Publications by authors named "Yin-Hsiu Chien"

208 Publications

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

Neuromuscul Disord 2021 Jan 13. Epub 2021 Jan 13.

Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder with a dramatic clinical presentation. It was recently discovered that MADD may present at an advanced age. The clinical and laboratory data of an index patient and patients previously diagnosed at our institution were collected. A systematic review of previous studies retrieved from the PubMed, MEDLINE, and Embase databases published by February 1, 2020 was performed to collect patients with very-late-onset MADD (VLO-MADD, onset age > 60 years) globally and patients with late-onset MADD (LO-MADD, onset age < 60 years) in Taiwan. The clinical characteristics of the VLO-MADD patients were compared to those of LO-MADD patients. We report a patient with VLO-MADD who developed the first symptom at the age of 61 years. The patient presented with a Reye-like syndrome after taking aspirin for coronary artery disease. Repeated bouts of weakness were noted. Two variants of c.250 G > A (;) 419C > T were observed in the ETFDH gene. Another four patients with VLO-MADD were identified globally. Eighteen patients with LO-MADD were collected from our department and previously reported patients in Taiwan. There was no difference in the clinical symptoms (except for the onset age) or laboratory data between these two groups. Homozygous variants were not observed in any patients in the VLO-MADD group but were detected in 12 patients (66.6%) in the LO-MADD group (p = 0.014). Patients with MADD may first show symptoms in their 6th decade or beyond. The disease course may lead to erroneous diagnoses in this age group.
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http://dx.doi.org/10.1016/j.nmd.2021.01.006DOI Listing
January 2021

Nusinersen in spinal muscular atrophy type 1 from neonates to young adult: 1-year data from three Asia-Pacific regions.

J Neurol Neurosurg Psychiatry 2021 Feb 11. Epub 2021 Feb 11.

Departments of Pediatrics and Laboratory Medicine, and Translational Research Center of Neuromuscular Diseases, Kaohsiung University Medicine Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

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http://dx.doi.org/10.1136/jnnp-2020-324532DOI Listing
February 2021

Development of Newborn Screening for Pompe Disease.

Int J Neonatal Screen 2020 Jan 24;6(1). Epub 2020 Jan 24.

Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan.

Pompe disease is an inborn error of lysosomal degradation of glycogen [...].
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http://dx.doi.org/10.3390/ijns6010005DOI Listing
January 2020

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

J Neurol 2021 Feb 5. Epub 2021 Feb 5.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University Munich, Ziemssenstr. 1, 80336, Munich, Germany.

Background: Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world long-term efficacy and safety of alglucosidase alfa.

Methods: This multicenter retrospective study (NCT02824068) collected data from adult Pompe disease patients receiving ERT for at least 3 years. Demographics and baseline characteristics, muscle strength, lung function (FVC), walking capability (6MWT), and safety were assessed once a year. Evaluation was done on the group and individual levels, using quantitative linear models (t test) and general univariate linear models (ANOVA).

Findings: Sixty-eight adult Pompe disease patients from four countries (Spain, Taiwan, Italy, Germany (STIG)) participated. The mean follow-up was 7.03 years ± 2.98. At group level in all outcome measures, an initial improvement followed by a secondary decline was observed. After 10 years, the 6MWT showed the most sustained positive effect (p = 0.304). The MRC remained stable with a mild decline (p = 0.131), however, FVC deteriorated significantly (p < 0.001) by 14.93% over 10 years of ERT. The progression rate of FVC under ERT could be explained in most of the patients (83.5%) by the disease severity at baseline. Furthermore, our study shows a decline in the FVC combined with an increase in non-invasive and invasive ventilation requirements in adult Pompe disease patients over time.

Conclusions: The STIG real-world study confirms an initial efficacy of ERT in the first years with a secondary sustained decline in multiple outcome measures. Further efforts are required to establish a more valid long-term monitoring and improved therapies.
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http://dx.doi.org/10.1007/s00415-021-10409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862044PMC
February 2021

Ultrastructural and diffusion tensor imaging studies reveal axon abnormalities in Pompe disease mice.

Sci Rep 2020 11 19;10(1):20239. Epub 2020 Nov 19.

Department of Medical Genetics, National Taiwan University Hospital, Taipei, 10041, Taiwan.

