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Background/Purpose Type 2 diabetes has become an important cause of diabetes in children. Since most children with type 2 diabetes are asymptomatic, a screening method is needed. However, physicians are required in the screening methods recommended by professional associations. We aimed to develop a simple and efficient screening method for children with diabetes. Methods A nationwide survey was conducted, which included 2,270,496 seventh-grade students. Students with two abnormal results in sequential urinalyses were given a fasting blood test. Three screening methods were developed. Results Among the screening methods, method C is simple, and can be performed by parents, teachers, or school nurses. It suggests children with two abnormal results in sequential urinalyses and who are overweight or have a family history of diabetes receive blood tests. As a result, 0.10% of boys and 0.16% of girls were recommended to receive blood tests, and 7.0% of boys and 6.7% of girls receiving blood tests were diagnosed diabetes. On average, 15,002 boys and 9056 girls had to be screened to find one child with diabetes. The cost per 1000 children by method C was 2466.84 US dollars. Conclusion Urinalysis screening followed by evaluation of risk factors is a simple and efficient way to identify children with diabetes in schools.

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 To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. Study design More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. Results Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic iduronate-2-sulfatase mutations, and 1 newborn was a carrier of an arylsulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. Conclusions The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible.

Background Mucopolysaccharidoses (MPS) are lysosomal storage diseases in which mutations of genes encoding for lysosomal enzymes cause defects in the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs in lysosomes results in cellular dysfunction and clinical abnormalities. The early initiation of enzyme replacement therapy (ERT) can slow or prevent the development of severe clinical manifestations. MPS I and II newborn screening has been available in Taiwan since August 2015. Infants who failed the recheck at recall were referred to MacKay Memorial Hospital for a detailed confirmatory diagnosis. Methods From August 2015 to November 2017, 294,196 and 153,032 infants were screened using tandem mass spectrometry for MPS I and MPS II, respectively. Of these infants, 84 suspected cases (eight for MPS I; 76 for MPS II) were referred for confirmation. Urinary first-line biochemistry examinations were performed first, including urinary GAG quantification, two-dimensional electrophoresis, and tandem mass spectrometry assay for predominant disaccharides derived from GAGs. If the results were positive, a confirmative diagnosis was made according to the results of leukocyte enzymatic assay and molecular DNA analysis. Leukocyte pellets were isolated from EDTA blood and used for fluorescent α-iduronidase (IDUA) or iduronate-2-sulfatase (IDS) enzymatic assay. DNA sequencing analysis was also performed. Results Normal IDS and IDUA enzyme activities were found in most of the referred cases except for four who were strongly suspected of having MPS I and three who were strongly suspected of having MPS II. Of these infants, three with novel mutations of the IDS gene (c.817C > T, c.1025A > G, and c.311A > T) and four with two missense mutations of the IDUA gene (C.300-3C > G, c.1874A > C; c.1037 T > G, c.1091C > T) showed significant deficiencies in IDS and IDUA enzyme activities (

Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso-Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants.

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.

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

Based on experiences and results from newborn screening for severe combined immunodeficiency (SCID), we evaluated the occurrence of chromosome 22q11.2 deletion syndrome (22q11.2DS) in newborns with different T cell receptor excision circles (TREC) results and established a second tier genetic test for 22q11.2DS.Recalled dried blood spots from 486 newborns with TREC results90 copies/uL were tested from the SCID newborn screening. Quantitative real-time polymerase chain reaction assay was used to detect the copy number of TBX1 and HIRA genes by simple DNA extraction method. Multiplex ligation dependent probe amplification was used for further confirmation.Four hundred sixty-eight cases were considered negative because their haploid copy number of TBX1 and HIRA genes was 0.75. Eighteen cases with TBX1 and/or HIRA gene copy number0.75 were suspected as positive, and 13 cases were further confirmed with 22q11.2DS. Detection rates of 22q11.2DS were 10.7% (6/56) in TREC 30 copies, 6.8% (9/132) in 50 TREC copies, 4.6% (12/260) in 70 TREC copies, and 2.7% (13/486) in 90 TREC copies.22q11.2DS detection can be incorporated into the second-tier assay in subjects with low TREC copies in SCID screening. The dried blood spot methods were feasible for 22q11.2DS newborn screening.

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.

The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m(2)). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes.

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.The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD.To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919GA (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.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.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.

Background: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.

