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A seven-month-old girl presented with bilateral roving nystagmus, hyperopia, and retinal dystrophy, and was brought to our ophthalmology clinic. Visual-evoked potentials (VEPs) were non-recordable in both the eyes. No other systemic symptoms or abnormalities were observed. Whole exome sequencing (WES) identified a compound heterozygous mutation in the

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

BackgroundStarting enzyme replacement therapy (ERT) before severe irreversible muscular damage occurs is important in infantile-onset Pompe disease (IOPD). This long-term follow-up study demonstrates our diagnostic and treatment strategies for IOPD and compares our clinical outcomes with those of other medical centres.MethodsIn this long-term follow-up study, we analysed the outcomes of very early ERT with premedication hydrocortisone in patients with IOPD. Out of 1 228 539 infants screened between 1 January 2010 and 28 February 2021, 33 newborns had confirmed IOPD in Taipei Veterans General Hospital. Twenty-six were regularly treated and monitored at Taipei Veterans General Hospital. Echocardiographic parameters, biomarkers, IgG antibodies against alglucosidase alpha, pulmonary function variables and developmental status were all assessed regularly over an average follow-up duration of 6.18±3.14 years. We compared the long-term treatment outcomes of our patients with those of other research groups.ResultsThe average age at ERT initiation was 9.75±3.17 days for patients with classic IOPD. The average of the latest antialglucosidase alpha IgG titre was 669.23±1159.23. All enrolled patients had normal heart sizes, motor milestones, cognitive function and pulmonary function that were near-normal to normal. Compared with patients in other studies, our patients had better outcomes in all aspects.ConclusionVery early ERT using our rapid diagnostic and treatment strategy enabled our patients with IOPD to have better outcomes than patients in other medical centres.

To evaluate lower urinary tract symptoms (LUTS) in children with infantile-onset Pompe disease (IOPD) who received early treatment.Pompe disease (PD), or glycogen storage disease II is a rare autosomal recessive lysosomal storage disease that affects multiple organ systems. To our knowledge, only one study has focused on the relationship between LUTS and incontinence in children with PD. This cross-sectional study was conducted from August 2019 through March 2021 and children with IOPD, who had received early and regular enzyme replacement therapy, were enrolled. Participants or their parents completed the Dysfunctional Voiding Scoring System (DVSS) questionnaire. All children underwent uroflowmetry and postvoid residual urine measurements. Fourteen children (age, 4-9 years) with IOPD were enrolled.Ten patients (71.4%) had abnormal uroflow curves. In addition, results of the DVSS revealed that approximately half (42.9%) of our IOPD patients had voiding dysfunction, with urinary incontinence as the most common symptom (64.3%, 9/14). No significant correlations were found between LUTS and uroflow curves in children with IOPD.The frequency of LUTS and lower urinary tract dysfunction noted on uroflowmetry should encourage pediatricians to actively identify IOPD patients with LUTS, regardless of the timing and frequency of their treatments, and refer them to a urologist for further evaluation and appropriate treatment.

We report a novel technique of flexible endoscopy with noninvasive ventilation (NIV) and sustained pharyngeal inflation (FE-NIV-SPI) in assessing aeroesophageal tracts (AET) to facilitate early detection of laryngeal clefts in infants.Medical charts and flexible endoscopy videos of the children who were diagnosed with laryngeal cleft in a tertiary care hospital between January 2000 and December 2020 were retrospectively reviewed and analyzed. The FE-NIV-SPI technique had been applied to all these children.Totally, 12 infants with laryngeal cleft were identified. This equates to a prevalence of 0.28% in all the children who underwent flexible endoscopy at our institution. Their mean age was 5.0 ± 4.9 months and mean body weight was 4.7 ± 2.3 kg. Nine (75%) infants were referred in without laryngeal cleft diagnosis, which was missed by 11 prior bronchoscopy and 5 computer tomography examinations. With the FE-NIV-SPI technique, the pharyngolaryngeal space could be pneumatically dilated permitting a detailed assessment. All laryngeal cleft types and coexisting AET lesions were visualized at the first FE-NIV-SPI examination with a mean time of 4.2 ± 0.9 min; they were eight Type I, two Type II, and one Type III. Ten (83.3%) infants had coexisting airway malacia.Routine use of FE-NIV-SPI technique can help in early detection of laryngeal clefts and other associated AET lesions. Further multicenter collaborative investigations are essential to verify the early detection of this rare and occult lesion of the laryngeal cleft with this technique.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