Pompe disease (PD) is caused by lysosomal glycogen accumulation in tissues, including muscles and the central nervous system (CNS). The intravenous infusion of recombinant human acid alpha-glucosidase (rhGAA) rescues the muscle pathologies in PD but does not treat the CNS because rhGAA does not cross the blood-brain barrier (BBB). To understand the CNS pathologies in PD, control and PD mice were followed and analyzed at 9 and 18 months with brain structural and ultrastructural studies. T2-weighted brain magnetic resonance imaging studies revealed the progressive dilatation of the lateral ventricles and thinning of the corpus callosum in PD mice. Electron microscopy (EM) studies at the genu of the corpus callosum revealed glycogen accumulation, an increase in nerve fiber size variation, a decrease in the g-ratio (axon diameter/total fiber diameter), and myelin sheath decompaction. The morphology of oligodendrocytes was normal. Diffusion tensor imaging (DTI) studies at the corpus callosum revealed an increase in axial diffusivity (AD) and mean diffusivity (MD) more significantly in 9-month-old PD mice. The current study suggests that axon degeneration and axon loss occur in aged PD mice and are probably caused by glycogen accumulation in neurons. A drug crossing the BBB or a treatment for directly targeting the brain might be necessary in PD.
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http://dx.doi.org/10.1038/s41598-020-77193-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677380PMC
November 2020

Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985-2019).

Orphanet J Rare Dis 2020 11 7;15(1):314. Epub 2020 Nov 7.

Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.

Background: Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs.

Methods: An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated.

Results: Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p < 0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy (p < 0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual (p < 0.01).

Conclusions: The life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.
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http://dx.doi.org/10.1186/s13023-020-01598-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648385PMC
November 2020

The Timely Needs for Infantile Onset Pompe Disease Newborn Screening-Practice in Taiwan.

Int J Neonatal Screen 2020 Jun 1;6(2):30. Epub 2020 Apr 1.

Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-C.C.); (K.-L.C.); (N.-C.L.); (W.-L.H.).

Pompe disease Newborn screening (NBS) aims at diagnosing patients with infantile-onset Pompe disease (IOPD) early enough so a timely treatment can be instituted. Since 2015, the National Taiwan University NBS Center has changed the method for Pompe disease NBS from fluorometric assay to tandem mass assay. From 2016 to 2019, 14 newborns were reported as high-risk for Pompe disease at a median age of 9 days (range 6-13), and 18 were with a borderline risk at a median age of 13 days (9-28). None of the borderline risks were IOPD patients. Among the 14 at a high-risk of Pompe disease, four were found to have cardiomyopathy, and six were classified as potential late-onset Pompe disease. The four classic IOPD newborns, three of the four having at least one allele of the cross-reactive immunologic material (CRIM)-positive variant, started enzyme replacement therapy (ERT) at a median age of 9 days (8-14). Western Blot analysis and whole gene sequencing confirmed the CRIM-positive status in all cases. Here, we focus on the patient without the known CRIM-positive variant. Doing ERT before knowing the CRIM status created a dilemma in the decision and was discussed in detail. Our Pompe disease screening and diagnostic program successfully detected and treated patients with IOPD in time. However, the timely exclusion of a CRIM-negative status, which is rare in the Chinese population, is still a challenging task.
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http://dx.doi.org/10.3390/ijns6020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422994PMC
June 2020

Development of Newborn Screening for Pompe Disease.

Int J Neonatal Screen 2020 Mar 24;6(1). Epub 2020 Jan 24.

Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan;

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http://dx.doi.org/10.3390/ijns6010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422982PMC
March 2020

CMAP changes upon symptom onset and during treatment in spinal muscular atrophy patients: lessons learned from newborn screening.

Genet Med 2021 Feb 9;23(2):415-420. Epub 2020 Oct 9.

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.

Purpose: Early identification and treatment of spinal muscular atrophy (SMA) are crucial but difficult. In this study, we aimed to assess the significance of compound motor action potential (CMAP) amplitude in patients identified through a newborn screening program.

Methods: We initiated a large-scale population newborn screening program for SMA in Taiwan in 2014. Patients had access to treatment through clinical trials or expanded use programs. Symptomatic patients were evaluated regularly, including CMAP exams.

