Research

Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report.

World J Clin Cases. 2020 Sep 06;8(17):3859-3866

Authors: Hu XM, Yuan K, Chen H, Chen C, Fang YL, Zhu JF, Liang L, Wang CL

Abstract
BACKGROUND: X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase (BTK). We found a new mutation point and summarized the correlation analysis and performed a literature review.
CASE SUMMARY: The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunodeficiency or recurrent infection history among his family members. Agammaglobulinemia was characterized as follows: Immunoglobulin (Ig) A, 90.0 mg/dL (90-450 mg/dL); IgG, 20.0 mg/dL (800-1800 mg/dL); and IgM, 18.0 mg/dL (60-280 mg/dL). Notably, the assessment of IgG subtypes revealed the following very low levels: Subtype 1, 0.26 g/L (3.62-12.28 g/L); subtype 2, 0.10 g/L (0.57-2.9 g/L); subtype 3, 0.009 g/L (0.129-0.789 g/L); and subtype 4, 0.003 g/L (0.013-1.446 g/L). Cellular immunological test results were as follows: CD3, 74.6% (50%-84.0%); CD4, 47.3% (27.0%-51.0%); and CD8, 24.9% (15.0%-44.0%). A de novo hemizygous deletion in BTK was detected: c.902_c.904delAAG/p.E301del. Transcript levels of the mutant BTK were similar to those of the wild-type gene, though overexpression resulted in markedly reduced levels of mutant BTK (9.49% ± 1.58%), relative to the wild-type BTK (75.8% ± 2.98%, P < 0.01).
CONCLUSION: This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK (c.902_c.904delAAG/p.E301del). The mutation resulted in markedly reduced BTK protein stability in vitro.

PMID: 32953865 [PubMed]

Powered by WPeMatico

Change of White Matter Integrity in Children With Hematopoietic Stem Cell Transplantation.

Pediatr Neurol. 2020 Oct;111:78-84

Authors: Sakaguchi Y, Natsume J, Kidokoro H, Tanaka M, Okai Y, Ito Y, Yamamoto H, Ohno A, Nakata T, Nakane T, Kawai H, Taoka T, Muramatsu H, Naganawa S, Takahashi Y

Abstract
BACKGROUND: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed.
METHODS: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared.
RESULTS: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and a higher mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation.
CONCLUSIONS: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation.

PMID: 32951667 [PubMed – in process]

Powered by WPeMatico

Integration of Genetic Variants and Gene Network for Drug Repurposing in Colorectal Cancer.

Pharmacol Res. 2020 Sep 17;:105203

Authors: Irham LM, Wong HS, Chou WH, Adikusuma W, Mugiyanto E, Huang WC, Chang WC

Abstract
Even though many genetic risk loci for human diseases have been identified and comprehensively cataloged, strategies to guide clinical research by integrating the extensive results of genetic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights into disease biology are expected to be especially useful for drug discovery. Herein, we use text mining of genetic studies on colorectal cancer (CRC) and assign biological annotations to identified risk genes in order to discover novel drug targets and potential drugs for repurposing. Risk genes for CRC were obtained from PubMed text mining, and for each gene, six functional and bioinformatic annotations were analyzed. The annotations include missense mutations, expression quantitative trait loci (eQTL), molecular pathway analyses, protein-protein interactions (PPIs), genetic overlap with knockout mouse phenotypes, and primary immunodeficiency. We then prioritized biological risk candidate genes according to a scoring system for the six functional annotations. Each functional annotation was assigned one point, and those genes with a score ≥2 were designated “biological CRC risk genes”. Using this method, we revealed 82 biological CRC risk genes, which mapped to 128 genes in an expanded PPI network. Further utilizing DrugBank and the Therapeutic Target Database (TTD), we found 21 genes in our list that are targeted by 166 candidate drugs. Based on data from ClinicalTrials.gov, we found our list contains four known target genes with six drugs approved for CRC treatment, as well as three known target genes with nine drugs under preclinical investigation for CRC. Additionally, 12 genes are targeted by 32 drugs approved for other indications, which can possibly be repurposed for CRC treatment. Finally, our analysis from Connectivity Map (CMap) showed that 18 of the 41 drugs under clinical and preclinical investigation have high potential to be useful for CRC.