Objectives To investigate the relationship among obesity, cardiovascular disease risk factors (CVDRFs), and plasma complement C3 concentration in children and adolescents. Methods In a nationwide survey conducted between 1992 and 2000, all school children aged 6–18 yr with abnormal results in repeated urine samples, including hematuria, proteinuria, and glucosuria (n = 97 312; 36 557 boys and 60 755 girls), were investigated for their body mass index (BMI), blood pressure, fasting plasma glucose, total cholesterol, and plasma complement C3 concentrations. Results Children in the higher percentile groups for BMI or having more CVDRFs, namely, hypertension, diabetes, and hypercholesterolemia, had higher plasma C3 concentrations independently (p for both trends

In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met valuesP97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy.Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly.The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.

Newborn screening for Fabry disease in Taiwan Chinese has revealed a high incidence of the late-onset GLA mutation IVS4 + 919G→A (∼1 in 1,500–1,600 males). We studied 94 adults with this mutation [22 men, 72 women; mean age: men 57.8 ± 6.0 (range 42–68), women 39.1 ± 14.1 years (range 19–82)]. Plasma α-galactosidase A activity assay was 10.4 ± 11.2% of normal in the men and 48.6 ± 19.5% of normal in the women. Echocardiography in 90 of the adults revealed left ventricular hypertrophy (LVH) in 19 (21%), including 14 of 21 men (67%) and 5 of 69 women (7%). Microalbuminuria, based on the urine albumin-to-creatinine ratio measured on at least two occasions, was present in 17 of 86 subjects (20%) (men: 5/20, 25%; women 12/66, 18%). At least one ocular manifestation consistent with Fabry disease was present in 41 of 52 subjects (79%) who underwent ophthalmologic examination, including 8 (15%) with conjunctival vessel tortuosity, 15 (29%) with cornea verticillata, 10 (19%) with Fabry cataract, and 34 (65%) with retinal vessel tortuosity. Among subjects over 40 years of age, men were more likely than women to have LVH [14/21 (67%) vs 5/25 (20%), p < 0.001]. Cardiovascular, renal and ocular abnormalities are highly prevalent in adult Taiwan Chinese subjects with the Fabry mutation IVS4 + 919G→A. Our findings contribute to the limited understanding of the course of this late-onset disease variant and underscore the need for close follow up in such patients.

BackgroundThe clinical course of methylmalonic aciduria (MMA) is fulminant in neonates and emergency management is necessary to save lives. It is therefore very important to differentiate affected from unaffected neonates immediately when there are abnormal results regarding MMA in newborn screening.MethodsBetween January 2002 and December 2008, 598,522 newborns were screened for MMA by 2 neonatal screening centers: the Chinese Foundation of Health and the Taipei Institute of Pathology. A total of 22 newborns were referred to confirmatory medical centers, and 7 were confirmed as having MMA. The initial propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio, plasma ammonia, liver function tests, blood pH and bicarbonate were compared between the true-positive and false-positive groups.ResultsThe C3/C2 ratio and plasma ammonia were markedly higher in the true-positive MMA group (p < 0.0001). Blood gas pH (p = 0.029), bicarbonate (p = 0.019), and aspartate aminotransferase (p = 0.005) also significantly differed between these 2 groups.ConclusionReferred newborns with elevated plasma C3/C2 ratios > 0.4 or ammonia levels > 200 mg/dL should be highly suspected of having MMA.

To explore the relationship between birth weight and type 1 diabetes, data from national birth registry and national surveillance of diabetes in Taiwanese schoolchildren were analyzed. From 1992 to 1997, all schoolchildren aged 6-18 years were screened for diabetes by a mass urine survey program in Taiwan Province. This cohort consisted of 1966 children with diabetes and 1780 of randomly selected subjects with normal fasting glycemia. Questionnaires were designed for telephone interviews with students' parents or physicians to classify subjects' types of diabetes. The birth history of each participant was obtained from the Taiwan's Birth Registry. After merging the data, there were 835 subjects, including 277 of type 1 diabetes and 533 of normal fasting glycemia available for the present analyses. The odds ratio (95% CI) for type 1 diabetes, after adjusting age, sex, socioeconomic status, family history of diabetes, birth order, breast-feeding, BMI, and gestational diabetes mellitus was 2.24 (1.11-4.50) for children with low birth weight (5th percentile, i.e.,or =2600 g) when compared with the referent group of a birth weight of 3000-3542 g (equivalent to the 25-75th percentile). In conclusion, low birth weight was associated with increased risk of type 1 diabetes in Taiwanese schoolchildren.