Results: Among 364,000 screened newborns, 21 were diagnosed with SMA. The incidence of SMA was around 1 in 17,000 live births, and 70% developed SMA type 1. All infants with two SMN2 copies became symptomatic before the age of 1 month. CMAP amplitudes of 12 newborns were available, including 6 who were subsequently treated with nusinersen. We found that a rapid decrease of CMAP amplitude was an early predictor of symptom onset. Pretreatment CMAP and rapid increment of post-treatment CMAP could predict better treatment outcomes.

Conclusion: This study prospectively demonstrated the incidence of SMA and its types. Our results imply the importance of pretreatment CMAP amplitude and rapid reversal of post-treatment CMAP amplitude with regard to disease presentation and also treatment outcomes.
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http://dx.doi.org/10.1038/s41436-020-00987-wDOI Listing
February 2021

Dietary intake and nutritional status of patients with phenylketonuria in Taiwan.

Sci Rep 2020 09 3;10(1):14537. Epub 2020 Sep 3.

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.

Phenylalanine hydroxylase (PAH) deficiency leads to phenylalanine accumulation and results in phenylketonuria (PKU). Phenylketonuria can contribute to severe inability such as mental impairment. Early diagnosis and dietary intervention can have beneficial effects on maintaining normal neural and cognitive function in patients with PKU. However, a long-term low phenylalanine diet may put children at risk of malnutrition. A food supplement was therefore used for children with PKU under dietician supervision according to dietary reference intakes (DRIs). In this cross-sectional study, we enrolled patients with PKU and age-matched controls to compare their anthropometry data [weight, height, body mass index (BMI), and body composition using bioelectrical impedance analysis (BIA)], and correlated it with their dietary intake based on 24-h dietary recall. For continuous parameters, the data were expressed as median ± standard deviation (SD), and the Mann-Whitney U test was used to test the difference among the groups. Correlation by natural proteins, body fat, and fat-free mass were evaluated using the Pearson correlation coefficient. Twenty-two participants diagnosed with PKU (ages 8-27 years; mean 15.23 ± 5.23) and a control group of 22 non-PKU participants (ages 8-39 years; mean 19.73 ± 10.6) were recruited for this study. Between the two groups of participants, no significant difference was found in height, weight, BMI, muscle mass, or fat mass. The percentage of natural protein has no effect on body composition. We found a significant positive correlation between the total protein intake percentage of DRIs and muscle mass (r = 0.491, p = 0.020) and a significant negative correlation in the total protein intake percentage of DRIs and fat mass (r = -0.475, p = 0.025) in participants with PKU. There were no significant differences in body composition and nutrition intake between patients with PKU (under metabolic control) and healthy subjects. Thus, giving proper nutrition treatment may have beneficial effects on body growth and nutrition status in patients with PKU in Taiwan.
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http://dx.doi.org/10.1038/s41598-020-71361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471922PMC
September 2020

Diversity in heritable disorders of connective tissue at a single center.

Connect Tissue Res 2020 Sep 8:1-6. Epub 2020 Sep 8.

Department of Pediatrics and Medical Genetics, National Taiwan University Hospital , Taipei, Taiwan.

Background: Heritable disorders of connective tissue (HDCT) is a heterogeneous group of conditions caused by defects in genes responsible for extracellular matrix elements. Although next-generation sequencing (NGS) technology can be used to analyze many genes at a time, precisely diagnosing HDCT is still challenging because of the overlapping phenotypes and genotypes.

Methods: A 67-gene NGS targeted panel or whole-exome sequencing was employed for the diagnosis of HDCT over 4 years. Phenotypes and genotypes of patients were analyzed retrospectively.

Results: Mutations in 16 genes were discovered in 34 patients with the suspicion of Ehlers-Danlos syndrome (n = 7), Marfan syndrome (n = 2), osteogenesis imperfecta (n = 3), skeletal dysplasia (n = 18), and others (n = 4). Eighteen patients were found to have mutations in collagen genes, three had mutations, two had mutations, two had mutations, two had mutations, and mutations in seven other genes were found in one patient each. The eight patients with mutations had a wide variation in phenotype. Patients with and mutations presented with classic EDS, those with mutations presented with typical OI type VI, those with mutations presented with severe spinal deformity, and those with mutations presented with syndromic or nonsyndromic bone dysplasia or only short stature.

Conclusion: A wide diversity in HDCT was observed. Therefore, knowledge about the phenotype-genotype correlation in HDCT is still crucial in the diagnosis of this group of diseases, and an improvement in the screening tool will be needed.
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http://dx.doi.org/10.1080/03008207.2020.1816994DOI Listing
September 2020

Frequency and spectrum of actionable pathogenic secondary findings in Taiwanese exomes.

