X linked agammaglobulinemia (XLA) is rarely reported from developing countries especially from South East Asia. It appears that X linked agammaglobulinemia is less common in certain ethnic groups. It is very uncommon in black people in USA and South Africa. In multiracial Malaysia we have documented five XLA in Malays and Indians but not in the Chinese that constitute about 31% of the population. First degree relatives afflicted with XLA or other primary immunodeficiencies occurred more often in our study. All showed lung involvement although the etiologic organisms involved were atypical, being Gram negative.
X-linked agammaglobulinemia is a rare primary immunodeficiency due to a BTK mutation. The patients are characteristically deficient in peripheral B cells and serum immunoglobulins. While they are susceptible to infections caused by bacteria, enteroviruses, and parasites, fungal infections are uncommon in XLA patients. Here, we report a boy of Malay ethnicity who suffered from recurrent upper respiratory tract infections and severe progressive necrotizing fasciitis caused by Saksenaea erythrospora. Immunological tests showed a B cell deficiency and hypogammaglobulinemia. Whole-exome sequencing identified a dinucleotide deletion (c.1580_1581del) in BTK, confirmed by Sanger sequencing and predicted to be disease causing by in silico functional prediction tools (Varsome and MutationTaster2) but was absent in the gnomAD database. This mutation resulted in a frameshift and premature termination (p.C527fs), which disrupted the protein structure. The mother was heterozygous at the mutation site, confirming her carrier status. Flow cytometric analysis of monocyte BTK expression showed it to be absent in the patient and bimodal in the mother. This study describes a novel BTK mutation in a defined hotspot and an atypical fungal phenotype in XLA. Further studies are required to understand the pathogenesis of fungal infection in XLA.
Bruton's tyrosine kinase (BTK), encoded by the BTK gene, is a cytoplasmic protein critical in B cell development. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency with characteristically low or absent B cells and antibodies. This report describes a five year-old boy who presented with otitis externa, arthritis, reduced immunoglobulins and no B cells. Flow cytometry showed undetectable monocyte BTK expression. Sequencing revealed a novel mutation at exon 13 of the BTK gene which created a de novo splice site with a proximal 5 nucleotide loss resulting in a truncated BTK protein. The patient still suffered from ear infection despite intravenous immunoglobulin replacement therapy. In this study, mosaicism was seen only in the mother's genomic DNA. These results suggest that a combination of flow cytometry and BTK gene analysis is important for XLA diagnosis and carrier screening.
Fungal osteomyelitis is a rare opportunistic infection. It exhibits some clinical and radiological similarities to several other bone pathologies. A diagnostic delay may result in significant increase in morbidity. We report a case of a 37-year-old man with underlying hypogammaglobulinaemia presented with isolated cryptococcal osteomyelitis of the femur.
X-linked agammaglobulinemia (XLA) is a rare genetic disorder, caused by mutations in BTK (Bruton's Tyrosine Kinase) gene. Deep high-throughput RNA sequencing (RNA-Seq) approach was utilized to explore the possible differences in transcriptome profiles of primary monocytes in XLA patients compared with healthy subjects. Our analysis revealed the differences in expression of 1,827 protein-coding genes, 95 annotated long non-coding RNAs (lncRNAs) and 20 novel lincRNAs between XLA patients and healthy subjects. GO and KEGG pathway analysis of differentially expressed (DE) protein-coding genes showed downregulation of several innate immune-related genes and upregulation of oxidative phosphorylation and apoptosis-related genes in XLA patients compared to the healthy subjects. Moreover, the functional prediction analysis of DE lncRNAs revealed their potential role in regulating the monocytes cell cycle and apoptosis in XLA patients. Our results suggested that BTK mutations may contribute to the dysregulation of innate immune system and increase susceptibility to apoptosis in monocytes of XLA patients. This study provides significant finding on the regulation of BTK gene in monocytes and the potential for development of innovative biomarkers and therapeutic monitoring strategies to increase the quality of life in XLA patients.
X-linked agammaglobulinemia (XLA) is a rare genetic disorder caused by mutations in the Bruton's tyrosine kinase (BTK) gene. These mutations cause defects in early B cell development. A patient with no circulating B cells and low serum immunoglobulin isotypes was studied as were his mother and sister. Monocyte BTK protein expression was evaluated by flow cytometry. The mutation was determined using PCR and followed by sequencing. Flow cytometry showed the patient lacked BTK protein expression in his monocytes while the mother and sister had 62% and 40% of the monocytes showing BTK protein expressions respectively. The patient had a novel base substitution in the first nucleotide of intron 9 in the BTK gene, and the mutation was IVS9+1Gagammaglobulinemia and may be used for subsequent genetic counseling, carrier detection and prenatal diagnosis.
We describe here a case of cryptococcal empyema thoracis and periauricular pyogenic abscess in a child with Bruton's agammaglobulinaemia. The cryptococcal empyema thoracis was treated with intravenous amphotericin B and intravenous fluconazole for six weeks followed by oral fluconazole. The pyogenic periauricular abscess was surgically drained and treated with intravenous ceftazidime and cloxacillin for two weeks. He also received monthly intravenous immunoglobulin.
Gene therapy is a method of treatment of disease aimed at its molecular level. The progress of gene therapy, however, was as promising as it was tardy mainly due to the limitations in the resources and financial part of its development as well as owing to the rarity of most diseases it can offer its benefits to. The methods of gene therapy can vary depending on factors such as the physiology of tissue of interest, affinity of vectors to a certain type of cells, depth and accessibility of the tissue of interest, and size of the gene to be replaced or edited. The concept behind gene therapy has inspired scientists and clinicians alike leading to a rapid expansion of its clinical utility that has become so widespread to not only include diseases of monogenic origin, but also polygenic diseases, albeit not so commonly. This article delves into notable success stories of gene therapy which has been regarded as the beacon of medical novelty expected to blossom in the near future to provide a holistic, targeted, precise, and individualistic personalised-medicine as well as laying out the future hopes of gene therapy in the treatment of debilitating diseases such as solid tumours, AIDS, Tuberculosis, Diabetes Mellitus, psychiatric illnesses, which are still at a standstill, from a gene therapy point of view.