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Hearing loss and the related otologic manifestations are receiving increased scrutiny as significant causes of morbidity in Fabry disease. However, the relative risks of auditory deficits among patients with Fabry disease relative to the general population without a diagnosis of Fabry disease have not been studied. This study aims to explore the associations between Fabry disease and hearing-related manifestations using a nationwide population-based dataset. We identified study patients for this cross-sectional study from the 2015–2017 claims databases of the Taiwan Longitudinal Health Insurance Database 2005. We first identified 2312 patients aged over 20 years with a diagnosis of Fabry disease. We used propensity score matching to select five comparison patients per patient with Fabry disease and 11,560 comparison patients without Fabry disease. We used multivariable logistic regressions to estimate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for tinnitus, hearing loss, and sudden deafness among Fabry disease patients vs. comparison patients. Chi-square tests showed statistically significant differences between patients with and without Fabry disease in the prevalence rates of tinnitus (16.7% vs. 11.7%, p < 0.001), hearing loss (7.5% vs. 6.2%, p = 0.014) and sudden deafness (1.7% vs. 1.0%, p = 0.005). Multiple logistic regression revealed that patients with Fabry disease were more likely to suffer from tinnitus, hearing loss and sudden deafness, with adjusted odds ratios of 1.513 (95% CI = 1.336–1.713), 1.246 (95% CI = 1.047–1.483), and 1.681 (95% CI = 1.166–2.423), respectively. We found that Fabry disease is significantly associated with certain auditory manifestations, including hearing loss, sudden deafness, and tinnitus. [ABSTRACT FROM AUTHOR]

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: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD.Results: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies.Conclusion: FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease. [ABSTRACT FROM AUTHOR]

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

Aims Fabry cardiomyopathy (FC) is characterized by progressive left ventricular hypertrophy (LVH). Conventional echocardiography is not sensitive in detecting preclinical FC before the development of LVH. We aim to investigate whether myocardial deformation analysis is useful to detect preclinical FC before LVH. Methods and results One hundred and sixty patients carrying mutated gene were prospectively enrolled, including 86 patients without LVH and 74 patients with LVH. Another 33 healthy individuals were also included for comparison. Standard transthoracic two-dimensional, Doppler, tissue Doppler echocardiography and deformation analysis were performed. The mean age of the overall 193 subjects was 48 ± 15 years, with 51% men. Fabry patients with LVH were older, more often to be men. They also had the worst diastolic function as evidenced by the largest left atrium, lowest E/A, and highest E/e′ ratio. The global longitudinal strain (GLS) deteriorated with the development of LVH (control vs. LVH− patients vs. LVH+ patients = −21.2 ± 2.7 vs. −19.0 ± 2.9 vs. −16.5 ± 4.2%, P  < 0.001). Despite similar LV systolic, diastolic function, and LV mass, LVH− Fabry patients still had a reduced GLS as well as regional longitudinal strains at mid-to-apical, anterior, and inferolateral wall when compared to healthy subjects. The basal longitudinal strain was consistently worse in male patients than in female patients, irrespective of LVH. Conclusion Reduced GLS could be a marker of early FC before the development of LVH. [ABSTRACT FROM AUTHOR]

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

Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease‐specific therapies when available. Fabry disease, an X‐linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end‐stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non‐specificity of early symptoms. Newborn screening and screening of at‐risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. Methods: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. Results: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. Conclusion: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases. [ABSTRACT FROM AUTHOR]