PMID: 32950641 [PubMed – as supplied by publisher]

Powered by WPeMatico

Successful auxiliary liver transplant followed by haematopoietic stem cell transplantation in a boy with X-linked lymphoproliferative disease type 1.

Liver Transpl. 2020 Sep 19;:

Authors: Chartier ME, Deheragoda M, Gattens M, Dhawan A, Heaton N, Booth C, Hadzic N

Abstract
We described a five-year-old boy who presented with acute liver failure of indeterminate aetiology, requiring urgent liver transplant. Post-operative course was complicated by pancytopaenia, hypogammaglobulinaemia and cerebral lesions, histologically confirmed as EBV-driven post-transplant lymphoproliferative disease. Genetic testing showed XLP1 mutation, prompting matched-unrelated haematopoietic stem cell transplant to cure his primary immunodeficiency.

PMID: 32949066 [PubMed – as supplied by publisher]

Powered by WPeMatico

Pediatric subset of primary immunodeficiency patients treated with SCIG: post hoc analysis of SHIFT and IBIS pooled data.

Allergy Asthma Clin Immunol. 2020;16:80

Authors: Moschese V, Canessa C, Trizzino A, Martire B, Boggia GM, Graziani S, SHIFT and IBIS Study Groups

Abstract
Background: Primary immunodeficiencies (PID) constitute a heterogeneous group of more than 350 monogenetic diseases. PID patients with antibody impairment require lifelong administration of immunoglobulin G replacement therapy, administered either intravenously (IVIG) or subcutaneously (SCIG). Although the effectiveness of weekly and biweekly (every other week) SCIG administration has been shown in several trials, data on the viability of these two regimens in pediatric PID patients are sparse.
Methods: Data on the pediatric subsets of PID patients enrolled in SHIFT (weekly) and IBIS (biweekly) studies were pooled and analyzed to indirectly compare two different 20%-concentrated SCIG (Hizentra®) regimens. The primary endpoints were to evaluate trough IgG levels and cumulative monthly doses; the secondary endpoint was to analyze incidence of infections.
Results: Fifteen and 13 children from the SHIFT and IBIS studies were included, respectively. Cumulative 20%-concentrated SCIG monthly dose was slight lower for the biweekly regimen (Δ = - 2.04, 90% CI - 8.3 to 4.23). However, the trough IgG levels were similar between the two groups (Δ = 0.28, 90% CI - 0.51 to 1.07) and constantly above the threshold of 5 g/L. After adjusting for potential confounders, the annualized rate of infections was similar between SHIFT and IBIS patients (incidence rate ratio = 1.09, 90% CI 0.72-1.67); only 1 serious bacterial infection was experienced by a patient in the IBIS group.
Conclusion: In pediatric PID patients, weekly and biweekly Hizentra® administrations appeared equally effective treatment options.

PMID: 32944034 [PubMed]

Powered by WPeMatico

Incidence of malignancy in patients with common variable immunodeficiency according to therapeutic delay: an Italian retrospective, monocentric cohort study.