Mol Genet Genomic Med 2020 10 14;8(10):e1455. Epub 2020 Aug 14.

Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Exome sequencing has recently become more readily available, and more information about incidental findings has been disclosed. However, data from East Asia are scarce. We studied the application of exome sequencing to the identification of pathogenic/likely pathogenic variants in the ACMG 59 gene list and the frequency of these variants in the Taiwanese population.

Methods: This study screened 161 Taiwanese exomes for variants from the ACMG 59 gene list. The identified variants were reviewed based on information from different databases and the available literature and classified according to the ACMG standard guidelines.

Results: We identified seven pathogenic/likely pathogenic variants in eight individuals, with five participants with autosomal recessive variants in one allele and three participants with autosomal dominant variants. Approximately 1.86% (3/161) of the Taiwanese individuals had a reportable pathogenic/likely pathogenic variant as determined by whole-exome sequencing (WES), which was comparable to the proportions published previously in other countries. We further investigated the high carrier rate of rare variants in the ATP7B gene, which might indicate a founder effect in our population.

Conclusion: This study was the first to provide Taiwanese population data of incidental findings and emphasized a high carrier rate of candidate pathogenic/likely pathogenic variants in the ATP7B gene.
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http://dx.doi.org/10.1002/mgg3.1455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549563PMC
October 2020

Lessons for the clinical nephrologist: dietary management of adult-onset type II citrullinemia in chronic kidney disease: a nutritional dilemma.

J Nephrol 2020 10 27;33(5):1111-1113. Epub 2020 Jul 27.

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.

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http://dx.doi.org/10.1007/s40620-020-00813-1DOI Listing
October 2020

Clinical, radiological, and genetic characteristics in patients with Huntington's disease in a Taiwanese cohort.

Am J Med Genet B Neuropsychiatr Genet 2020 09 9;183(6):352-359. Epub 2020 Jul 9.

Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

Characteristics of Huntington's disease (HD) differ among various ethnicities. Few studies have explored the relationship between phenotypes and genotypes of HD in Asians. We evaluated the relationship between integrated clinical and imaging phenotypes and genotypes in a Taiwanese HD cohort, enrolling 123 HD patients genetically diagnosed between August 1994 and February 2019. The clinical presentations and brain magnetic resonance imaging characteristics were analyzed from 67 patients and examined the correlation with genetic findings. Chorea was the most common initial manifestation (66.1%), especially in patients with late-onset disease (onset age > 60 years old), followed by psychiatric symptoms (25%) and cognitive impairment (14.3%). Compared to patients with adult-onset HD, the prevalence of parkinsonism was significantly higher in juvenile-onset HD patients (onset age < 20 years old, p = .007). Disease burden, which was measured by CAG repeats and age, was significantly associated with atrophy in caudate nucleus (p = .004), followed by putamen (p = .029), nucleus accumbens (p = .002), thalamus (p = .003), and total cortical volume (p = .001) after correcting for total intracranial volume. Our findings, that provided the first series of Taiwanese HD patients, delineated the clinical, radiological, and genetic characteristics in Asian HD patients.
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http://dx.doi.org/10.1002/ajmg.b.32810DOI Listing
September 2020

Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences.

Mol Genet Metab Rep 2020 Jun 29;23:100591. Epub 2020 Apr 29.

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.

Objective: Enzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect.

Study Design: A retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT.

Results: Twenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage ( = 23) or a high dosage exclusively ( = 5). At a median age of 8.3 years (0.8-17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline ( < .001). In patients with classical IOPD diagnosed through newborn screening, those late in ERT initiation ( = .006) or late in high-dosage ERT initiation ( = .044) had a higher risk of motor decline. At the latest assessment, both serum creatine kinase (CK) and urinary glucose tetrasaccharide (uGlc4) levels were lowest in the walkers. During follow up, the biomarker levels, once rose, never returned to normal.

Conclusion: Low CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients, although CK may be more fluctuated than uGlc4. High-dose ERT instituted immediately at newborn screening seems to give the best outcome, and a dosage increase is necessary upon - or, even better, before - a rise in biomarker levels.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193123PMC
June 2020

Turner syndrome and cardiovascular anomalies: Care for girls and women.