Background: Cardiac abnormalities have been observed in patients with mucopolysaccharidosis type II (MPS II). The aim of this study was to investigate the cardiac features and natural progression of Taiwanese patients with MPS II, and evaluate the impact of enzyme replacement therapy (ERT) on cardiac structure and function.Methods: The medical records and echocardiograms of 48 Taiwanese patients with MPS II (median age, 6.9 years; age range, 0.1-27.9 years) were reviewed. The relationships between age and each echocardiographic parameter were analyzed.Results: The mean z-scores of left ventricular mass index (LVMI), interventricular septum diameter in diastole (IVSd), left ventricular posterior wall diameter in diastole (LVPWd), and aortic diameter were 1.10, 2.70, 0.95 and 1.91, respectively. Z scores > 2 were identified in 33%, 54%, 13%, and 46% for LVMI, IVSd, LVPWd, and aortic diameter, respectively. The most prevalent cardiac valve abnormality was mitral regurgitation (MR) (56%), followed by aortic regurgitation (AR) (33%). The severity of mitral stenosis (MS), MR, aortic stenosis (AS), AR, and the existence of valvular heart disease were all positively correlated with increasing age (p < 0.01). We also compared the echocardiographic parameters between two groups: (1) 12 patients who had up to 17 years of follow-up echocardiographic data without ERT, and (2) nine patients who had up to 12 years of follow-up data with ERT. The results showed that z-score changes of LVMI significantly improved in the patients who received ERT compared to those who did not receive ERT (0.05 versus 1.52, p < 0.05). However, the severity score changes of MS, MR, AS, and AR all showed gradual progression in both groups (p > 0.05).Conclusions: High prevalence rates of valvular heart disease and cardiac hypertrophy were observed in the MPS II patients in this study. The existence and severity of cardiac hypertrophy and valvular heart disease in these patients worsened with increasing age, reinforcing the concept of the progressive nature of this disease. ERT for MPS II appeared to be effective in stabilizing or reducing the progression of cardiac hypertrophy, but it only had a limited effect on valvulopathy. [ABSTRACT FROM AUTHOR]

The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population. Given these observed risk factors, it is best to reinforce all recommended safety precautions for individuals with advanced FD. Diagnosis of FD should not preclude providing full therapeutic and organ support as needed for patients with FD and severe or critical COVID-19, although a FD-specific safety profile review should always be conducted prior to initiating COVID-19-specific therapies. Continued specific FD therapy with enzyme replacement therapy, chaperone therapy, dialysis, renin–angiotensin blockers or participation to clinical trials during the pandemic is recommended as FD progression will only increase susceptibility to infection. In order to compile outcome data and inform best practices, an international registry for patients affected by Fabry and infected by COVID-19 should be established. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Early enzyme replacement therapy (ERT) improve long‐term outcomes in patients with infantile‐onset Pompe disease (IOPD). Our cohort of patients with IOPD at Taipei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening program from 2008, testing more than one million newborns until 2018. By 2010, we had established rapid diagnostic strategies. Now, the average age of ERT initiation starts at an average age of <10 days‐old, the earliest group in the world. However, they still presented some airway problems. We present a retrospective study focused on airway abnormalities in these patients along 8 years of observation. Fifteen patients with IOPD, who received very early treatment at a mean age of 8.94 ± 3.75 days, underwent flexible bronchoscopy (FB) for dynamic assessment of the whole airway. Long‐term clinical outcomes and relevant symptoms of the upper airway were assessed. All patients in the study had varying degrees of severity of upper airway abnormalities and speech disorders. The three oldest children (Age 94, 93, and 88 months, respectively) had poor movement of the vocal cords with reduced abduction and adduction and had silent aspiration of saliva through the glottis during respiration. This is the largest cohort study presented to date about airway abnormalities in very early treated patients with IOPD patients by FB. Despite very early treatment, we observed upper airway abnormalities in these IOPD patients. In IOPD, upper airway abnormalities seem inevitable over time. We suggest early and continuous monitoring for all IOPD patients, even with early and regular treatment. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to use the liquid chromatography/tandem mass spectrometry (LC‐MS/MS) method to quantitate levels of three urinary glycosaminoglycans (GAGs; dermatan sulfate [DS], heparan sulfate [HS], and keratan sulfate [KS]) to help make a correct diagnosis of mucopolysaccharidosis (MPS). Methods: We analyzed the relationships between phenotypes and levels of urinary GAGs of 79 patients with different types of MPS. Results: The patients with mental retardation (n = 21) had significantly higher levels of HS than those without mental retardation (n = 58; 328.8 vs. 3.2 μg/ml, p < 0.001). The DS levels in the patients with hernia, hepatosplenomegaly, claw hands, coarse face, valvular heart disease, and joint stiffness were higher than those without. Twenty patients received enzyme replacement therapy (ERT) for 1–12.3 years. After ERT, the KS level decreased by 90% in the patients with MPS IVA compared to a 31% decrease in the change of dimethylmethylene blue (DMB) ratio. The DS level decreased by 79% after ERT in the patients with MPS VI compared to a 66% decrease in the change of DMB ratio. Conclusions: The measurement of GAG fractionation biomarkers using the LC‐MS/MS method is a more sensitive and reliable tool than the DMB ratio for MPS high‐risk screening, diagnosis, subclass identification, and monitoring the efficacy of ERT. The measurement of GAG fractionation biomarkers using the LC‐MS/MS method is a more sensitive and reliable tool than the DMB ratio for MPS high‐risk screening, diagnosis, subclass identification, and monitoring the efficacy of ERT. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) has a variable age of onset and variable rate of progression. However, information regarding the natural history of this disorder in Asian populations is limited. A retrospective analysis was carried out for 28 patients with MPS III (types IIIA [n = 3], IIIB [n = 23], and IIIC [n = 2]; 15 males and 13 females; median age, 8.2 years; age range, 2.7–26.5 years) seen in six medical centers in Taiwan from January 1996 through October 2017. The median age at confirmed diagnosis was 4.6 years. The most common initial symptom was speech delay (75%), followed by hirsutism (64%) and hyperactivity (54%). Both z scores for height and weight were negatively correlated with age (r = –.693 and −0.718, respectively; p < .01). The most prevalent clinical manifestations were speech delay (100%) and intellectual disability (100%), followed by hirsutism (93%), hyperactivity (79%), coarse facial features (68%), sleep disorders (61%), and hepatosplenomegaly (61%). Ten patients (36%) had epilepsy, and the median age at the first seizure was 11 years. Thirteen patients (46%) experienced at least one surgical procedure. At the time of the present study, 7 of the 28 patients had passed away at the median age of 13.0 years. Molecular studies showed an allelic heterogeneity without clear genotype and phenotype correlations. MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population. An understanding of the natural history of MPS III may allow early diagnosis and timely management of the disease facilitating better treatment outcomes. [ABSTRACT FROM AUTHOR]

