De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma.

BACKGROUND: X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of all immunoglobulins and the absence of mature B cells, is caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). Most patients have recurrent sinopulmonary infection. Infections usually occur in multiple locations across time, but single infection may be limited to one anatomic location. OBJECTIVES: To report a case of atypical XLA with recurrent pyoderma and to observe the immunologic changes in the patient in 10 years. METHODS: Immunologic investigations, skin wound culture, and molecular study with DNA sequencing were performed. RESULTS: The patient was originally diagnosed as having common variable immunodeficiency disease because of the presence of circulating B cells (CD19+ B cells: 7%) at 11 years old. On further evaluation at the age of 20 years, flow cytometric analysis of lymphocytes showed only 0.4% B cells. The molecular study with DNA sequencing of the patient showed a point mutation in complementary DNA 1630 A>G(p.R544G) in the BTK gene, indicating that the patient has XLA. The mutation analysis of the BTK gene revealed a normal DNA sequence in the other family members. CONCLUSIONS: This case is an important example of a possible presentation of XLA with a predominant skin manifestation, and it demonstrates that maintaining a high level of clinical suspicion is essential for the diagnosis of XLA in a child with recurrent pyoderma.     

STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa

Journal of Neurology - Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world...     

A systematic review of late-onset and very-late-onset multiple acyl-coenzyme A dehydrogenase deficiency: Cohort analysis and patient report from Taiwan

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder with a dramatic clinical presentation. It was recently discovered that MADD may present at an advanced age.The clinical and laboratory data of an index patient and patients previously diagnosed at our institution were collected. A systematic review of previous studies retrieved from the PubMed, MEDLINE, and Embase databases published by February 1, 2020 was performed to collect patients with very-late-onset MADD (VLO-MADD, onset age > 60 years) globally and patients with late-onset MADD (LO-MADD, onset age < 60 years) in Taiwan. The clinical characteristics of the VLO-MADD patients were compared to those of LO-MADD patients.We report a patient with VLO-MADD who developed the first symptom at the age of 61 years. The patient presented with a Reye-like syndrome after taking aspirin for coronary artery disease. Repeated bouts of weakness were noted. Two variants of c.250 G > A (;) 419C > T were observed in the ETFDH gene. Another four patients with VLO-MADD were identified globally. Eighteen patients with LO-MADD were collected from our department and previously reported patients in Taiwan. There was no difference in the clinical symptoms (except for the onset age) or laboratory data between these two groups. Homozygous variants were not observed in any patients in the VLO-MADD group but were detected in 12 patients (66.6%) in the LO-MADD group (p = 0.014).Patients with MADD may first show symptoms in their 6th decade or beyond. The disease course may lead to erroneous diagnoses in this age group.     

Efficacy and safety of intermittent hemodialysis in infants and young children with inborn errors of metabolism

Background

Intermittent hemodialysis (IHD) is the most efficient form of renal replacement therapy (RRT) for removing toxic substances from patients’ bodies. However, the efficacy and safety of IHD in infants and young children with inborn errors of metabolism are still not clear.

Methods

This retrospective study included patients with urea cycle disorders, maple syrup urine disease, and methylmalonic acidemia who received IHD or non-IHD RRT at our hospital between 2001 and 2012 to remove ammonia, leucine, or methylmalonic acid. Both the efficacy and safety of the RRT were evaluated.

Results

Thirty-five courses of RRT, including 25 courses of IHD and ten courses of non-IHD RRT, for 15 patients were included in the analysis. Before 2006, non-IHD RRT procedures, including peritoneal dialysis (PD) and continuous venous-venous hemofiltration (CVVH), were the most often used; from 2006 onwards IHD was used. There was one procedure-unrelated death. Catheter penetration occurred in one course of IHD. The efficacy data revealed that both the median duration of dialysis and the median 50 % toxin reduction time were shorter in IHD than in non-IHD RRT.

Conclusions

In infants and young children with inborn errors of metabolism, IHD is safe and more efficient than non-IHD RRT at removing toxins.     

Selection of nonlinear interactions by a forward stepwise algorithm: Application to identifying environmental chemical mixtures affecting health outcomes

In this paper, we propose a stepwise forward selection algorithm for detecting the effects of a set of correlated exposures and their interactions on a health outcome of interest when the underlying relationship could potentially be nonlinear. Though the proposed method is very general, our application in this paper remains to be on analysis of multiple pollutants and their interactions. Simultaneous exposure to multiple environmental pollutants could affect human health in a multitude of complex ways. For understanding the health effects of multiple environmental exposures, it is often important to identify and estimate complex interactions among exposures. However, this issue becomes analytically challenging in the presence of potential nonlinearity in the outcome-exposure response surface and a set of correlated exposures. Through simulation studies and analyses of test datasets that were simulated as a part of a data challenge in multipollutant modeling organized by the National Institute of Environmental Health Sciences ( http://www.niehs.nih.gov/about/events/pastmtg/2015/statistical/ ), we illustrate the advantages of our proposed method in comparison with existing alternative approaches. A particular strength of our method is that it demonstrates very low false positives across empirical studies. Our method is also used to analyze a dataset that was released from the Health Outcomes and Measurement of the Environment Study as a benchmark beta-tester dataset as a part of the same workshop.     

Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan

In Taiwan, during the period March 2000 to June 2009, 1,495,132 neonates were screened for phenylketonuria (PKU) and homocystinuria (HCU), and 1,321,123 neonates were screened for maple syrup urine disease (MSUD), methylmalonic academia (MMA), medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, isovaleric academia (IVA), and glutaric aciduria type 1 (GA-1) using tandem mass spectrometry (MS/MS). In a pilot study, 592,717 neonates were screened for citrullinemia, 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC) and other fatty acid oxidation defects in the MS/MS newborn screening. A total of 170 newborns and four mothers were confirmed to have inborn errors of metabolism. The overall incidence was approximately 1/5,882 (1/6,219 without mothers). The most common inborn errors were defects of phenylalanine metabolism [five classic PKU, 20 mild PKU, 40 mild hyperphenylalaninemia (HPA), and 13 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency]. MSUD was the second most common amino acidopathy and, significantly, most MSUD patients (10/13) belonged to the Austronesian aboriginal tribes of southern Taiwan. The most frequently detected among organic acid disorders was 3-MCC deficiency (14 newborns and four mothers). GA-1 and MMA were the second most common organic acid disorders (13 and 13 newborns, respectively). In fatty acid disorders, five carnitine transport defect (CTD), five short-chain acyl-CoA dehydrogenase deficiency (SCAD), and two medium-chain acyl-CoA dehydrogenase (MCAD) deficiency were confirmed. This is the largest case of MS/MS newborn screening in an East-Asian population to date. We hereby report the incidences and outcomes of metabolic inborn error diseases found in our nationwide MS/MS newborn screening program.     

Association between levels of TNF-alpha and TNF-alpha promoter -308 A/A polymorphism in children with Kawasaki disease.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) has been shown to play a central role in the pathogenesis of vasculitis in Kawasaki disease (KD). We investigated the serum levels of TNF-alpha and soluble TNF receptor 1 (STNFR1) levels, and genetic polymorphisms of the TNF-alpha promoter gene in children with KD to delineate the genetic basis of KD. METHODS: A total of 18 children (12 boys and 6 girls) with KD were studied, 9 of whom had the complication of coronary artery lesion (CAL) within 30 days after the onset of symptoms. Serum levels of TNF-alpha and STNFR1 were assayed by enzyme-linked immnosorbent assay, and DNA polymorphisms of the 5' flanking region of TNF-alpha promoter gene at position -308 [guanine (G) to adenine (A)] and -238 (G to A) were studied by direct nucleotide sequencing. RESULTS: The serum TNF-alpha level in KD patients was 113 +/- 209.9 pg/mL (range, 2.0 to 756.9 pg/mL; median, 24.7 pg/mL; normal, < 10 pg/mL). The serum levels of STNFR1 in KD (4255 +/- 2425 pg/mL) were higher than those of the control group (160 +/- 116 pg/mL). Allele frequencies of -308A and -238A were 11.1% and 0% in the KD patients, and 0% and 3.1% in the control group. Neither TNF-alpha promoter polymorphism nor any significant risk factor for CAL was identified in KD patients. One patient, who was homozygous for -308A, showed the highest TNF-alpha level and elevated STNFR1 level but had no evidence of CAL. Positive correlations were found between serum levels of STNFR1 and C-reactive protein (r = 0.731, p = 0.007), and between STNFR1 and leukocyte counts at admission (r = 0.620, p = 0.008). CONCLUSIONS: Increased serum levels of TNF-alpha and STNFR1 were found in KD patients but there was no correlation between these levels. The relationship between the pathogenesis of KD and TNF-alpha gene promoter -308G to A mutation towards cytokine production remains to be clarified.     

A Novel 3670-Base Pair Mitochondrial DNA Deletion Resulting in Multi-systemic Manifestations in a Child

Mitochondrial DNA (mtDNA) deletion is a rare occurrence that results in defects to oxidative phosphorylation. The common clinical presentations of mtDNA deletion vary but include mitochondrial myopathy, Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. Here, we report the case of a 10-year-old boy who presented with progressive deterioration of his clinical status (which included hypoglycemia, short stature, sensorineural hearing loss, retinitis pigmentosa, and chronic gastrointestinal dysmotility) that progressed to acute deterioration with pancreatitis, Fanconi syndrome, lactic acidosis, and acute encephalopathy. Following treatment, the patient was stabilized and his neurological condition improved. Through a combination of histological examinations and biochemical and molecular analyses, mitochondrial disease was confirmed. A novel 3670-base pair deletion (deletion of mtDNA nt 7,628-11,297) was identified in the muscle tissue. A direct repeat of CTACT at the breakpoints was also detected.