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Measurement of Typhim Vi® IgG antibodies in healthy donors as a tool for the diagnostic of patients with antibody deficiencies.

January 30, 2021 By Manish Butte

Measurement of Typhim Vi® IgG antibodies in healthy donors as a tool for the diagnostic of patients with antibody deficiencies.

Clin Immunol. 2020 06;215:108416

Authors: Barrios Y, Franco A, Alonso-Larruga A, García C, Suarez-Toste I, Sánchez-Machín I, Rivera-Dean A, Garcia-Marín NM, Guerra-Neira A, Matheu V

PMID: 32283323 [PubMed – indexed for MEDLINE]

Does DNA Methylation Matter in FSHD?

January 30, 2021 By Manish Butte

Does DNA Methylation Matter in FSHD?

Genes (Basel). 2020 02 28;11(3):

Authors: Salsi V, Magdinier F, Tupler R

Abstract
Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

PMID: 32121044 [PubMed – indexed for MEDLINE]

Recent Advances in the Clinical Application of Next-Generation Sequencing.

January 29, 2021 By Manish Butte

Recent Advances in the Clinical Application of Next-Generation Sequencing.

Pediatr Gastroenterol Hepatol Nutr. 2021 Jan;24(1):1-6

Authors: Ki CS

Abstract
Next-generation sequencing (NGS) technologies have changed the process of genetic diagnosis from a gene-by-gene approach to syndrome-based diagnostic gene panel sequencing (DPS), diagnostic exome sequencing (DES), and diagnostic genome sequencing (DGS). A priori information on the causative genes that might underlie a genetic condition is a prerequisite for genetic diagnosis before conducting clinical NGS tests. Theoretically, DPS, DES, and DGS do not require any information on specific candidate genes. Therefore, clinical NGS tests sometimes detect disease-related pathogenic variants in genes underlying different conditions from the initial diagnosis. These clinical NGS tests are expensive, but they can be a cost-effective approach for the rapid diagnosis of rare disorders with genetic heterogeneity, such as the glycogen storage disease, familial intrahepatic cholestasis, lysosomal storage disease, and primary immunodeficiency. In addition, DES or DGS may find novel genes that that were previously not linked to human diseases.

PMID: 33505888 [PubMed]

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice.

January 29, 2021 By Manish Butte

Icon for S. Karger AG, Basel, Switzerland

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice.

Int Arch Allergy Immunol. 2020;181(12):941-946

Authors: Ferriani MPL, Trevisan-Neto O, Costa JS, Melo JML, Moreno AS, Dias MM, Garibaldi PMM, Pereira GC, Chahud F, Traina F, Arruda LK

Abstract
BACKGROUND: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema.
OBJECTIVES: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema.
METHODS: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method.
RESULTS: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up.
CONCLUSIONS: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.

PMID: 32894844 [PubMed – indexed for MEDLINE]

[Gene analysis of a family with Wiskott-Aldrich syndrome].

January 29, 2021 By Manish Butte

[Gene analysis of a family with Wiskott-Aldrich syndrome].

Zhonghua Xue Ye Xue Za Zhi. 2020 07 14;41(7):593-594

Authors: Wang Y, Hao CL

PMID: 32810968 [PubMed – indexed for MEDLINE]

Thromboembolic Risk of C1 Esterase Inhibitors: A Systematic Review on Current Evidence.

January 29, 2021 By Manish Butte

Thromboembolic Risk of C1 Esterase Inhibitors: A Systematic Review on Current Evidence.

Expert Rev Clin Pharmacol. 2020 Jul;13(7):779-786

Authors: Burnham K, Reinert JP

Abstract
INTRODUCTION: The exact risk of developing a thromboembolic event (TEE) while using complement 1 esterase inhibitors (C1-INHs) is currently undetermined for patients with hereditary angioedema (HAE). This systematic review aimed to define the potential risk of TEEs from these agents.
AREAS COVERED: This evaluation covers publications examining or mentioning the risk of TEEs in association with C1-INHs. A systematic literature search was conducted utilizing PubMed, Scopus, and ProQuest. This review utilized search results through January 2020 and followed the PRISMA recommendations for a systematic review. Articles not available in English and animal or in-vitro studies were excluded. For inclusion, studies had to be open-label, randomized-controlled, cross-sectional, or clinical observational studies. A total of 13 studies met inclusion criteria and yielded 1716 patients receiving at least one dose of C1-INH, though only 41 incidences of thrombosis were documented.
EXPERT OPINION: Significant heterogeneity exists in the available literature concerning both study design and the reporting of data; therefore, interpretation of thrombotic risk is difficult. TEEs are rarely reported in the literature, and they seem unlikely to occur in patients without underlying risk factors. Important risk factors include those found in the prescribing information of C1-INHs.

PMID: 32476505 [PubMed – indexed for MEDLINE]

Human RAD50 deficiency: Confirmation of a distinctive phenotype.

January 29, 2021 By Manish Butte

Human RAD50 deficiency: Confirmation of a distinctive phenotype.