Prader–Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty‐five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 ± 18.5 for deletion and 104.8 ± 18.3 for nondeletion type (p = .405), 104.8 ± 19.3 in boys and 102.6 ± 17.3 in girls (p = .293). The mean self‐care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem‐solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self‐care tasks. [ABSTRACT FROM AUTHOR]

While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in cancer cells, could reverse aberrant histone modification patterns and disrupt the association of splicing complex with GLA. It could also reverse aberrant GLA splicing in a PP1-dependant manner. Our findings revealed the alternative splicing mechanism of GLA (IVS4+919G>A), and a potential treatment for this specific genetic type of Fabry disease by amiloride in the future. [ABSTRACT FROM AUTHOR]

Background: Patients with the later-onset IVS4+919G>A (IVS4) Fabry mutation are known to have positive central nervous system involvement compared with age- and sex-matched controls. This study compares central nervous system manifestations in patients with the IVS4 mutation or classical Fabry mutations.Methods: This was a retrospective analysis of magnetic resonance imaging (MRI) data from Taiwanese patients enrolled in the Fabry Outcome Survey (sponsored by Shire; data extracted March 2015).Results: Twenty-five IVS4 (19 males) and 12 (four males) classical Fabry patients underwent MRI at a median (range) age of 60.7 (45.0-70.4) and 43.0 (18.0-61.4) years, respectively. All patients received agalsidase alfa enzyme replacement therapy; two (16.7%) classical Fabry patients underwent MRI before treatment start. The pulvinar sign occurred in eight (32.0%; seven males) IVS4 and six (50.0%; three males) classical Fabry patients. Infarction occurred in eight (32.0%) IVS4 and four (33.3%) classical Fabry patients. Fazekas scores of 0, 1, 2, and 3 were found for 15 (60.0%), seven (28.0%), two (8.0%), and one (4.0%) of the IVS4 patients and for six (50.0%), four (33.3%), two (16.7%), and 0 classical Fabry patients, respectively. Abnormal height bifurcation of the basilar artery was observed in 40.0% of IVS4 and 58.3% of classical Fabry patients; abnormal laterality was observed in 4.0% of IVS4 and 16.7% of classical Fabry patients. Median (range) basilar artery diameter was 2.7 (1.4-4.0) mm in IVS4 and 3.2 (2.3-4.7) mm in classical Fabry patients (P = 0.0293); vascular stenosis was noted in 8.3% of IVS4 patients but in no classical Fabry patients.Conclusions: A similar range of MRI findings was found for both IVS4 and classical Fabry patients. Notably, basilar artery diameter was larger in classical Fabry patients than IVS4 patients. [ABSTRACT FROM AUTHOR]