LT is a treatment option for MMA patients, but renal function impairment is one of the long-term concerns. The aim of this study was to evaluate the outcomes of early LT in these patients.A total of 11 MMA mut-type patients (including 10 mut0 cases and 1 mut-case) who received LT in our institute were reviewed. Their metabolic profiles were compared between the pre/post-transplant periods. Their immunosuppressant and renal function changes after transplantation were assessed.After a mean follow-up of 97.5 ± 38.4 months, there were two deaths, and the actual survival rate was 81.8%. Their metabolic profiles had improved (mean blood ammonia level 366.8 ± 105.5 vs. 53.1 ± 17.4 μg/dl, p .001; C3/C2 ratio 2.68 ± 0.87 vs. 0.73 ± 0.22, p = .003; mean urine MMA level 920.5 ± 376.6 vs. 196.2 ± 85.4, p = .067), and hospital stays were decreased (78.8 ± 74.5 vs. 7.4 ± 7.0 days/year, p = .009) after transplantation. The mean age at transplant was 1.81 ± 2.02 years old, and nine of these patients received LT before the age of 1.5 years old (early LT). Under prospective immunosuppressant dose reduction, three of these early LT patients discontinued the drug and were sustained for more than 5 years. Most of the patients had a preserved renal function, and no patient is currently on dialysis.In addition to the improvement in the metabolic parameters, early LT in MMA patients may allow for a dose reduction of the immunosuppressant, and the patient's renal function could be preserved in the long term.

Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Methods: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p &lt, 0.05) between the “IC1 hypomethylation” and “mUPD7” groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). Conclusions: The SRS score was positively correlated with the molecular diagnosis rate (p &lt, 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

Background: Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. The aim of this study was to identify the epigenotype-phenotype correlations of these patients using quantitative DNA methylation analysis. Methods: One hundred and four subjects with clinically suspected BWS were enrolled in this study. All of the subjects had been referred for diagnostic testing which was conducted using methylation profiling of H19-associated imprinting center (IC) 1 and KCNQ1OT1-associated IC2 in high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between the quantitative DNA methylation status and clinical manifestations of the enrolled subjects were analyzed. Results: Among the 104 subjects, 19 had IC2 hypomethylation, 2 had IC1 hypermethylation, and 10 had paternal uniparental disomy (pUPD). The subjects with IC2 hypomethylation were characterized by significantly more macroglossia but less hemihypertrophy compared to the subjects with pUPD (p &lt, 0.05). For 19 subjects with IC2 hypomethylation, the IC2 methylation level was significantly different (p &lt, 0.05) between the subjects with and without features including macroglossia (IC2 methylation level: 11.1% vs. 30.0%) and prenatal or postnatal overgrowth (8.5% vs. 16.9%). The IC2 methylation level was negatively correlated with birth weight z score (p &lt, 0.01, n = 19) and birth height z score (p &lt, 0.05, n = 13). For 36 subjects with clinically diagnosed BWS, the IC2 methylation level was negatively correlated with the BWS score (r = −0.592, p &lt, 0.01). The IC1 methylation level showed the tendency of positive correlation with the BWS score without statistical significance (r = 0.137, p &gt, 0.05). Conclusions: Lower IC2 methylation and higher IC1 methylation levels were associated with greater disease severity in the subjects with clinically diagnosed BWS. Quantitative DNA methylation analysis using the MassARRAY assay could improve the detection of epigenotype-phenotype correlations, which could further promote better genetic counseling and medical care for these patients.

