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Background: Mucopolysaccharidosis II (MPS II) is an X-linked disorder resulting from a deficiency in lysosomal enzyme iduronate-2-sulfatase (IDS), which causes the accumulation of glycosaminoglycans (GAGs) in the lysosomes of many tissues and organs, leading to progressive cellular dysfunction. An MPS II newborn screening program has been available in Taiwan since 2015. The aim of the current study was to collect and analyze the long-term follow-up data of the screen-positive subjects in this program. Methods: From August 2015 to April 2022, 548,624 newborns were screened for MPS II by dried blood spots using tandem mass spectrometry, of which 202 suspected infants were referred to our hospital for confirmation. The diagnosis of MPS II was confirmed by IDS enzyme activity assay in leukocytes, quantitative determination of urinary GAGs by mass spectrometry, and identification of the IDS gene variant. Results: Among the 202 referred infants, 10 (5%) with seven IDS gene variants were diagnosed with confirmed MPS II (Group 1), 151 (75%) with nine IDS gene variants were classified as having suspected MPS II or pseudodeficiency (Group 2), and 41 (20%) with five IDS gene variants were classified as not having MPS II (Group 3). Long-term follow-up every 6 months was arranged for the infants in Group 1 and Group 2. Intravenous enzyme replacement therapy (ERT) was started in four patients at 1, 0.5, 0.4, and 0.5 years of age, respectively. Three patients also received hematopoietic stem cell transplantation (HSCT) at 1.5, 0.9, and 0.6 years of age, respectively. After ERT and/or HSCT, IDS enzyme activity and the quantity of urinary GAGs significantly improved in all of these patients compared with the baseline data. Conclusions: Because of the progressive nature of MPS II, early diagnosis via a newborn screening program and timely initiation of ERT and/or HSCT before the occurrence of irreversible organ damage may lead to better clinical outcomes. The findings of the current study could serve as baseline data for the analysis of the long-term effects of ERT and HSCT in these patients. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2). 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. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: The 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. Methods: Between 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. Results: The 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. Conclusion: Referred newborns with elevated plasma C3/C2 ratios > 0.4 or ammonia levels > 200 mg/dL should be highly suspected of having MMA. [Copyright &y& Elsevier]

The article presents a study on the diagnosis of the cardiac variant of the Fabry disease through newborn screening. Disease incidence were ascertained in the Taiwan Chinese population using the newborn screening program based on the assessment of the enzyme activity. Results show that Fabry mutations among newborns were high, highlighting the importance of early detection to allow therapeutic intervention with enzyme replacement therapy.

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 < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07).Conclusion: MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]