Most patients with infantile-onset Pompe disease die in early infancy before beginning enzyme replacement therapy, which has made it difficult to evaluate the impact of Pompe disease on cognitive development. Patients with infantile-onset Pompe disease can survive with enzyme replacement therapy, and physicians can evaluate cognitive development in these patients. We established an effective newborn screening program with quick clinical diagnostic criteria. Cognitive and motor development were evaluated using the Bayley Scales of Infant and Toddler Development–Third Edition at 6, 12, and 24 months of age. The patients who were treated very early demonstrate normal cognitive development with no significant change in cognition during this period (P = .18 > .05). The cognitive development was positively correlated with motor development (r = 0.533, P = .011). The results indicated that very early enzyme replacement therapy could protect cognitive development in patients with infantile-onset Pompe disease up to 24 months of age. [ABSTRACT FROM AUTHOR]

Aim: Information regarding the functional strengths and weaknesses of children with Down syndrome is important for early intervention programmes and for agencies providing family support and educational services.Method: This study used the Functional Independence Measure for Children (WeeFIM) questionnaire for the parents or caregivers of 166 Taiwanese children (101 males and 65 females; median age 12y 7mo; range 3y 2mo-19y 1mo) with Down syndrome to assess their functional skills.Results: Out of a potential score of 126, the mean total WeeFIM score was 101.2. There was no statistically significant difference between the scores from the male and female participants (100.4 [SD 21.4] vs 102.4 [SD 24.7]; p>0.05). The mean scores for three domains (self-care, mobility, and cognition) were 45, 33, and 23 respectively (maximum of 56, 35, and 35 respectively). Performance was strongest in the mobility domain and weakest in the cognition domain. The total WeeFIM scores and 18 subscores for the three domains all positively correlated with age (p<0.05).Interpretation: For children with Down syndrome, some support and supervision is required for cognition and self-care tasks. The WeeFIM questionnaire may be useful for identifying the strengths and limitations of children with developmental disabilities and their families. [ABSTRACT FROM AUTHOR]

Background: Osteogenesis imperfecta (OI) is a congenital disorder characterized by increased bone fragility and low bone mass.Methods: The presence of COL1A1 or COL1A2 mutation was investigated by direct sequencing in 72 patients with OI type I, III, or IV (27 males and 45 females; age range 0.2-62 years) from 37 unrelated families. The clinical features of these patients were also recorded.Results: Thirty-seven COL1A1 and COL1A2 mutations were identified, including 28 COL1A1 mutations and 9 COL1A2 mutations. Fifteen (41%) were novel mutations, and twelve (32%) were familial mutations. A review of their medical records revealed that the 72 patients could be classified into OI type I (n = 42), III (n = 5), and IV (n = 25). Twenty-nine patients had helical mutations (caused by the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix), and 42 had haploinsufficiency mutations (caused by frameshift, nonsense, and splice-site mutations). Compared with haploinsufficiency, the patients with helical mutations had more severely impaired skeletal phenotypes, including shorter height, lower bone mineral density, poorer walking ability, more frequent manifestations of dentinogenesis imperfecta and scoliosis (p < 0.05).Conclusions: Genotype and phenotype databases are expected to promote better genetic counseling and medical care of patients with OI. [ABSTRACT FROM AUTHOR]