Allergy Asthma Clin Immunol. 2020;16:54

Authors: Pedini V, Verga JU, Terrenato I, Menghini D, Mezzanotte C, Danieli MG

Abstract
Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and has a broad spectrum of clinical manifestations. Among non-infectious complications, an increased incidence of malignancies may have a special relevance for survival, but little is known about treatment efficacy on malignant complications.
Methods: This was a monocenter retrospective study on CVID patients, designed to provide preliminary data for the investigation of the possible link between therapeutic delay and tumor incidence.
Results: A total of 67 CVID subjects were included. The median diagnostic delay was 7.5 years (range: 0-63 years), and the median therapeutic delay was 8.5 years (range: 0-67 years). Malignancies were diagnosed in 18 (27%) patients. Eight out of 18 (44%) patients with a malignancy had lymphoma. Patients who developed a malignancy showed a longer therapeutic delay in comparison to patients with no malignancy, although no statistical significance was achieved (11 years vs 8 years, respectively, p = 0.424). We observed a lower frequency of malignancy in CVID patients with reduced therapeutic delay compared with patients with therapeutic delay ≥ 10 years. With a therapeutic delay of > 1 year, 74% had no tumor, and 25% had a tumor; with a therapeutic delay of > 10 years, 65% had no tumor and 35% had a malignancy. Among patients who had no malignancy, 64% had a therapeutic delay of < 10 years, and 36% had a therapeutic delay of ≥ 10 years. Among patients with malignancy, 47% of subjects had a therapeutic delay < 10 years, and 53% a therapeutic delay ≥ 10 years.
Conclusions: The observation of clinical characteristics of our patients with CVID may suggest that an early institution of IgG replacement therapy could be of benefit for the prevention of malignant complications.Name of the registry: Comitato Etico Regionale delle Marche. Trial registration number: 1505. Date of registration: 27/10/2016, Retrospectively registered URL of trial registry record: http://www.ospedaliriuniti.marche.it/portale/archivio13_cerm-ancona_0_446_1.html. The trial was not registered before the first participant was enrolled.

PMID: 32944022 [PubMed]

Powered by WPeMatico

The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations.

Allergy Asthma Clin Immunol. 2020;16:65

Authors: Lin L, Wang Y, Sun B, Liu L, Ying W, Wang W, Zhou Q, Hou J, Yao H, Hu L, Sun J, Wang X

Abstract
Background: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation.
Methods: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed.
Results: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin.
Conclusion: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

PMID: 32944025 [PubMed]

Powered by WPeMatico

No SARS-CoV-2 neutralization by intravenous immunoglobulins produced from plasma collected before the 2020 pandemic.

J Infect Dis. 2020 Sep 17;:

Authors: Schwaiger J, Karbiener M, Aberham C, Farcet MR, Kreil TR

Abstract
The 2020 SARS-CoV-2 pandemic is caused by a zoonotic coronavirus transmitted to humans, similar to earlier events. Whether the other, seasonally circulating coronaviruses induce cross-reactive, potentially even cross-neutralizing antibodies to the new species in humans is unclear. The question is of particular relevance for people with immune deficiencies, as their health depends on treatment with immunoglobulin preparations that need to contain neutralizing antibodies against the pathogens in their environment. Testing 54 IVIG preparations, produced from plasma collected in Europe and the US, highly potent neutralization of a seasonal coronavirus was confirmed, yet no cross-neutralization of the new SARS-CoV-2 was seen.

PMID: 32941626 [PubMed – as supplied by publisher]

Powered by WPeMatico

New developments in respiratory medicine: a primary immunodeficiency perspective.

Curr Opin Allergy Clin Immunol. 2020 Sep 15;:

Authors: Ng K, Hurst JR

Abstract
PURPOSE OF REVIEW: To consider recent developments in respiratory medicine that are of relevance to clinicians caring for adults affected by primary immunodeficiency disorders.
RECENT FINDINGS: We consider impulse oscillometry, new bronchoscopic techniques for sampling, MRI and PET, the concept of the human airway microbiome, and new treatment approaches for bronchiectasis and interstitial lung disease to better understand the future of respiratory care for people with PID.
SUMMARY: New approaches to the diagnosis and management of respiratory manifestations of PID have been driven by better understanding of the lung in health and disease, progress in imaging and sampling modalities, and new therapeutics.

PMID: 32941317 [PubMed – as supplied by publisher]

Powered by WPeMatico