OBJECTIVE—To study the effect of body composition and adiponectin on insulin resistance and β-cell function in schoolchildren during puberty. RESEARCH DESIGN AND METHODS—Plasma adiponectin level and its relationships with insulin sensitivity and β-cell function were analyzed in 500 randomly recruited nondiabetic Taiwanese schoolchildren (245 boys and 255 girls) aged 6–18 years in a national survey program for diabetes in 1999. Insulin resistance and β-cell function were evaluated by homeostasis model assessment (HOMA). Plasma adiponectin concentrations were determined with radioimmunoassay. RESULTS—Plasma glucose levels remained stable, whereas insulin resistance increased with a compensatory rise in β-cell function during this period. A transient drop of adiponectin level with a trough at 10–12 years was found in boys but not in girls. This pubertal drop of adiponectin levels in boys coincides with the sharp rise in testosterone concentration. A negative correlation between testosterone levels and adiponectin concentration was also noted in boys (r = −0.142, P = 0.032). Plasma adiponectin levels correlated inversely with relative body weight, fasting insulin concentrations, and insulin resistance index by HOMA in boys aged 15–18 years and in girls aged 11–14 years. No association was observed between adiponectin levels and β-cell function by HOMA. CONCLUSIONS—There is a transient drop in the level of adiponectin during male puberty, correlated with the increase in testosterone level in boys. Plasma adiponectin levels were inversely correlated with obesity and insulin resistance in boys and girls during the pubertal period.

OBJECTIVE—To study the effect of birth weight on risk of type 2 diabetes in the schoolchildren in Taiwan. RESEARCH DESIGN AND METHODS—From 1992 to 1997, all schoolchildren aged 6–18 years were screened for diabetes in Taiwan Province. This cohort consisted of 1,966 patients with diabetes and 1,780 randomly selected subjects with normal fasting glycemia (NFG). Questionnaire interviewing was designed to classify diabetes. The birth weight was obtained from the Taiwan’s Birth Registry. After merging the data, there were 978 subjects, including 429 with type 2 diabetes and 549 with of NFG enrolled in the present analyses. RESULTS—The odds ratios (95% CI) for type 2 diabetes, after adjusting age, sex, BMI, family history of diabetes, and socioeconomic status, were 2.91 (1.25–6.76) for children with low birth weight ( CONCLUSIONS—A U-shaped relationship between birth weight and risk of type 2 diabetes was found in the schoolchildren aged 6–18 years in Taiwan. Schoolchildren with type 2 diabetes who were born with low birth weight had different metabolic phenotypes compared with those born with high birth weight.

Background Interest in lysosomal storage diseases in newborn screening programs has increased in recent years. Two techniques, fluorescence (4-MU) and tandem mass spectrometry (MS/MS) methods are frequently used. We report a pilot study of large scale newborn screening for Fabry, Pompe, Gaucher, and MPS I diseases by using the MS/MS method in Taiwan and compared the performance of the MS/MS with 4-MU methods. Methods More than 100,000 dried blood spots (DBSs) were collected consecutively as part of the national Taiwan newborn screening programs. The enzyme activities were detected by the MS/MS method from a DBS punch. Mutation analysis was further performed for newborns with detected enzyme deficiency. Results The DNA sequence analysis for suspected cases revealed 64 newborns with confirmed Fabry mutations, 16 were classified as infantile or late-onset Pompe disease, and 1 was characterized as Gaucher disease. The positive predict value increased from 4.0% to 7.1% in the Pompe study, and from 61.0% to 95.5% in the Fabry study by the MS/MS method compared to 4-MU assay. Conclusions The MS/MS method has been validated as a more specific, powerful and efficient tool than the 4-MU assay. It also provided a multiplex solution of newborn screening for lysosomal storage diseases.