Propionyl-CoA carboxylase (PCC) is involved in the catabolism of branched chain amino acids, odd-numbered fatty acids, cholesterol, and other metabolites. PCC consists of two subunits, α and β, encoded by the PCCA and PCCB genes, respectively. Mutations in the PCCA or PCCB subunit gene may lead to propionic acidemia. In this study, we performed mutation analysis on ten propionic acidemia patients from eight unrelated and nonconsanguineous families in Taiwan. Two PCCA mutations, c.229C→T (p.R77W) and c.1262A→C (p.Q421P), were identified in a PCCA-deficient patient. Six mutations in the PCCB gene, including c.-4156_183+3713del, c.580T→C (p.S194P), c.838dup (p.L280Pfs*11), c.1301C→T (p.A434V), c.1316A→G (P.Y439C), and c.1534C→T (p.R512C), were identified in seven PCCB-deficient families. The c.-4156_183+3713del mutation is the first known large deletion that affects the PCCB gene functions. Furthermore, the c.1301C→T and c.-4156_183+3713del mutations in the PCCB gene have not been reported previously. Clinical features demonstrated that these two frequent mutations are associated with low enzyme activity and a classic propionic acidemia phenotype. [ABSTRACT FROM AUTHOR]

© 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). In this study of the PAH mutation spectrum in the Taiwanese population, 139 alleles were identified including 34 different mutations. The V190G, Q267R and F392I mutations are first reported in this study. The most common mutations, R241C, R408Q and Ex6-96A>G, account for 23.2%, 12.0% and 9.2%, of the mutant alleles, respectively. Haplotype analysis shows that R241C and Ex6-96A>G are exclusively associated with haplotype 4.3 to suggest founder effects. On the other hand, R408Q is found on two distinct haplotypes suggesting recurrent mutations. The spectrum of PAH mutations in Taiwan shows various links to those of other Asian regions, yet remarkable differences exist. Notably, R408Q, E286K and −4173_−407del, accounting for 21% of all mutant alleles in Taiwan, are very rare or are undetected among PKU cohorts of other Asian regions to suggest local founder effects. Moreover, the low homozygosity value of 0.092 hints at a high degree of ethnic heterogeneity within the Taiwanese population. Our study of PAH mutation spectrum and the associated haplotypes is useful for subsequent study on the origin and migration pattern via Taiwan, an island at the historical crossroad of migration of ancient populations. [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]

Liu C, Niu D-M, Hsia C-Y, Loong C-C, Lin N-C, Tsai H-L, Tsou M-Y, Chin T. Living donor liver transplantation using a graft from a donor with Dubin-Johnson syndrome. Pediatr Transplantation 2012: 16: E25-E29. © 2010 John Wiley & Sons A/S. Abstract: DJS is an autosomal recessive disorder that causes an increase in conjugated bilirubin without elevation of liver enzymes. Most patients are asymptomatic and have normal life spans, but to the best of our knowledge, their livers have never been reported to be grafts in liver transplantation. Herein, we report an infant patient with MMA that received a partial liver graft from his mother, who had DJS. A biliary anastomosis stricture was noted five months after transplantation and was successfully treated with radiological interventions. Otherwise, the patient's liver functions were normal, and a liver biopsy showed a pathognomonic picture of DJS nine months after the transplantation. The patient was followed for one yr, and the results were satisfactory for an increase in oral intake and protein uptake, no recurrence of metabolic stroke and there was a gradual catch-up with regard to physical development despite having a persistently abnormal profile of amino acid analysis. From the experience of our case, we suggest that a liver from a donor with DJS can be used as a graft for liver transplantation, although long-term follow-up is mandatory to examine the grafted liver under the use of immunosuppressive medications. [ABSTRACT FROM AUTHOR]

