Tandem hematopoietic stem cell transplant considerations in families with multiple siblings affected by DOCK8 deficiency.
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ABSTRACT:
SUBMITTER: Silbert S
PROVIDER: S-EPMC10391740 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
Publications
Tandem hematopoietic stem cell transplant considerations in families with multiple siblings affected by DOCK8 deficiency.
Silbert Sara S Cole Kristen K Bedoya Sima Z SZ Freeman Alexandra F AF Whangbo Jennifer S JS Avila Daniele N DN Su Helen C HC Yates Bonnie B Epstein Monica M Wendler David S DS Pai Sung-Yun SY Hickstein Dennis D DD Wiener Lori L Shah Nirali N NN
Bone marrow transplantation 20220823 11
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Project description:BackgroundAn 11-year-old girl with dedicator of cytokinesis 8 (DOCK8) deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease caused by chronic Cryptosporidium infection required liver transplantation before HSCT.MethodsConsequently, a staged approach of a sequential liver transplant followed by a HSCT was planned with her mother as the donor for both liver and HSCT.ResultsThe patient successfully underwent a left-lobe orthotopic liver transplant; however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3% donor lymphocyte chimerism in her peripheral blood immediately before HSCT. Haploidentical-related donor HSCT performed 2 months after liver transplantation was complicated by the development of acyclovir-resistant herpes simplex virus viremia, primary graft failure, and sinusoidal obstruction syndrome. The patient died from sinusoidal obstruction syndrome-associated multiorgan failure with Candida sepsis on day +40 following HSCT.ConclusionsWe discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection before immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.
| S-EPMC6667308 | biostudies-literature
Project description:BackgroundAminoacylase 1 (ACY1, EC 3.5.1.14) deficiency (ACY1D) is a very rare inherited metabolic disease (IMD) with autosomal recessive inheritance (OMIM #609924). Up to date, only 15 cases have been reported in the literature. It is diagnosed by detecting acetylated amino acids among the patient's urine organic acids by gas chromatography-mass spectrometry. Its clinical manifestations are highly variable, ranging from severe neurological symptoms to being asymptomatic.Case descriptionWe present a 14-year-old boy with mild intellectual disability, speech sound disorder and non-alcoholic fatty liver disease who exhibited increased urinary excretion of N-acetylalanine, N-acetylmethionine and N-acetylglutamine during testing for inherited metabolic disorders. A suspected ACY1D was subsequently confirmed by targeted next generation sequencing, which revealed the presence of a homozygous pathogenic missense mutation in the ACY1 gene, c.1057C>T (p.Arg353Cys). The proband underwent speech education with good outcome. The same homozygous mutation in ACY1 gene was found in the boy's two brothers, who exhibited slightly varied intellectual abilities. Follow-up examinations of the siblings revealed no deterioration in their mental skills.ConclusionsThese results suggest that uneven mental abilities in pediatric patients with various disorders including autism spectrum disorder may be sufficient grounds to warrant metabolic testing for ACY1D. The acylglycines urine excretion could be a promising novel metabolic marker for ACY1D testing.
| S-EPMC10789890 | biostudies-literature
Project description:We performed allogeneic hematopoietic stem cell transplantation in 6 patients with mutations in the dedicator-of-cytokinesis-8 (DOCK8) gene using a myeloablative conditioning regimen consisting of busulfan 3.2 mg/kg/day i.v. for 4 days and fludarabine 40 mg/m(2)/day for 4 days. Three patients received allografts from matched related donors and 3 patients from matched unrelated donors. Two patients received peripheral blood stem cells and 4 patients bone marrow hematopoietic stem cells. Tacrolimus and short-course methotrexate on days 1, 3, 6, and 11 were used for graft-versus-host-disease (GVHD) prophylaxis. All 6 patients are alive at a median follow-up of 22.5 months (range, 14 to 35). All patients achieved rapid and high levels of donor engraftment and complete reversal of the clinical and immunologic phenotype. Adverse events consisted of acute skin GVHD in 2 patients and post-transplant pulmonary infiltrates in a patient with extensive bronchiectasis pretransplant. Thus, a uniform myeloablative conditioning regimen followed by allogeneic hematopoietic stem cell transplantation in DOCK8 deficiency results in reconstitution of immunologic function and reversal of the clinical phenotype with a low incidence of regimen-related toxicity.
| S-EPMC4426076 | biostudies-literature
Project description:Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.
| S-EPMC6629099 | biostudies-literature
Project description:BACKGROUND: A genome-wide search for genes that predispose to type 1 diabetes using linkage analysis was performed using 900 microsatellite markers in 70 nuclear families with affected siblings from Finland, a population expected to be more genetically homogeneous than others, and having the highest incidence of type 1 diabetes in the world and, yet, the highest proportion in Europe of cases (10%) carrying neither of the highest risk HLA haplotypes that include DR3 or DR4 alleles. RESULTS: In addition to the evidence of linkage to the HLA region on 6p21 (nominal p = 4.0 x 10-6), significant evidence of linkage in other chromosome regions was not detected with a single-locus analysis. The two-locus analysis conditional on the HLA gave a maximum lod score (MLS) of 3.1 (nominal p = 2 x 10-4) on chromosome 9p13 under an additive model; MLS of 2.1 (nominal p = 6.1 x 10-3) on chromosome 17p12 and MLS of 2.5 (nominal p = 2.9 x 10-3) on chromosome 18p11 under a general model. CONCLUSION: Our genome scan data confirmed the primary contribution of the HLA genes also in the high-risk Finnish population, and suggest that non-HLA genes also contribute to the familial clustering of type 1 diabetes in Finland.