Objective To evaluate whether very early treatment in our patients would result in better clinical outcomes and to compare these data with other infantile-onset Pompe disease (IOPD) cohort studies. Methods In this nationwide program, 669 797 newborns were screened for Pompe disease. We diagnosed IOPD in 14 of these newborns, and all were treated and followed in our hospital. Results After 2010, the mean age at first enzyme-replacement therapy (ERT) was 11.92 days. Our patients had better biological, physical, and developmental outcomes and lower anti-rh acid α-glucosidase antibodies after 2 years of treatment, even compared with one group that began ERT just 10 days later than our cohort. No patient had a hearing disorder or abnormal vision. The mean age for independent walking was 11.6 ± 1.3 months, the same age as normal children. Conclusions ERT for patients with IOPD should be initiated as early as possible before irreversible damage occurs. Our results indicate that early identification of patients with IOPD allows for the very early initiation of ERT. Starting ERT even a few days earlier may lead to better patient outcomes.

To investigate the relationship among obesity, cardiovascular disease risk factors (CVDRFs), and plasma complement C3 concentration in children and adolescents.In a nationwide survey conducted between 1992 and 2000, all school children aged 6-18 yr with abnormal results in repeated urine samples, including hematuria, proteinuria, and glucosuria (n = 97 312; 36 557 boys and 60 755 girls), were investigated for their body mass index (BMI), blood pressure, fasting plasma glucose, total cholesterol, and plasma complement C3 concentrations.Children in the higher percentile groups for BMI or having more CVDRFs, namely, hypertension, diabetes, and hypercholesterolemia, had higher plasma C3 concentrations independently (p for both trends0.05, adjusted for age and gender). The odds ratios (ORs) for having one, two, or three CVDRFs in obese children were 4.74 [95% confidence interval (CI) = 4.47-5.03], 19.8 (95% CI = 17.8-22.0), and 139 (95% CI = 96.6-200), respectively, adjusted for age, gender, and family history of diabetes, which were substantially reduced after adjustment for plasma C3 concentrations. The ORs for children with plasma C3 concentrations in the highest quartile to have one, two, or three CVDRFs were 2.32 (95% CI = 2.21-2.44), 5.68 (95% CI = 4.83-6.67), and 58.6 (95% CI = 19.7-174), respectively, adjusted for age, gender, family history of diabetes, and BMI.Obesity is associated with clustering of CVDRFs in children and adolescents. Obesity and clustering of CVDRFs are associated with elevated plasma complement C3. Children and adolescents with higher plasma C3 concentrations have higher risk of clustering of CVDRFs independent of obesity.

Li H-Y, Wei J-N, Ma W-Y, Sung F-C, Lin M-S, Lin C-H, Chiang C-C, Chuang L-M. Hypertension and hypercholesterolemia aggregate in nondiabetic children and adolescents with higher fasting plasma glucose levels. Objective: To investigate how hypertension and hypercholesterolemia aggregate at different fasting plasma glucose (FPG) levels in children aged 6–16 yr. Research design and methods: In a nationwide survey conducted between 1992 and 2000, all schoolchildren aged 6–18 yr with abnormal results in repeated urine samples were included. In this study, we recruited 27 535 students aged 6- to 16-yr whose FPG levels were 90–125 mg/dL. Another 17 907 children were randomly selected as control from schoolchildren with FPG

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.

Background— Fabry disease is a treatable lysosomal storage disorder, which is often misdiagnosed or belatedly diagnosed. Methods and Results— To determine the disease incidence in the Taiwan Chinese population, a Fabry disease newborn screening study was initiated. A total of 110 027 newborns were screened by assaying the α-galactosidase A (α-Gal A) activity using dry blood spots. Low plasma α-Gal A activity and presence of a Fabry mutation was demonstrated in 45 neonates (3 females). Eight different mutations were identified, including 3 known missense mutations (R112H, A143T, and R356W), 4 novel missense mutations (G104V, M296L, G360C, and K391T), and one known intronic mutation (IVS4+919G→A). The IVS4+919G→A mutation was most common (82% of patients). A total of 20 maternal grandparents of infants harboring this intronic mutation were evaluated by echocardiography, mutation analysis and α-Gal A activity assay. The intronic mutation was found in 9 grandfathers and 11 grandmothers. Of these grandparents, 3 grandfathers (33%) but none of the grandmothers had hypertrophic cardiomyopathy. Additionally, 16 males who had been diagnosed with idiopathic hypertrophic cardiomyopathy were screened by mutation analysis and α-Gal A activity; 4 (25%) showed deficient plasma α-Gal A activity in combination with the intronic mutation. Conclusion— We found an unexpected high prevalence of the cardiac variant Fabry mutation IVS4+919G→A among both newborns (≈1 in 1600 males) and patients with idiopathic hypertrophic cardiomyopathy in the Taiwan Chinese population. The early identification of undiagnosed patients allows timely therapeutic intervention providing a better clinical outcome.