The enzyme 6-pyruvoyl-tetrahydropterin synthase (PTPS, gene symbol: PTS) is involved in the second step of the de novo biosynthesis of tetrahydrobiopterin (BH4), which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases; the latter are important enzymes in the production of neurotransmitters. We conducted a study of PTS mutations in East Asia, including Taiwan, Mainland China, Japan, South Korea, the Philippines, Thailand and Malaysia. A total of 43 mutations were identified, comprising 22 previously reported mutations and 21 new discovered mutations. Among these, the c.155A>G, c.259C>T, c. 272A>G, c.286G>A and c.84-291A>G mutations were the most common PTS mutations in East Asia, while the c.58T>C and c.243G>A mutations were, respectively, specific to Filipinos and Japanese originating from Okinawa. Further studies demonstrated that each of the mutations listed above was in linkage disequilibrium to a specific allele of polymorphic microsatellite marker, D11S1347. These results suggest the presence of founder effects that have affected these frequent mutations in East Asia populations. In this context, D11S1347 should become one of the most reliable polymorphic markers for use in prenatal diagnosis among PTPS deficient families, especially where mutations are yet to be identified. [ABSTRACT FROM AUTHOR]

Aim. To extend nursing knowledge of distress experienced by family caregivers of children with rare genetic disorders, by exploring the perspectives of caregivers of children with Russell-Silver Syndrome in Taiwan. Background. Caring for a child with a rare genetic disorder often has profound effects on families, especially when diagnosis and treatment is complex or not yet well developed, such as that in Russell-Silver Syndrome (or Silver-Russell syndrome). This disorder causes dwarfism and developmental difficulties, requiring long-term care planning. Previous research has focused mostly on medical care, but little is known about families' perspectives of caring difficulties, the help they need and nursing care required. Design. An exploratory qualitative approach was used to inform this study. Methods. Family caregivers, whose children were undergoing medical care in a leading Taiwan medical centre, were invited to participate in face-to-face, in-depth interviews. Data were analysed by content analysis. Results. Fifteen caregivers including 11 mothers, two fathers and two grandmothers participated. Five major themes and 13 sub-themes of care-giving distress were identified: endless psychological worries; the lengthy process to confirm a medical diagnosis; adjustment efforts in modifying family roles; dilemmas in deciding between Western or Chinese traditional medicine; and negative responses to society's concerns. Their primary sources of support were spouses, parents and health professionals, accordingly. Conclusion. Complex physio-psycho-social and decision-making distress in caring for children with a rare genetic disorder were systematically revealed from the perspectives of ethnic-Chinese family caregivers. Relevance to clinical practice. Long-term care plans for children with a rare genetic disorder such as Russell-Silver Syndrome need to focus on positive dynamic family interactions, life-stage development and family caregiver support. Research on care-giving in rare genetic disorders is also warranted across cultures and countries to develop a substantial knowledge basis for nursing practice. [ABSTRACT FROM AUTHOR]

Background: The AJCC 7th edition changes the classification of T- and N-factors and the TNM stage of gastric cancer. We evaluated its prognostic impact. Methods: From December 1987 to December 2006, a total of 1,380 patients underwent curative surgery for gastric cancer at the Department of Surgery, Taipei Veterans General Hospital, with a retrieved lymph node number ≥15. Survival was compared for disease classified according to the AJCC 6th and 7th editions. Results: There is a significant difference in 5-year survival between T2 and T3 gastric cancer classified according to the AJCC 7th edition (75.2 vs. 54.9%, p < 0.001), as well as between N1 and N2 (71.4 vs. 44.1%, p < 0.001). Although patients with N3a had a better 5-year survival than did those with N3b (27.6 vs. 11.3%, p < 0.001), the N3 categories were combined and not applied in the TNM stage in the 7th edition. Multivariate analysis using Cox's proportional hazards model with a forward logistics regression stepwise procedure demonstrates that age, N category of 6th edition, and T and N categories of 7th edition are independent prognostic factors; however, T category of 6th edition is no longer significant. Furthermore, the discriminative power of survival difference between each TNM stage seems to be comparable between the 6th and 7th editions. Conclusions: The AJCC 7th edition provides a more stratified survival difference in staging of gastric cancer. Future division of N3a and N3b in the classification of the TNM stage is recommended. [ABSTRACT FROM AUTHOR]