Am J Med Genet A. 2020 06;182(6):1378-1386

Authors: Ragamin A, Yigit G, Bousset K, Beleggia F, Verheijen FW, de Wit MY, Strom TM, Dörk T, Wollnik B, Mancini GMS

Abstract
DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.

PMID: 32212377 [PubMed – indexed for MEDLINE]

Primary Immunodeficiency Disease Mimicking Pediatric Bechet’s Disease.

January 28, 2021 By Manish Butte

Primary Immunodeficiency Disease Mimicking Pediatric Bechet’s Disease.

Children (Basel). 2021 Jan 22;8(2):

Authors: Shiraki M, Kadowaki S, Kadowaki T, Kawamoto N, Ohnishi H

Abstract
Behcet’s disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the well-studied HLA-B51, were mainly identified by genome-wide association studies. A heterozygous mutation in TNFAIP3, which leads to A20 haploinsufficiency, was found to cause an early-onset autoinflammatory disease resembling BD in 2016. Several monogenic diseases associated with primary immunodeficiency disease and trisomy 8 have recently been reported to display BD-like phenotypes. Among the genes causing these diseases, TNFAIP3, NEMO, RELA, NFKB1 and TNFRSF1A are involved in the NF-κB (nuclear factor κ light-chain enhancer of activated B cells) signaling pathway, indicating that this pathway plays an important role in the pathogenesis of BD. Because appropriate treatment may vary depending on the disease, analyzing the genetic background of patients with such diseases is expected to help elucidate the etiology of pediatric BD and assist with its treatment. Here, we summarize recently emerging knowledge about genetic predisposition to BD.

PMID: 33499153 [PubMed]

Combined Immunodeficiency (CVID and CD4 lymphopenia) is associated with a high risk of malignancy among adults with primary immune deficiency.

January 27, 2021 By Manish Butte

Combined Immunodeficiency (CVID and CD4 lymphopenia) is associated with a high risk of malignancy among adults with primary immune deficiency.

Clin Exp Immunol. 2021 Jan 26;:

Authors: Shavit R, Maoz-Segal R, Prizinsky S, Haj-Yahia S, Offengenden I, Machnas-Mayan D, Tunisky Y, Iancovici-Kidon M, Agmon-Levin N

Abstract
Primary immunodeficiency disorders (PID) are a group of heterogeneous disorders characterized by recurrent infections, autoimmunity, increased lympho-proliferative disorders and other malignancies. PID is classified into cellular or humoral disorders, or a combination of both. We evaluated the clinical differences among adult patients with 3 variants of PID: Common Variable Immunodeficiency (CVID), Idiopathic CD4 Lymphopenia (ICL), and Combined Immunodeficiency (CID). We retrospectively compared demographics, immunologic characteristics, clinical presentations and outcomes of CVID, CID and ICL patients followed during 2012- 2018. In our cohort we identified 44 adult patients diagnosed with CVID (22p), CID (11p) and ICL (11p). Malignancy was associated with CID as 7/11 patients in this group were diagnosed with malignancy compared to CVID (3/22) or ICL (2/11) (p =0.002 and 0.03 respectively). Malignancies were also linked to male gender [OR 5 CI 95% (1.12 to 22.18) P= 0.0342] and a low ratio of CD4/CD8< 0.8 [OR 5.1, CI 95% (1.22 to 21.28) P= 0.025]. Among CID and ICL, 2/11 patients died in each group while no death was documented among CVID group (P= 0.04). Autoimmune manifestations did not differ between groups. Alike, the rate of infections was similar between groups though infectious agents vary. CID is associated with a high risk of malignancy compare to CVID or ICL. Among adults with PID, male gender, low CD4, CD4/CD8 ratio of <0.8 may serve as risk factors of concomitant malignancy. Surveillance of lymphocyte subpopulations should be considered for all adults.

PMID: 33497464 [PubMed – as supplied by publisher]

Legionella pneumophila as a cause of cavitary lung disease in systemic lupus erythematous.

January 27, 2021 By Manish Butte

Legionella pneumophila as a cause of cavitary lung disease in systemic lupus erythematous.

Lupus. 2021 Jan 26;:961203321990102

Authors: Khokher W, Kesireddy N, Adunse J, Mudiyanselage PH, Iftikhar S, Assaly R

Abstract
Legionnaire’s disease (LD) is most commonly caused by Legionella pneumophila (L. pneumophila). In immunocompromised patients LD can cause necrosis of the lung parenchyma with abscess formation and cavitation. Systemic lupus erythematosus (SLE) is an autoimmune disorder with features of both primary and secondary immunodeficiency. SLE patients often develop pulmonary abnormalities, but rarely develop lung cavitations. We report a case of cavitary pneumonia caused by L. pneumophila in a 64-year-old female patient with SLE. We also highlight reasons why SLE patients are more prone to L. pneumophila infections. The importance of using correct diagnostic methods for recognizing and treating such infections is also discussed, as mistreatment of cavitary lesions in SLE patients with steroid therapy can have fatal outcomes as the infectious process can significantly worsen.

PMID: 33497300 [PubMed – as supplied by publisher]