Objectives To investigate the association of blood pressure elevation with body mass index (BMI) and total cholesterol levels in children who screened positive for proteinuria, glucosuria, and/or hamaturia. Study design From 1992 to 2000, a mass urine screening program was conducted annually for nearly 3 000 000 students aged 6 to 18 years. Of 99 350 students with positive results on urine tests, further examination found 17 548 students (17.7%) had blood pressure elevation. A case-control analysis was performed with randomly selected subjects with normal blood pressure who were frequency matched by sex and age. Results The adjusted odds ratio for blood pressure elevation in obese students was 3.45 (95% CI, 3.20-3.72), compared with students of normal weight. The odds ratio for blood pressure elevation increased to 6.15 (95% CI, 4.12-9.18) for students with a total cholesterol level ≥250 mg/dL and obesity, compared with students with a total cholesterol level Conclusion This study found a high prevalence of elevated blood pressure in children with abnormal urinalysis results, with a strong association with BMI and total choleterol level.

WEI, JUNG-NAN, HUNG-YUAN LI, FUNG-CHANG SUNG, CHAU-CHING LIN, CHUAN-CHI CHIANG, CHUNG-YI LI, AND LEE-MING CHUANG. Birth weight correlates differently with cardiovascular risk factors in youth. Obesity. 2007;15:1609–1616. Objective: Childhood obesity has become prevalent, resulting in a greater risk of hypertension, diabetes, and dyslipidemia. However, the relationship between these comorbid conditions and birth weight remains uncertain. We conducted this study to evaluate the relationship between birth weight and cardiovascular risk factors in children and adolescents. Research Methods and Procedures: In a nationwide survey conducted between 1992 and 2000, all schoolchildren 6 to 18 years old with glucosuria, proteinuria, or microscopic hematuria in repeated urine samples were included and received a physical examination and blood test. Those with gestational age 37 weeks were excluded. We enrolled 81,538 children (51,111 girls and 30,427 boys) and obtained their birth weights from the Taiwan Birth Registry. Obesity and hypertension were defined by age- and sex-specific cut-offs. Diabetes was diagnosed if the fasting glucose was 7m M. Results: The risk of obesity was higher for those with birth weights 4000 grams [odds ratio (OR), 1.65] and 3543 to 3999 grams (OR, 1.28) and lower for those with birth weights 2601 to 2999 grams (OR, 0.90), using 3000 to 3542 grams as the reference group. An increased risk of diabetes was associated with both higher and lower birth weights, indicating a U-shaped relationship (OR, 2600 grams, 1.607; 2601 to 2999 grams, 1.119; 3543 to 3999 grams, 1.112; 4000 grams, 1.661). In the 10- to 12-year-old age group, the risk of hypertension was higher in those with birth weights 2600 grams (OR, 1.20). Discussion: Low birth weight was associated with childhood diabetes. High birth weight was correlated with childhood obesity and diabetes. Our data indicate different relationships between birth weight and the development of obesity, hypertension, and diabetes in childhood.

ContextDespite a disturbing trend of increasing prevalence of type 2 diabetes mellitus (DM) in childhood, little is known about the epidemiology of childhood type 2 DM, especially in the Taiwanese population.ObjectiveTo study the rate and risk factors for childhood type 2 DM based on a nationwide screening program in Taiwan.Design, Setting, and ParticipantsScreening in 1999 for type 2 DM using urine and blood testing and confirmed by follow-up telephone survey among schoolchildren aged 6 to 18 years in Taiwan, followed by a nested case-control study conducted in 2002 comparing 137 children with type 2 DM with 1000 randomly selected children without diabetes chosen to represent the age and sex distribution of the whole student population.Main Outcome MeasuresRate and identification of risk factors associated with childhood type 2 DM.ResultsThe rate of newly identified diabetes was 9.0 per 100 000 for boys and 15.3 per 100 000 for girls. Follow-up at 3 years revealed that, of 253 children with newly diagnosed diabetes, 24 (9.5%) had type 1 DM, 137 (54.2%) had type 2 DM, and 22 (8.7%) had secondary diabetes. Compared with children aged 6 to 9 years, the odds ratios (ORs) and 95% confidence intervals (CIs) of type 2 DM increased to 6.59 (3.23-13.4) for those aged 13 to 15 years and to 4.59 (2.07-10.2) for those aged 16 to 18 years. The OR (95% CI) of type 2 DM in children with a body mass index in the 95th percentile or higher (obesity) was 18.8 (9.22-38.5) compared with those with a body mass index in less than the 50th percentile. Other factors significantly associated with type 2 DM were hypercholesterolemia (OR, 1.80; 95% CI, 1.04-3.23), blood pressure greater than the 85th percentile (OR, 1.70; 95% CI, 1.07-2.70), and positive family history of diabetes (OR, 3.95; 95% CI, 2.01-7.78).ConclusionsOur mass screening program showed that type 2 DM is the leading cause of childhood DM in Taiwan. Obesity is a major risk factor for the development of type 2 DM in children.