Objectives Flexible endoscopy (FE) assessed the whole approachable aeroesophageal (AE) tracks and changes of management in infants with severe bronchopulmonary dysplasia (sBPD). Methods A 10 years (2011-2020) retrospective study of sBPD infants who had FE with and without artificial airway in AE tracks. FE with noninvasive ventilation (FE-NIV) of pharyngeal oxygen with nose-close and abdomen-compression was supported. Data of found pathologies, changes of consequent management and therapeutic interventions were collected and analyzed. Results Total 42 infants enrolled. Two scopes of 1.8mm and 2.6mm were used. FE revealed 129 AE pathologies in 38 (90.5%) infants. Twenty-eight (66.7%) infants detected more than one lesion. In 35 (83.3%) infants with 111 airway lesions, bronchial granulations (28, 25.2%), tracheomalacia (18, 16.2%) and bronchial granulations (15, 13.5%) were the leadings. Fifteen (35.7%) infants had 18 esophageal lesions. No significant FE-NIV complication noted. FE findings resulted consequent changes of management in all 38 infants. Thirty-six (85.7%) infants involved respiratory care of pressure titrations (29, 45.3%), shorten suctioning depth (17, 26.6%), changed endotracheal or tracheostomy tube depth (10, 15.6%) and extubation (8, 12.5%). Twenty-one (50%) infants had 50 medication changes included add steroids, anti-reflux medicine, antibiotics and stop antibiotics. Eighteen (42.8%) infants had received 37 therapeutic FE-NIV procedures which included 14 balloon dilatation, 13 laser-plasty and 10 stent implantations. Seven (16.7%) infants had surgeries included 4 tracheostomies and 3 fundoplications. Conclusion FE-NIV can be a safe and valuable modality for direct visual assessment of AE pathologies which contributed subsequent changes of clinical management in sBPD infants.

Background Studies suggest that enzyme-replacement therapy (ERT) is crucial to the survival of patients with infantile-onset Pompe disease (IOPD). Hearing impairment (HI) is one of the clinical sequelae observed in long-term survivors. However, the benefits of early ERT for hearing outcomes have not yet been reported. This study aimed to investigate the impact of early ERT on IOPD patients. Methods This retrospective longitudinal study recruited IOPD patients who were referred by newborn screening for confirmatory diagnosis based on our rapid diagnostic criteria and received early ERT treatment between January 1, 2010, and January 31, 2018. The hearing test battery included a tympanogram, otoacoustic emission, auditory brainstem evoked response (ABR), pure-tone audiometry or conditioned play audiometry. Results Nineteen patients with IOPD were identified, 6 of whom had hearing impairment (HI); 1 had conductive HI, 2 had sensorineural HI (one had bilateral mild HI and one had mild HI in a single ear) and 1 had moderate mixed-type HI. Two patients failed the newborn screening test and had mild HI in the ABR. The mean age of the initial time to ERT was 11.05 ± 4.31 days, and the HI rate was 31.6% (6/19). Conclusion Our study is the largest cohort to show the characteristic hearing outcomes of IOPD patients after ERT. Early ERT within 2 weeks after birth may contribute to better hearing outcomes. Clinicians should be vigilant in testing for the hearing issues associated with IOPD and should intervene early if any HI is detected.

Background Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016. Results During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p

OBJECTIVE: Sustained pharyngeal inflation (SPI) with pharyngeal oxygen and nose-close (PhO2-NC) can create positive peak inflation pressure (PIP) inside the pharyngolaryngeal space (PLS). This study measured and compared effects of four different SPI durations in the PLS. METHOD: In this prospective observational study, 20 consecutive infants aged less than 3 years, scheduled for elective flexible-bronchoscopy were enrolled. SPI was performed twice in four different durations (0, 1, 3 and 5 seconds) sequentially in each infant. PIP was measured for each SPI in the pharynx, and simultaneously took images at two locations of oropharynx and supra-larynx. Infants’ demographic details and PIP levels, lumen expansion scores and images of PLS were measured and analyzed. RESULTS: Twenty infants with 40 measurements were collected. The mean (SD) age and weight were 11.6 (9.1) months and 6.8 (2.4) kg, respectively. The measured mean (SD) pharyngeal PIPs were 4.1 (3.3), 21.9 (7.0), 42.2 (12.3) and 65.5 (18.5) cm H2O at SPI duration of 0, 1, 3 and 5 seconds, respectively; which showed significant positive association (p