Background: Despite curative surgery for gastric cancer, many patients die of recurrent cancer. Few studies have investigated the time to recurrence after curative resection for gastric cancer. Methods: Data were collected prospectively between December 1987 and December 2006. A total of 1,549 patients underwent curative resection of adenocarcinoma of the stomach at Taipei Veterans General Hospital. Among them, 419 patients had recurrence; they were divided into early recurrence (<2 years) and late recurrence (≥2 years). The clinicopathological characteristics, survival time after recurrence, and recurrence patterns were compared between the two groups. Results: Multivariate analysis showed that stage III gastric cancer patients with early recurrence had larger tumors and more lymph node metastasis than patients with late recurrence, while no difference between early and late recurrence was observed in stage I and II patients. Early recurrence was associated with more distant metastasis than was late recurrence. Patients with advanced TNM stage tended to die within 2 years after recurrence. Conclusions: Gastric cancer patients with larger tumors and more lymph node metastasis tended to have early recurrence, especially stage III patients. Advanced TNM stage was associated with early cancer death after recurrence. [ABSTRACT FROM AUTHOR]

Idiopathic calcinosis cutis (CC) is a rare disease in a child. The chemical composition of the calcified deposits in idiopathic CC was first qualitatively and quantitatively examined using vibrational microspectroscopy via spectral diagnosis. The combined application of the Fourier transform infrared (FT-IR) and Raman microscopic techniques was used to detect and identify the nature of the components of the calcified deposits in idiopathic CC and to compare the results with histopathological findings. Two major components of type B carbonated apatite and β-carotene interspersing subcutaneous tissue were clearly evidenced to make up the calcified deposits in idiopathic CC in our pediatric patient. Moreover, the calcified deposits of idiopathic CC contained a relatively larger amount of type B carbonated apatite and a smaller amount of type A carbonated apatite than the calcified deposits analyzed in dystrophic CC. This is the first report on the chemical composition of calcified deposits in idiopathic CC established by spectral analysis. The combination of FT-IR and Raman microscopic techniques was very useful for simultaneous assessment of the intact components of the calcified deposits in idiopathic CC. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11-36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 ± 18.8 vs. 27.2 ± 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan. [ABSTRACT FROM AUTHOR]

Nance-Horan syndrome (NHS) is a rare X-linked disorder characterized by congenital cataracts, dental anomalies and mental retardation. The disease has been linked to a novel gene termed NHS located at Xp22.13. The majority of pathogenic mutations of the disease include nonsense mutations and small deletions and insertions that lead to truncation of the NHS protein. In this study, we identified a microdeletion of ∼0.92 Mb at Xp22.13 detected by array-based comparative genomic hybridization in two brothers presenting congenital cataract, dental anomalies, facial dysmorphisms and mental retardation. The deleted region encompasses the REPS2, NHS, SCML1 and RAI2 genes, and was transmitted from their carrier mother who presented only mild cataract. Our findings are in line with several recent case reports to indicate that genomic rearrangement involving the NHS gene is an important genetic etiology underlying NHS. [ABSTRACT FROM AUTHOR]

Abstract: Information regarding the clinical outcome of enzyme replacement therapy (ERT) with recombinant human N‐acetylgalactosamine 4‐sulfatase (rhASB) for mucopolysaccharidosis (MPS) VI in Asian patients is limited. We reviewed nine Taiwanese patients with MPS VI (four males and five females; age range 1.4–21.1 years) treated with weekly intravenous infusions of rhASB (1.0 mg/kg) for at least 2 years. We assessed the biochemical and clinical response every 3 months. After 2 years of treatment, seven patients experienced improvement over baseline in the 6‐min walk by a mean of 69.3 m (27.3%), and seven also increased the 3‐min stair climb by a mean of 47 steps (35.7%). Shoulder range of motion in all patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.597 points (30.5%). Four patients had improved pulmonary function [forced expiratory volume in 1 s increased by 0.130 L (26.3%) and forced vital capacity by 0.148 L (27.6%)]. The respiratory disturbance index decreased in the four patients who underwent polysomnography. A mean overall 51% decrease in urinary glycosaminoglycan excretion indicated a satisfactory biochemical response. ERT was well tolerated by all patients. This treatment is thus beneficial and appears to be safe for treatment of MPS VI in Taiwanese patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients. [ABSTRACT FROM AUTHOR]