| S-EPMC2225422 | biostudies-literature
Project description:Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.
| S-EPMC8452590 | biostudies-literature
Project description:BackgroundMutations in the dedicator of cytokinesis 8 gene (DOCK8) cause a combined primary immunodeficiency syndrome that is characterized by elevated serum IgE levels, depressed IgM levels, eosinophilia, sinopulmonary infections, cutaneous viral infections, and lymphopenia. Many patients with DOCK8 deficiency were previously thought to have a variant of Job's syndrome. Distinguishing between DOCK8 deficiency and Job's syndrome, also referred to as autosomal dominant hyper-IgE syndrome, on the basis of clinical findings alone is challenging. The discovery of the DOCK8 mutation has made it possible to differentiate the cutaneous manifestations of these hyper-IgE syndromes.ObservationsTwenty-one patients from 14 families with confirmed homozygous or compound heterozygous mutations in DOCK8 were evaluated. Clinical findings included dermatitis, asthma, food and environmental allergies, recurrent sinopulmonary infections, staphylococcal skin abscesses, and severe cutaneous viral infections. Malignant neoplasms, including aggressive cutaneous T-cell lymphoma, anal and vulvar squamous cell carcinomas, and diffuse large B-cell lymphoma, developed in 5 patients during adolescence and young adulthood.ConclusionsDOCK8 deficiency and Job's syndrome share several clinical features, including elevated serum IgE levels, dermatitis, recurrent sinopulmonary infections, and cutaneous staphylococcal abscesses. However, the presence of recalcitrant, widespread cutaneous viral infections, asthma, and food and environmental allergies, as well as the absence of newborn rash and coarse facies, favors the clinical diagnosis of DOCK8 deficiency. Rates of malignancy and overall mortality in patients with DOCK8 deficiency were higher than in those with Job's syndrome, highlighting the value of distinguishing between these conditions and the importance of close monitoring for neoplasia.
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Project description:Linkage analysis is often followed by association mapping to localize disease variants. In this paper, we evaluate approaches to determine how much of the observed linkage evidence, namely the identity-by-descent (IBD) sharing at the linkage peak, is explained by associated SNPs. We study several methods: Homozygote Sharing Tests (HST), Genotype Identity-by-Descent Sharing Test (GIST), and a permutation approach. We also propose a new approach, HSTMLB, combining HST and the Maximum Likelihood Binomial (MLB) linkage statistic. These methods can identify SNPs partially explaining the linkage peak, but only HST and HSTMLB can identify SNPs that do not fully explain the linkage evidence and be applied to multiple-SNPs. We contrast these methods with the association tests implemented in the software LAMP. In our simulations, GIST is more powerful at finding SNPs that partially explain the linkage peak, while HST and HSTMLB are equally powerful at identifying SNPs that do not fully explain the linkage peak. When applied to the North American Rheumatoid Arthritis Consortium data, HST and HSTMLB identify marker pairs that may fully explain the linkage peak on chromosome 6. In conclusion, HST and HSTMLB provide simple and flexible tools to identify SNPs that explain the IBD sharing at the linkage peak.
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Project description:ObjectiveAccelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as 'pseudoatrophy', related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage.MethodsSera were collected from 22 MS patients pre- and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay.ResultsPre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL).InterpretationThere is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.
| S-EPMC7261754 | biostudies-literature
Project description:Association analyses may follow an initial linkage analysis for mapping and identifying genes underlying complex quantitative traits and may be conducted on unrelated subsets of individuals where only one member of a family is included. We evaluate two methods to select one sibling per sibship when multiple siblings are available: (1) one sibling with the most extreme trait value; and (2) one sibling using a combination score statistic based on extreme trait values and identity-by-descent sharing information. We compare the type I error and power. Furthermore, we compare these selection strategies with a strategy that randomly selects one sibling per sibship and with an approach that includes all siblings, using both simulation study and an application to fasting blood glucose in the Framingham Heart Study. When genetic effect is homogeneous, we find that using the combination score can increase power by 30-40% compared to a random selection strategy, and loses only 8-13% of power compared to the full sibship analysis, across all additive models considered, but offers at least 50% genotyping cost saving. In the presence of genetic heterogeneity, the score offers a 50% increase in power over a random selection strategy, but there is substantial loss compared to the full sibship analysis. In application to fasting blood sample, two SNPs are found in common for the selection strategies and the full sample among the 10 highest ranked single nucleotide polymorphisms. The EV strategy tends to agree with the IBD-EV strategy and the analysis of the full sample.
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