Sustained pharyngeal inflation (SPI) with pharyngeal oxygen and nose-close (PhO2-NC) can create positive inflation pressure (PIP) inside the pharyngolaryngeal space (PLS). This study measured and compared effects of different SPI durations in the PLS. Method: A one-year prospective study, 20 consequent infants whose age less than 3-year-old and scheduled for elective FB were enrolled. SPI performed in four different durations (0.0, 1.0, 3.0 and 5.0 seconds) consequently. Each infant did two cycles of SPI. Measured the PIP of each SPI in the pharynx, and simultaneously took images at three locations of oropharynx, supra-larynx and larynx. Data of infant’s demographics, PIP levels, space expansion scores and images were collected and analyzed. Results: Total 20 studied infants, the mean (SD) age was 11.6 (9.1) month-old, the mean (SD) body weight was 6. 8 (2.4) kg and the mean (SD) study time was 3.8 (1.1) minutes. The measured mean (SD) pharyngeal PIPs were 4.1 (3.3), 21.9 (7.0), 42.2 (12.3) and 65.5 (18.5) cmH2O at SPI duration of 0.0, 1.0, 3.0 and 5.0 seconds, respectively. Which showed positively and significantly (p

Objective To provide strategies for monitoring and treating severe lung involvement in Gaucher disease. Study design We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. Results His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of β-glucocerebrosidase were reported in three months. Conclusion This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

Epidemiological studies have reported the relationship between bisphenol A (BPA) exposure and increased prevalence of asthma, but the mechanisms remain unclear. Here, we investigated whether BPA exposure and DNA methylation related to asthma in children. We collected urinary and blood samples from 228 children (Childhood Environment and Allergic Diseases Study cohort) aged 3 years. Thirty-three candidate genes potentially interacting with BPA exposure were selected from a toxicogenomics database. DNA methylation was measured in 22 blood samples with top-high and bottom-low exposures of BPA. Candidate genes with differential methylation levels were validated by qPCR and promoter associated CpG islands have been investigated. Correlations between the methylation percentage and BPA exposure and asthma were analyzed. According to our findings, MAPK1 showed differential methylation and was further investigated in 228 children. Adjusting for confounders, urinary BPA glucuronide (BPAG) level inversely correlated with MAPK1 promoter methylation (&beta, = &minus, 0.539, p = 0.010). For the logistic regression analysis, MAPK1 methylation status was dichotomized into higher methylated and lower methylated groups with cut off continuous variable of median of promoter methylation percentage (50%) while performing the analysis. MAPK1 methylation was lower in children with asthma than in children without asthma (mean &plusmn, SD, 69.82 &plusmn, 5.88% vs. 79.82 &plusmn, 5.56%) (p = 0.001). Mediation analysis suggested that MAPK1 methylation acts as a mediation variable between BPA exposure and asthma. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation.

Background Increasing prevalence of allergic diseases has been matched by parallel trends in attention-deficit/hyperactivity disorder (ADHD). However, previous studies concerning the association between ADHD and allergic diseases have been inconsistent. Moreover, it is not clear whether this association is modified by allergic sensitization status. Therefore, we evaluated the association between allergic diseases, allergic sensitization, and ADHD in children. Methods We conducted a large-scale cross-sectional, population-based survey to investigate the relationship between allergic diseases, allergic sensitization, and ADHD. Children aged between 3 and 6 years were selected from kindergartens, and received skin prick tests (SPTs) for mite, cockroach, dog, milk, egg, and crab allergens. Information about allergic diseases, environmental exposures, and physician-diagnosed ADHD were collected. Multiple logistic regressions were performed to estimate the association between allergic diseases and ADHD, with adjustments made for potential confounders. Result A total of 2772 children were found to be eligible for analysis; of these 411 (14.8%) had atopic dermatitis (AD), 954 (34.4%) had allergic rhinitis (AR), 451 (16.3%) had asthma, and 28 (1.01%) had ADHD. Children who had AD and asthma with allergic sensitization were found to be at increased risk for ADHD, with adjusted ORs (95% CI) of 4.50 (1.28–15.86) and 3.65 (1.07–12.49). Children who had AR, allergic conjunctivitis, or food allergies were also related to ADHD, though failed to reach statistical significance. Conclusion Our results suggest that AD and asthma with allergic sensitization are associated with ADHD in children. As allergic sensitization is an increased factor of developing allergic diseases, early control of environmental and allergens exposure could help to modify the burden of ADHD.

Objectives Flexible endoscopy (FE) is frequently used to diagnose tracheobronchial foreign bodies (TBFB). However, it is still controversial for retrieval of TBFB in pediatric field. This study aims at reporting and evaluating our experiences of using short-length FE with a non-invasive ventilation (NIV) technique and intensive care unit (ICU) support in retrieving pediatric TBFB. Methods A retrospective review of the hospital database and FE videos of pediatric patients aged less than 18 year-old who were diagnosed of TBFB and managed in our hospital over a 17-year period (1999–2015). The demographic data were collected and analyzed. A NIV technique of providing nasopharyngeal oxygen with intermittent nose closure and abdominal compression was routinely performed in procedural sedated patients throughout the whole FE procedures. Results Sixty-six consecutive patients with 76 TBFB were enrolled. Among them, 72 (94.7%) TBFB in 64 patients were successfully retrieved at the first attempt of FE immediately after the diagnosis was made. There were 13 iatrogenic TBFB in patients who already had coexisting airway problems. The median age was 16 months (range 1.5 months–17 years) and the median body weight was 10.5 kg (range 3.5–48.5 kg). Seventy (70/72, 97.2%) TBFB were retrieved by short-length FE and among them, 55 procedures (55/72, 76.4%) used FE with no working channel. No significant acute or late adverse effects were noted. The mean retrieval procedural time was 23.6 ± 15.1 min. Conclusion Using short-length FE with this NIV technique, appropriate sedation and ICU support is a safe, simple and effective modality for the retrieval of TBFB immediately after confirming the diagnosis in pediatric patients.

Background Glutaric aciduria type 1 (GA-1) is an organic acidemia with potentially severe neurological sequelae. In Taiwan, newborn screening (NBS) for GA-1 began in 2001, but large-scale reporting is lacking. This study describes Taiwan's largest newborn screening population to date. Methods Between 2001 and 2015, 1,490,636 newborns were screened for GA-1. Confirmatory examinations included the carnitine loading test. Confirmed patients were treated with a low lysine diet, carnitine, and high-energy intake during illness. Clinical, laboratory, and neuroimaging data were analyzed. Results Fourteen newborns were diagnosed with GA-1 (incidence: 1/106,474). C5DC concentration was clearly increased after carnitine loading in the affected newborns, but not in false-positive newborns (p = 0.004), indicating that this test is useful as an adjuvant diagnostic method. Eleven patients followed in our hospital were enrolled, namely nine NBS patients and two patients diagnosed clinically. IVS10-2A>C was the most common mutation. Two novel mutations (T36fs and N291K) were identified. Pendular nystagmus was found in two pediatric GA-1 patients. The corresponding pathology was optic atrophy in one patient, but remained undetermined in the other patient. The frequency of encephalopathic crisis decreased substantially following NBS. Among patients diagnosed by NBS, cognitive functioning was better among patients with good compliance than patients with poor compliance (p = 0.03). Abnormalities were detected by brain MRI including diffusion-weighted imaging and apparent diffusion coefficient maps; these affected various brain regions at different stages of the disease. Basal ganglion injuries occurred after an encephalopathic crisis. White matter disease was prevalent among older patients, either with or without an encephalopathic crisis. Conclusion Early diagnosis by newborn screening followed by full compliance with treatment guidelines is important to a good outcome.

Background Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement. Objectives The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD. Methods To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults. Results LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes. Conclusions Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD.

Advances in the treatment of Pompe disease have improved life expectancy and quality of life, but speech and oromotor function remain significantly affected. The purpose of this study was to expand on existing data and present new findings of speech acoustic and physiologic outcomes in Pompe disease. A retrospective analysis was carried out on results of speech, language and oromotor tests carried out in 14 children diagnosed with Pompe disease. The assessment battery included standardized tests of language, picture naming, maximum performance tests, and oromotor resistance tasks. Speech production was scored with respect to intelligibility, hypernasality, and articulatory accuracy. Language delays ranged from mild to severe in 1/3 of the children. Reduced speech intelligibility, disordered articulation, and hypernasality were present in at least 2/3 of the children. Maximum performance tests all fell at least 1 SD below normative means. Significant correlations were identified between maximum phonation time and articulation and between the S/Z ratio and intelligibility. Positive correlations were also found between tongue strength and articulation. Results confirm previous reports of speech and language function in Pompe disease. Clinical acoustic measures provide important insights into the speech deficits in this group of children and suggest possible treatment strategies.

The Fabry disease-causing mutation, the GLA IVS4+919GA (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919GA mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919GA mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

Background: This study presented a 3 years old boy with Gaucher disease (GD) who was treated with enzyme replacement therapy (ERT) for 19 months and then developed multiple Gaucheroma. Review of literature was performed simultaneously. Methods: The medical chart and literature were reviewed. A boy presented at the age of 15 months with anemia, thrombocytopenia, and hepatosplenomegaly. GD was confirmed by enzyme assay and gene mutations. ERT was administered right after the diagnosis. When the boy was 3 years old, multiple masses were discovered during a regular checkup abdominal MRI and biopsy revealed Gaucheroma. We also reviewed 20 GD patients with Gaucheroma and Gaucher cell infiltrated lymphadenopathies. Conclusion: Gaucheroma is a rare condition of regularly treated GD patients. This patient even showed poor response to doubled ERT doses. The imaging studies are necessary for Gaucher patients to detect Gaucheroma and determine their malignancy. Regular checkups are recommended in all GD patients even with regular treatment, due to the possibility of having deteriorating change, like Gaucheroma. Keywords: Gaucher disease, Gaucheroma, Enzyme replacement therapy(ERT), Lysosomal storage disease(LSD), Liver mass

Early enzyme replacement therapy (ERT) improve long-term outcomes in patients with infantile-onset Pompe disease (IOPD). Our cohort of patients with IOPD at Taipei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening program from 2008, testing more than one million newborns until 2018. By 2010, we had established rapid diagnostic strategies. Now, the average age of ERT initiation starts at an average age of

Background Pediatricians are physicians trained to provide comprehensive nonsurgical health care for children, but parents may consult other specialists when seeking medical help for their children. This study was designed to analyze the role of pediatricians and the changes in the patterns of ambulatory visits among different specialties for children under the age of 18 years in Taiwan during the past 13 years. Methods Data on ambulatory visits of children aged 0–17 years from 1999 to 2011 were retrieved from the National Health Insurance Research Database. The physician's specialty, level of the hospital, year of visit, age of the patient, and diagnoses of each ambulatory visit were analyzed. Four of the most commonly visited specialties—pediatrics, otolaryngology, family medicine, and internal medicine—were compared. The yearly trend of ambulatory visits to different specialties, difference in various age groups, influence of hospital levels, and the top 10 diagnoses were analyzed. Results A total of 1,618,033 ambulatory visits were identified and enrolled into our study. A comparison of the proportions of ambulatory visits between 1999–2003 and 2007–2011 showed that the proportions of visits increased from 27.1 ± 1.3% to 35.4 ± 1.0% for pediatricians, decreased from 32.8 ± 1.8% to 17.0 ± 0.8% for family physicians, and did not change for otolaryngologists and internal medicine physicians. Specifically, pediatricians were visited more often if the children were younger, or if the health-care facility (level of hospital) was either a medical center or a regional hospital. Upper respiratory tract infection was the top diagnosis, followed by acute bronchitis, and acute and chronic tonsillitis. Conclusions The role of pediatricians in children's ambulatory care increased in importance from 1999 to 2011 in Taiwan. However, approximately two thirds of children sought ambulatory medical help from nonpediatric physicians. Thus, it is important to educate and encourage parents to visit pediatricians if their children require medical help.

The incidence of acute kidney injury (AKI) in critically ill children varies among countries. Here we used claims data from the Taiwanese National Health Insurance program from 2006 to 2010 to investigate the epidemiological features and identify factors that predispose individuals to developing AKI and mortality in critically ill children with AKI. Of 60,338 children in this nationwide cohort, AKI was identified in 850, yielding an average incidence rate of 1.4%. Significant independent risk factors for AKI were the use of extracorporeal membrane oxygenation, mechanical ventilation or vasopressors, intrinsic renal diseases, sepsis, and age more than 1 year. Overall, of the AKI cases, 46.5% were due to sepsis, 36.1% underwent renal replacement therapy, and the mortality rate was 44.2%. Multivariate analysis showed that the use of vasopressors, mechanical ventilation, and hemato-oncological disorders were independent predictors of mortality in AKI patients. Thirty-two of the 474 patients who survived had progression to chronic kidney disease or end-stage renal disease. Thus, although not common, AKI in critically ill children still has a high mortality rate associated with a variety of factors. Long-term close follow-up to prevent progressive chronic kidney disease in survivors of critical illnesses with AKI is mandatory.

