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- OPEN ACCESSBackground: Inherited defects in the function of the purine nucleoside phosphorylase (PNP) enzyme can cause severe T cell immune deficiency and early death from infection, autoimmunity, or malignancy. In addition, more than 50% of patients suffer diverse non-infectious neurological complications. However the cause for the neurological abnormalities are not known.Objectives: Differentiate induced pluripotent stem cells (iPSC) from PNP-deficient patients into neuronal cells to better understand the effects of impaired purine metabolism on neuronal development.Methods: Sendai virus was used to generate pluripotent stem cells from PNP-deficient and healthy control lymphoblastoid cells. Cells were differentiated into neuronal cells through the formation of embryoid bodies.Results: After demonstration of pluripotency, normal karyotype, and retention of the PNP deficiency state, iPSC were differentiated into neuronal cells. PNP-deficient neuronal cells had reduced soma and nuclei size in comparison to cells derived from healthy controls. Spontaneous apoptosis, determined by Caspase-3 expression, was increased in PNP-deficient cells.Conclusions: iPSC from PNP-deficient patients can be differentiated into neuronal cells, thereby providing an important tool to study the effects of impaired purine metabolism on neuronal development and potential treatments.Statement of novelty: We report here the first generation and use of neuronal cells derived from induced pluripotent stem cells to model human PNP deficiency, thereby providing an important tool for better understanding and management of this condition.
- OPEN ACCESSBackground: Cartilage-hair hypoplasia (CHH), caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene, is associated with diverse immune abnormalities including combined immune deficiency (CID). Most patients with CHH are managed with supportive measurements, while few have received allogeneic hematopoietic stem cell transplantations (HSCT). The progression of the immune abnormalities and the impact of HSCT in patients with CHH and CID have not been well characterized.Methods: The clinical and laboratory findings of 2 siblings diagnosed in infancy with CHH and CID due to the common 70A>G mutation in RMRP, including the effects of HSCT performed in 1 of them, were compared.Results: Both patients suffered from recurrent respiratory infections at early age with reduced T cells numbers and responses. Patient 1 immune function continued to deteriorate leading to HSCT from an HLA-matched sibling at 4.5 years of age. The patient suffered acute and chronic graft versus host disease of the skin with residual mild joint contractures and scleroderma-like skin changes. Seven years after HSCT patient 1 has normal immune function. Immune evaluations of patient 2 in the first years of life indicated mild improvement. The patient did not have a suitable related HSCT donor and the family elected to continue with supportive care. At 7 years of age, patient 2 is clinically well and thriving with persistent T cell abnormalities.Conclusions: Close monitoring of immune function in early life for patients with CHH and CID as well as the availability of suitable donors assists in determining management, including HSCT.Statement of novelty: The manuscript demonstrates the importance of close monitoring and personalized approach in the management of patients affected by CHH.
- OPEN ACCESS
- Anne Pham-Huy,
- Vy Hong-Diep Kim,
- Elizabeth Nizalik,
- Gabrielle Weiler,
- Jennifer Vethamuthu, and
- Eyal Grunebaum
Inherited defects in the ubiquitous adenosine deaminase (ADA) enzyme disrupt the function of the immune system as well as many other organs and tissues. Some patients may also suffer from kidney damage. Here we report on an ADA-deficient patient who was treated with ADA replacement therapy from infancy and at 6 years of age developed acute kidney failure, thrombocytopenia, and severe anemia. A kidney biopsy demonstrated mesangiolysis and occlusion of kidney loops by erythrocytes and platelet aggregates, which is consistent with hemolytic-uremic syndrome (HUS). There was no evidence of exposure to Shiga toxins, nor were any complement abnormalities detected. The kidney function improved following hemodialysis. Our report demonstrates the increased susceptibility of ADA-deficient patients to develop HUS and expands the nonimmune abnormalities associated with ADA deficiency. This further emphasizes the vigilance required when caring for such patients.Statement of novelty: Here we provide the first detailed clinical and histological characterization of hemolytic-uremic syndrome developing in an ADA-deficient patient. - OPEN ACCESS
- Vy H.D. Kim,
- Rae Brager,
- Julia Upton,
- Bo Ngan,
- Andrea Newell,
- Maian Roifman,
- Aleixo M. Muise,
- Susanne M. Benseler,
- Eyal Grunebaum, and
- Chaim M. Roifman
Mutations in IL-10R1, IL-10R2, and IL-10 have been identified in infants with severe colitis. The only possible hope for cure in these conditions is a hematopoietic stem cell transplantation (HSCT). We report here on a patient with IL-10R1 deficiency who suffered severe colitis and arthritis. She received a HSCT from a matched unrelated donor and her post-transplant course was uneventful. She has fully engrafted and her immune reconstitution was complete and robust. Although signs of colitis were completely resolved, arthritis was not reversed by HSCT. She continues to have joint swelling in the knees and inflammatory changes in the wrists. In conclusion, HSCT seems to have reversed colitis, but was insufficient to improve arthritis and possibly other autoimmune manifestations.Statement of novelty: This report describes a successful HSCT in severe infantile colitis caused by mutations in IL-10R1. Yet, the arthritis remains active, suggesting that conditions such as severe rheumatic disorders in childhood may not be reversed by replacement of the hematopoietic system. - OPEN ACCESSIntroduction: The transcription factor Signal Transducer and Activator of Transcription 1 (STAT1) is a key element in many of the signalling cascades involved in immune system function. Different mutations in STAT1 are associated with heterogeneous clinical phenotypes that range from early fatality due to overwhelming infection to limited involvement of the mucus membrane with recurrent Candida infections. Multiple genes related to immune function have been associated with the development of hemophagocytic lymphohistiocytosis (HLH), but the association between STAT1 mutation and HLH has not been described in detail.Methods: We report the genetic background of a patient with chronic mucocutaneous candidiasis (CMC) as well as an unusual clinical course.Results: In this study we describe a patient with a mutation in the STAT1 DNA-binding domain and a history of CMC who developed a refractory and fatal case of HLH despite having bone marrow transplantation.Conclusion: We describe a patient with refractory and fatal HLH who was found to have a mutation in the DNA-binding domain of STAT1.Statement of novelty: The association of chronic mucocutaneous candidiasis with HLH.
