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Astrovirus encephalitis in boy with X-linked agammaglobulinemia.

ABSTRACT: Encephalitis is a major cause of death worldwide. Although >100 pathogens have been identified as causative agents, the pathogen is not determined for up to 75% of cases. This diagnostic failure impedes effective treatment and underscores the need for better tools and new approaches for detecting novel pathogens or determining new manifestations of known pathogens. Although astroviruses are commonly associated with gastroenteritis, they have not been associated with central nervous system disease. Using unbiased pyrosequencing, we detected an astrovirus as the causative agent for encephalitis in a 15-year-old boy with agammaglobulinemia; several laboratories had failed to identify the agent. Our findings expand the spectrum of causative agents associated with encephalitis and highlight unbiased molecular technology as a valuable tool for differential diagnosis of unexplained disease.

SUBMITTER: Quan PL

PROVIDER: S-EPMC4102142 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Neurologic Clinical Signs in Cattle With Astrovirus-Associated Encephalitis.

Project description:Evidence of neurotropic astroviruses has been established using novel genetic methods in cattle suffering from viral encephalitis of previously unknown origin.To describe the clinical signs observed in cattle with astrovirus-associated encephalitis.Eight cattle (4 cows, 3 heifers, and 1 bull of 4 different breeds) admitted to the Clinic for Ruminants for neurologic disease and 1 cow investigated in the field.Cases were selected based on neuropathologic diagnosis of nonsuppurative encephalitis, positive in situ hybridization result for astrovirus, and availability of the results of physical and neurologic evaluations. Laboratory results were evaluated if available.The most frequently observed clinical signs were decreased awareness of surroundings (7), cranial nerve dysfunction (5), and recumbency (5). The cow seen in the field was the only animal that had severe behavioral changes. Cell counts in cerebrospinal fluid (CSF) were increased in 4 animals, and protein concentration was increased in 3 of 5 specimens. In 1 case, the presence of astrovirus could be identified in a CSF sample by reverse transcriptase polymerase chain reaction. Other laboratory abnormalities were nonspecific.Astrovirus infection may be an important differential diagnosis in cattle with clinical signs of brain disease and should be considered after exclusion of other causes. The clinical and epidemiological relevance of encephalitis associated with astrovirus infection should be further investigated.

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Neurotropic astrovirus in cattle with nonsuppurative encephalitis in Europe.

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| S-EPMC4313157 | biostudies-literature

Membranoproliferative glomerulonephritis and x-linked agammaglobulinemia: an uncommon association.

Project description:Introduction. X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by agammaglobulinemia requiring replacement treatment with immunoglobulin. The association of XLA and membranoproliferative glomerulonephritis (MPGN) is unexpected and, to our knowledge, only one case was previously published. Case Report. The authors report the case of a 10-year-old boy with family history and prenatal diagnosis of XLA, treated from birth with intravenous immunoglobulin replacement therapy. He presented with pneumonia, macroscopic hematuria, nephrotic proteinuria, hypoalbuminemia, and hypercholesterolemia with normal renal function and serum complement levels. Renal histology showed immune complex mediated MPGN. He was started on high dose prednisolone and ramipril and switched to weekly subcutaneous immunoglobulin. After a 4-month treatment, hematuria and proteinuria significantly improved and prednisolone was gradually tapered without relapse. Conclusion. The pathogenic process underlying MPGN development in this patient is unknown but residual humoral immunity might play an important role. Thus, this case highlights the risk of autoimmune disorders among patients with XLA.

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Project description:Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus.

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X-linked agammaglobulinemia presenting as polymicrobial pneumonia, including Pneumocystis jirovecii.

Project description: Not available

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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.

Project description:X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.

| S-EPMC4151202 | biostudies-literature

Naive Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia.

Project description:The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

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Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia.

Project description:BackgroundX-linked agammaglobulinemia (XLA) is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. It is caused by mutations of the Bruton tyrosine kinase (BTK) gene and is the most common form of inherited antibody deficiency. To our knowledge, this is the first report of XLA from Vietnam.MethodsWe investigated the BTK gene mutations and clinical features of four unrelated Vietnamese children.ResultsThe mean ages at onset and at diagnosis were 2.5 and 8 years, respectively. All patients had a medical history of otitis media, pneumonia, and septicemia at the time of diagnosis. Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. We identified one previously reported mutation (c.441G >A) and three novel mutations: two frameshifts (c.1770delG and c.1742 delG), and one nonsense (c.1249A >T).ConclusionsThe delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results further support the importance of molecular genetic testing in diagnosis of XLA.

| S-EPMC4054903 | biostudies-literature

Mutations in btk in patients with presumed X-linked agammaglobulinemia.

Project description:In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to mutations in a tyrosine kinase now called Btk. Most laboratories have been able to detect mutations in Btk in 80%-90% of males with presumed XLA. The remaining patients may have mutations in Btk that are difficult to identify, or they may have defects that are phenotypically similar to XLA but genotypically different. We analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in Btk were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in Btk were identified in 43 of 46 patients with presumed sporadic XLA. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have XLA, on the basis of results of extensive Btk analysis. Our techniques were unable to identify a mutation in Btk in one male with both a family history and laboratory findings suggestive of XLA. DNA samples from 41 of 49 of the mothers of males with sporadic disease and proven mutations in Btk were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed XLA have mutations in Btk. The other patients are likely to have defects in other genes.

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