article i nfo Purpose: The aim of this study is to examine the relationship between physician case volume and the outcomes of critically ill children with pneumonia. Materials and methods: This is a population-based cohort study analyzed data provided from by the National Health Insurance Research Database of Taiwan, 2006-2009. Children (aged 3 months to 17 years) having records of intensive care unit (ICU) admission and a diagnosis of pneumonia were included. A total of 9754 critically ill children and 1042 attending physicians were enrolled. The children were assigned to 1 of 4 groups based on the physician's pneumonia case volume. Results: The patients in the very high case volume group had a significantly lower length of hospital stay, in- hospital mortality rate, and hospitalization expenses, and a significantly higher ratio of ICU to hospital stays than the other 3 groups (P b .001). The probability of death tended to be lower when the physician's case volume was higher. The risk-adjusted odds ratio for in-hospital mortality of very-high case volume group was 0.48 (95% confidence interval, 0.35-0.65; P b .001) compared to low case volume group. Conclusions: A higher physician's pneumonia case volume is associated with a lower length of hospital stay, lower in-hospital mortality rate, and lower hospitalization expenses among critically ill children with pneumonia.

Objectives To assess the placement, surveillance management and long-term outcomes of the tracheobronchial (TB) balloon expandable metallic stent (BEMS) managed by therapeutic flexible endoscopy (TFE). Methods This is a retrospective review and analysis of all computerized medical records and related flexible endoscopy videos of pediatric patients who received TB BEMS during 20 years period, from January 1997 to December 2016. TFE techniques with forceps debridement, balloon dilatation and laser ablation were used to implant stents, perform regular surveillance, maintain their functions, and expand the diameters of BEMS. Short-length (30cm-36cm) endoscopes of OD 3.2mm to 5.0mm coupled with the noninvasive ventilation, without ventilation bag, mask or airway tube, supported the whole procedures. Results 146 BEMS were implanted in 87 consecutive children, including 84 tracheal, 15 carinal and 47 bronchial stents. At the time of placement, the mean age was 35.6 ± 54.6 month-old (range 0.3–228) and the mean body weight was 13.9 ± 10.6 kg (range 2.2–60). Surveillance period was 9.4 ± 6.7 years (range, 0.3–18.0). Satisfactory clinical improvements were noted immediately in all but two patients. Seventy-two (82.8%) patients were still alive with stable respiratory status, except two patients necessitating TFE management every two months. Fifty-one stents, including 35 tracheal and 16 bronchial ones, were successfully retrieved mainly with rigid endoscopy. Implanted stents could be significantly (< .001) further expanded for growing TB lumens. The final stent diameters were positively correlated to the implanted duration. Altogether, 33 stents expired (15 patients), 51 were retrieved (40 patients), and 62 remained and functioning well (38 patients), with their mean duration of 7.4 ± 9.5, 34.9 ± 36.3 and 82.3 ± 62.5 months, respectively. Conclusion In pediatric patients, TFE with short-length scopes coupled with this NIV support has provided a safe, feasible and effective modality in placing and subsequently managing TB BEMS with acceptable long-term outcomes.

BACKGROUND Deficiency of the lysosomal enzyme acid α-glucosidase (GAA) causes Pompe disease. Newborn screening for Pompe disease is ongoing, and improved methods for distinguishing affected patients from those with pseudodeficiency, especially in the Asian population, would substantially reduce the number of patient referrals for clinical follow-up. METHODS We measured the enzymatic activity of GAA in dried blood spots on newborn screening cards (DBS) using a tandem mass spectrometry (MS/MS) assay. The assay displayed a relatively large analytical range compared to the fluorimetric assay with 4-methylumbelliferyl-α-glucoside. DBS from newborns confirmed to have infantile-onset Pompe disease (IOPD, n = 11) or late-onset Pompe disease (LOPD) (n = 12) and those from patients bearing pseudodeficiency alleles with or without Pompe mutations, or Pompe disease carriers (n = 230) were studied. RESULTS With use of the MS/MS GAA assay in DBS, 96% of the pseudodeficiency newborns and all of the Pompe disease carriers were well separated from the IOPD and LOPD newborns. The fluorimetric assay separated CONCLUSIONS The relatively large analytical range MS/MS GAA assay but not the fluorimetric assay in DBS provides a robust approach to reduce the number of referrals and should dramatically facilitate newborn screening of Pompe disease.