Pediatr Neonatol 2020 04;61(2):129-130

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.

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http://dx.doi.org/10.1016/j.pedneo.2020.03.008DOI Listing
April 2020

Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.

Orphanet J Rare Dis 2020 02 3;15(1):38. Epub 2020 Feb 3.

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.

Background: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease.

Methods: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis.

Results: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively.

Conclusions: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.
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http://dx.doi.org/10.1186/s13023-020-1322-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998831PMC
February 2020

Early initiation of high-dose oral ambroxol in combination with enzyme replacement therapy in a neuropathic Gaucher infant.

Blood Cells Mol Dis 2020 03 2;81:102402. Epub 2020 Jan 2.

Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.bcmd.2019.102402DOI Listing
March 2020

Cardiac manifestations and gene mutations of patients with RASopathies in Taiwan.

Am J Med Genet A 2020 02 14;182(2):357-364. Epub 2019 Dec 14.

Department of Pediatrics and Rare Disease Center, Mackay Memorial Hospital, Taipei, Taiwan.

RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.
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http://dx.doi.org/10.1002/ajmg.a.61429DOI Listing
February 2020

Composite Scores of Plasma Tau and β-Amyloids Correlate with Dementia in Down Syndrome.

ACS Chem Neurosci 2020 01 23;11(2):191-196. Epub 2019 Dec 23.

Department of Neurology , National Taiwan University Hospital, College of Medicine, National Taiwan University , Taipei 100 , Taiwan.

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.
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http://dx.doi.org/10.1021/acschemneuro.9b00585DOI Listing
January 2020

Clinical features of Pompe disease with motor neuronopathy.

Neuromuscul Disord 2019 11 25;29(11):903-906. Epub 2019 Sep 25.

Department of Medical Genetics, National Taiwan University Hospital, Room 19005, 19F, Children's Hospital Building, 8 Chung-Shan South Road, Taipei 10041, Taiwan; Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Pathological studies on rodent models and patients with Pompe disease have demonstrated the accumulation of glycogen in spinal motor neurons; however, this finding has rarely been evaluated clinically in patients with Pompe disease. In this study, we analyzed seven patients (age, 7-11 years) with Pompe disease who received long-term enzyme replacement therapy. In addition to traditional myopathy-related clinical and electrophysiological features, these patients often developed bilateral foot drop, distal predominant weakness of four limbs, and hypo- or areflexia with preserved sensory function. Electrophysiological studies showed not only reduced amplitudes of compound muscle action potential, but also absent or impersistent F waves and mixed small and large/giant polyphasic motor unit action potentials with normal sensory study. Muscle biopsy usually showed the existence of angular fingers, fiber type grouping or group atrophy. Taken together, these features support the co-existence of motor neuronopathy additionally to myopathy.
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http://dx.doi.org/10.1016/j.nmd.2019.09.011DOI Listing
November 2019

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population.

Brain Behav 2019 10 16;9(10):e01414. Epub 2019 Sep 16.

Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Spinocerebellar ataxia (SCA) presents with variable clinical presentations in addition to ataxia. The aim of this study was to reappraise the diverse nonataxic clinical characteristics of the five most common SCA subtypes in the Asian population.

Methods: The clinical presentations of 90 patients with genetically confirmed SCA1, SCA2, SCA3, SCA6, or SCA17 were assessed retrospectively between November 2008 and September 2018 at a tertiary referral center in Taiwan.

Results: Parkinsonism was the most common nonataxic phenotype (21.1%), with a greater prevalence than Caucasian and other Asian SCA carriers. Patients with parkinsonism feature had fewer CAG repeats in SCA2 (31.0 ± 4.5 vs. 36.9 ± 6.0, p = .03) and SCA3 (65.6 ± 7.9 vs. 70.0 ± 4.2, p = .02) compared to those with pure ataxia presentation. The average age of symptom onset was significantly higher in the parkinsonism group of SCA2 (51.5 ± 8.9 vs. 35.3 ± 12.6 years, p = .007) than those with pure ataxia. Focal or segmental dystonia was identified in 4.4% of SCA patients (n = 2 each SCA2 and SCA3). Nonmotor symptoms, including impaired cognition (6.1% of SCA2 and 8.3% of SCA3 patients) and depression (9.1% of SCA2 and 8.3% of SCA3 patients), were also common nonataxic features in our SCA patients.

