Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

BackgroundBruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.ResultsTwenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.ConclusionThis report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis

Estimating the Risk of Attention Deficit Hyperactivity Disorder (ADHD) in Parents of Children with ADHD and the Association with Their Children’s Disease Severity and Adherence to Medication

Background: Attention deficit hyperactivity disorder (ADHD) is characterised by inattentiveness, hyperactivity, and impulsivity. Up to half of the affected children have a parent with ADHD. In this study, the risk of ADHD among parents of ADHD children was estimated. The associations between parental ADHD and child ADHD severity and medication adherence were determined. Methodology: Parents of children and adolescents diagnosed with ADHD attending the University Kebangsaan Malaysia Medical Centre (UKMMC) were recruited between June to August 2022 and the administered Conners’ Adult ADHD Rating Scale (CAARS) self-report short form, Vanderbilt ADHD Parent Rating Scale (performance section), and Medication Adherence Report Scale (MARS). Results: Forty-five children with ADHD were recruited and 15 out of 45 (33%) parents were detected to have ADHD. ADHD severity was worse in children with ADHD parents for total severity (mean of 34.67 vs. 29.13, p = 0.047) and difficult behaviours at home (mean of 7.87 vs. 6.27, p = 0.036). The children’s academic performance and behavioural challenges at home and school were positively correlated with the parental ADHD scores for ‘inattention’ and ‘problems with self-care’ subscales. Conclusions: A total of 33% of ADHD children had parents with ADHD. ADHD children with ADHD parents were more likely to have behavioural problems at home and more severe ADHD. However, no statistical significance was noted with medication adherence

Table_1_Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia.docx

BackgroundBruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.ResultsTwenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.ConclusionThis report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.</p