Objective: To describe the gender differences in cases and characteristics of diabetes mellitus (DM) that can be identified from a mass urine screen program for school children in Taiwan. Method: Screening for the childhood asymptomatic proteinuria and glucosuria began in 1992 for school children. Students were instructed to collect mid-stream samples of the first morning urine for glucosuria and proteinuria tests using urine strip devices. Students with positive results for glucose and/or protein and/or occult blood in the first examination received a second urine test. The third screening test was performed for urine and fasting blood sample for 11-item examinations if the second test was positive. The 1997 criteria of American Diabetes Association were used for defining DM. Results: Approximately 2 615 000–2 932 000 students received the preliminary screening each semester. The overall average rates of newly identified diabetes from 1993 to 1999 were 8.3 per 100 000 among boys, and 12.0 per 100 000 among girls. The average rate of new cases increased significantly from sixth grade for boys and fourth grade for girls, with peak rates of 14.7 per 100 000 in eighth grade for boys and 19.0 per 100 000 in sixth grade for girls. Similar prevalence trends by sex and grade were observed, higher in girls than in boys. Conclusions: This mass screening data suggest that childhood diabetes of all types in Taiwan is elevated in the age of puberty and higher in girls than in boys.

Background In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation Methods and results Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis. Conclusions All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation.

Objective Current studies of newborn screening for Fabry disease in Taiwan have revealed a remarkably high prevalence of cardiac-type Fabry disease with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A). Design Retrospective cohort study. Setting Tertiary medical centre. Participants 21 patients with cardiac-type Fabry disease (15 men and 6 women) as well as 15 patients with classic Fabry disease (4 men and 11 women) treated with biweekly intravenous infusions of agalsidase β (1 mg/kg) or agalsidase α (0.2 mg/kg) for at least 6 months. Outcome measures These data were collected at the time before enzyme replacement therapy (ERT) began and followed up after ERT for at least 6 months, including patient demographics, medical history, parameter changes of cardiac status and renal functions, plasma globotriaosylsphingosine (lyso-Gb3) and Mainz Severity Score Index. Results After 6–39 months of ERT, plasma lyso-Gb3 was found to be reduced in 89% (17/19) and 93% (14/15) of patients with cardiac-type and classic Fabry disease, respectively, which indicated an improvement of disease severity. For patients with cardiac-type Fabry disease, echocardiography revealed the reduction or stabilisation of left ventricular mass index (LVMI), the thicknesses of intraventricular septum (IVS) and left posterior wall (LPW) in 83% (15/18), 83% (15/18) and 67% (12/18) of patients, respectively, as well as 77% (10/13), 73% (11/15) and 60% (9/15) for those with classic type. Most patients showed stable renal function after ERT. There were statistically significant improvements (p

BackgroundPrevious studies revealed a high incidence of late-onset Fabry disease mutation, IVS4+919G>A, in Taiwan. However, the natural course is largely unclear and suitable biomarkers for monitoring disease progress are unavailable.Methods and resultsPatients carrying IVS4+919G>A or classical Fabry mutations were enrolled in this study. The subjects ranged from newborn to eighty year old adults. Plasma globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) were measured by LC-MS/MS in subjects to evaluate the sensitivity of these two biomarkers. All adult males and symptomatic females could be distinguished from healthy controls by an elevated plasma lysoGb3 level. The lysoGb3 level was also related to the left ventricular mass considering gender and age (pA mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates that the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation.

Background Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. Methods The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. Results After 12–112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. Conclusion The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease.