Persis; Silva, Juliana; Chiesa, Robert; Rao, Kanchan; Noble‐Jamieson, G.; Gasparetto, Marco; Ellershaw, Drew; Uhlig, Holm H.; Sebire, Neil J.; Elawad, Mamoun; Notarangelo, Luigi D.; Shah, Neil; Veys, Paul

doi:10.1182/blood-2016-01-696385

Cited by 49 publications

(52 citation statements)

References 18 publications

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“…Surgical resection is the main strategy to relieve single and multiple intestinal obstructions. After relieving the obstruction, refractory diarrhea underlying apoptotic enteropathy occurs, persists, and barely responds to immunosuppressive treatments including steroids, azathioprine, methotrexate, cyclosporine, sirolimus, tacrolimus, and anti-TNF-α agonists (infliximab and adalimumab) ( 40 , 51 ), as seen in our patients. In addition to the comorbidity of CID, defective intestinal barriers and long-term central TPN lines increase infection susceptibility to the gut Gram-negative and cutaneous Gram-positive pathogens, which are slightly different from common opportunistic pathogens in patients with classic CID.…”

Section: Discussionsupporting

confidence: 54%

“…Tetratricopeptide repeat domain 7A mutations were first identified by WES in a French–Canadian family in 2013, who had the founder effect of four nucleotide deletions leading to skipping exon 7 and losing seven TPR domains ( 32 ). Since then, the two female siblings in the current study plus a few patients from Caucasian ( 35 ), Saudi Arabia ( 36 ), Norway ( 34 ), Sri Lanka ( 34 ), Israel ( 37 ), Serbia ( 36 ), Bosnia ( 36 ), Italy ( 36 ), Malaysia ( 38 ), Turkey ( 39 ), and Britain ( 40 ) have been reported to have TTC7A mutations causing the complex phenotype of MIA–CID–IBD disorders. Of note, approximately 75% of the patients (37/49) had the CID phenotype, which was mainly caused by a disorganized thymus prohibiting lymphocyte development, thus causing CID (combined B and T cell deficiencies in 27 and T cell deficiency in 10 patients).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the comorbidity of CID, defective intestinal barriers and long-term central TPN lines increase infection susceptibility to the gut Gram-negative and cutaneous Gram-positive pathogens, which are slightly different from common opportunistic pathogens in patients with classic CID. Successful HSCT can restore immunity to overcome thymus dysfunction ( 40 ). However, the severity of intestinal inflammation and the frequency of stenosis underlying persistent apoptotic enteropathy can only marginally attenuate flare-ups rather than completely cure them ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

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Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison

et al. 2017

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The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodeficiency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two siblings who began to suffer from refractory diarrhea with a poor response to aggressive antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal obstruction. Their lymphocyte proliferation was low, but superoxide production and IL-10 signaling were normal. Candidate genetic approach targeted to genes involved in PIDs with inflammatory bowel disease (IBD)-like manifestation was unrevealing. Whole-genome sequencing revealed novel heterozygous mutations Glu75Lys and nucleotide 520–521 CT deletion in the tetratricopeptide repeat domain 7A (TTC7A) gene. A Medline search identified 49 patients with TTC7A mutations, of whom 20 survived. Their phenotypes included both multiple intestinal atresia (MIA) and combined T and/or B immunodeficiency (CID) in 16, both IBD and CID in 14, isolated MIA in 8, MIA, IBD, and CID complex in 8, and isolated IBD in 3. Of these 98 mutant alleles over-through the coding region clustering on exon 2 (40 alleles), exon 7 (12 alleles), and exon 20 (10 alleles), 2 common hotspot mutations were c.211 G>A (p.E71K in exon 2) in 26 alleles and AAGT deletion in exon 7 (+3) in 10 alleles. Kaplan–Meier analysis showed that those with biallelic missense mutations (p = 0.0168), unaffected tetratricopeptide repeat domains (p = 0.0311), and developing autoimmune disorders (p = 0.001) had a relatively better prognosis. Hematopoietic stem cell transplantation (HSCT) restored immunity and seemed to decrease the frequency of infections; however, refractory diarrhea persisted. Clinical improvement was reported upon intestinal and liver transplantation in a child with CID and MIA of unknown genetic etiology. In conclusion, patients with TTC7A mutations presenting with the very early onset of refractory diarrhea had limit improvement by HSCT or/and tailored immunosuppressive therapy in the absence of suitable intestine donors. We suggest that MIA–CID–IBD disorder caused by TTC7A mutations should also be included in the PID classification of “immunodeficiencies affecting cellular and humoral immunity” to allow for prompt recognition and optimal treatment.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison

et al. 2017

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“…HSCT did not correct for the epithelial-intrinsic defect and enteral tolerance. 182 This further highlights the importance of identifying underlying genetic cause of VEO-IBD to reduce treatment-related mortality. More research needs to be performed in order to elucidate the roles of gene defects in cell types in which they were not implicated before.…”

Section: G Enomi C S and Its Influen Ce On Ther Apeuti C G U Idelinmentioning

confidence: 96%

“…In the case of a genetic mutation in a gene that affects both the immune and epithelial barrier (for example TTC7A deficiency), HSCT did not correct for the epithelial‐intrinsic defect and enteral tolerance . This further highlights the importance of identifying underlying genetic cause of VEO‐IBD to reduce treatment‐related mortality.…”

Section: Genomics and Its Influence On Therapeutic Guidelines For Veomentioning

confidence: 99%

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Pázmándi

Kalinichenko

Ardy

et al. 2018

Immunological Reviews

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Summary Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

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Immune‐mediated inflammatory diseases of the gastrointestinal tract: Beyond Crohn's disease and ulcerative colitis

et al. 2022

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Immune‐mediated inflammatory diseases (IMIDs) are a diverse group of complex inflammatory diseases that result from dysregulated immune pathways and can involve any system of the human body. Inflammatory bowel disease (IBD) is one such disease involving the gastrointestinal (GI) system. With high prevalence in the West and increasing incidence in newly industrialized countries, IBD poses a significant burden on health care. IMIDs of the GI system other than IBD can have similar clinical features, causing diagnostic and therapeutic challenges. Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation. Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD. This review describes various IMIDs of the GI tract that mimic IBD.

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Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up

Cited by 49 publications

References 18 publications

Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison

Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Immune‐mediated inflammatory diseases of the gastrointestinal tract: Beyond Crohn's disease and ulcerative colitis

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