Conclusions: Parkinsonism, dystonia, and cognitive-psychiatric symptoms are common features in patients with SCA mutations in our population. Our study identifies a different clinical spectrum of SCA1, SCA2, SCA3, SCA6, and SCA17 compared to Caucasians.
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http://dx.doi.org/10.1002/brb3.1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790309PMC
October 2019

Primary coenzyme Q10 deficiency-7: expanded phenotypic spectrum and a founder mutation in southern Chinese.

NPJ Genom Med 2019 5;4:18. Epub 2019 Aug 5.

1Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in . Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.
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http://dx.doi.org/10.1038/s41525-019-0091-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683205PMC
August 2019

Newborn screening: Taiwanese experience.

Ann Transl Med 2019 Jul;7(13):281

Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.

Newborn screening (NBS) aims to diagnose patients with Pompe disease earlier so that timely treatment can be applied. We describe the evolution of the screening methods in Taiwan with a population in which a pseudodeficiency variant is prevalent. We review and update the outcome of NBS-identified patients and discuss the limitations of the current therapy. We also address the challenges associated with caring for the babies with diagnosed acid alpha-glucosidase deficiency but yet without significant clinical manifestations. Further modifications of the current treatment and better predictive biomarkers should be explored.
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http://dx.doi.org/10.21037/atm.2019.05.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642927PMC
July 2019

REM sleep and sleep apnea are associated with language function in Down syndrome children: An analysis of a community sample.

J Formos Med Assoc 2020 Jan 1;119(1 Pt 3):516-523. Epub 2019 Aug 1.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Center of Sleep Disorder, National Taiwan University Hospital, Taipei, Taiwan; Center for Electronics Technology Integration, National Taiwan University, Taipei, Taiwan. Electronic address:

Background: The prevalence rate of obstructive sleep apnea (OSA) in the community Down syndrome (DS) children is not clear. Moreover, the impact of OSA and sleep structure on the cognitive function is inconclusive. The present study aimed to investigate 1) the prevalence rate of OSA in the community DS children and 2) the impact of OSA and sleep structure on cognitive performance.

Methods: Thirty DS children aged 6-18 years were recruited and evaluated with the performance of the language domain and sensorimotor domain, combining neuropsychological tests and parent-rated behavior. The outcomes were the age-adjusted scores, of which the lower the score was, the better was the patient's ability. The association of score with OSA and sleep structures was determined by linear regression. To diminish the age-related difference, all analyses were conducted separately for all subjects and 6-12-year-old subjects.

Results: The median age was 11.3 years and median Full-Scale Intelligence Quotient (FSIQ) was 44. The prevalence of OSA (apnea-hypopnea index ≥ 1/h) was 80% and 62.5% in all subjects and 6-12-year-old subjects, respectively. For 6-12-year-old subjects, after adjustment for age and FSIQ, both %REM and OSA were associated with lower score of the subtest of language domain, WPPSI-R Vocabulary, while %REM was also associated with lower score of VABS-II Communication - Expressive. In contrary, % slow wave sleep was not associated with any subtest.

Conclusion: This study identified that OSA may be highly prevalent in community DS children. Among 6-12-year-old DS children, OSA and % REM were associated with their language function.
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http://dx.doi.org/10.1016/j.jfma.2019.07.015DOI Listing
January 2020

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

Hum Mutat 2019 11 7;40(11):2146-2164. Epub 2019 Aug 7.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.

Identification of variants in the acid α-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long-term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ≤ 12 months of age with cardiomyopathy; Group B: Symptom onset ≤ 12 years of age (includes patients with symptom onset ≤ 12 months of age without cardiomyopathy); or Group C: Symptom onset > 12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.
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http://dx.doi.org/10.1002/humu.23878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852536PMC
November 2019

Critical Trio Exome Benefits In-Time Decision-Making for Pediatric Patients With Severe Illnesses.

Pediatr Crit Care Med 2019 11;20(11):1021-1026

Department of Paediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Objectives: Critical illnesses caused by undiagnosed genetic conditions are challenging in PICUs. Whole-exome sequencing is a powerful diagnostic tool but usually costly and often fail to arrive at a final diagnosis in a short period. We assessed the feasibility of our whole-exome sequencing as a tool to improve the efficacy of rare diseases diagnosis for pediatric patients with severe illness.

Design: Observational analysis.

Method: We employed a fast but standard whole-exome sequencing platform together with text mining-assisted variant prioritization in PICU setting over a 1-year period.

Setting: A tertiary referral Children's Hospital in Taiwan.

Patients: Critically ill PICU patients suspected of having a genetic disease and newborns who were suspected of having a serious genetic disease after newborn screening were enrolled.

Interventions: None.

Measurements And Main Results: Around 50,000 to 100,000 variants were obtained for each of the 40 patients in 5 days after blood sampling. Eleven patients were immediately found be affected by previously reported mutations after searching mutation databases. Another seven patients had a diagnosis among the top five in a list ranked by text mining. As a whole, 21 patients (52.5%) obtained a diagnosis in 6.2 ± 1.1 working days (range, 4.3-9 d). Most of the diagnoses were first recognized in Taiwan. Specific medications were recommended for 10 patients (10/21, 47.6%), transplantation was advised for five, and hospice care was suggested for two patients. Overall, clinical management was altered in time for 81.0% of patients who had a molecular diagnosis.

Conclusions: The current whole-exome sequencing algorithm, balanced in cost and speed, uncovers genetic conditions in infants and children in PICU, which helps their managements in time and promotes better utilization of PICU resources.
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http://dx.doi.org/10.1097/PCC.0000000000002068DOI Listing
November 2019

Thyroid disorders in Taiwanese children with Down syndrome: The experience of a single medical center.

J Formos Med Assoc 2020 Jan 27;119(1 Pt 2):345-349. Epub 2019 Jun 27.

Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taiwan. Electronic address:

Background/purpose: Thyroid disorders are common in children with Down syndrome (DS), however, such data have rarely been reported in Taiwanese children. This study presents our experience with the management of these children.

Methods: Between 2006 and 2016, 51 children (31 boys and 20 girls) with DS were enrolled. Thyroid function was evaluated and natural course of thyroid status were analyzed.

Results: Of 51 patients with DS, 2 had congenital hypothyroidism due to dyshormonogenesis. Of the remaining 49 patients, 30 (61%) had euthyroidism (EuT), and 19 (39%) had subclinical hypothyroidism (SH). Eighteen (37%) had detectable thyroid antibodies. It occurred at any age and the incidence was not affected by sex. The mean follow-up duration for 39 DS children was 3.8 ± 2.4 years. Of the 26 children who had EuT at enrollment and were followed up, 22 remained EuT, 2 developed SH, 1 developed overt hypothyroidism, and 1 developed overt hyperthyroidism. Of the 13 patients with SH who were followed up, 1 was treated for high thyroid-stimulating hormone levels, 8 became EuT, and 4 maintained SH status. Children with DS and persistent SH had significantly higher maximum thyroid-stimulating hormone levels during follow-up than did those with transient SH. Fluctuation in thyroid status during follow-up was not uncommon in children with DS.

Conclusion: The prevalence of thyroid disorders is higher in Taiwanese children with DS than in the general population. Because symptoms of hypothyroidism overlap those inherent to DS, regular follow-up of thyroid function in children with DS is indicated.
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http://dx.doi.org/10.1016/j.jfma.2019.06.003DOI Listing
January 2020

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Mol Genet Metab 2019 05 26;127(1):1-11. Epub 2019 Apr 26.

Genetic Metabolic Disorders Service, University of Sydney, Children's Hospital Westmead Clinical School, Sydney, NSW, Australia. Electronic address:

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.
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http://dx.doi.org/10.1016/j.ymgme.2019.04.004DOI Listing
May 2019

Rare Concurrence of Two Congenital Disorders: Miller-Dieker Syndrome and T-Cell Lymphopenia.

Cytogenet Genome Res 2019 27;157(4):227-230. Epub 2019 Apr 27.

Miller-Dieker syndrome (MDS; OMIM 247200) is a rare contiguous gene deletion syndrome associated with lissencephaly and characteristic facial dysmorphism. T-cell lymphopenia is an immunodeficiency disorder which can be early detected by newborn blood screening, and all live vaccines should be avoided. We report a 2.32-Mb microdeletion at chromosome 17p13.3p13.2 and T-cell lymphopenia in a 6-month-old male infant with MDS. This is, to our knowledge, the first description of these 2 conditions co-occurring in the same patient.
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http://dx.doi.org/10.1159/000499956DOI Listing
July 2019