Search

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]

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]

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]

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]

© 2014 Wiley Periodicals, Inc. [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]

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]

Objectives We report two siblings, a boy and a girl, with Cornelia de Lange syndrome (CdLS), born to unaffected parents, and attempt to delineate the underlying molecular mechanism leading to familial recurrence. Methods Nipped-B-like ( NIPBL) gene mutations were screened using in denaturing high-performance liquid chromatography and sequencing in peripheral blood samples, from one of the affected siblings and her parents, as well as from a sperm sample from the father. Results A heterozygous missense NIPBL mutation, D2433G, was identified in the peripheral blood sample of the affected girl, but not in the peripheral blood samples of her parents. The D2433G mutation was also found in the sperm sample of the father. Conclusion Gonadal mosaicism represents an underappreciated feature of the inheritance pattern of CdLS. To our knowledge, the girl represents the first CdLS patient whose father was documented to have a population of mutant sperm. When a sperm analysis indicates the presence of a mutant allele, it may be reasonable to offer prenatal genetic testing to the family in subsequent pregnancies, given that the sensitivity of fetal ultrasonography is relatively low. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Information on functional strengths and weaknesses of mucopolysaccharidosis (MPS) patients is important for early intervention programs and enzyme replacement therapy (ERT). Methods: We used the Functional Independence Measure for Children (WeeFIM) questionnaire to assess the functional skills of 63 Taiwanese MPS patients (median age, 13 years 3 months; range, 3–20 years) from January 2012 to December 2018. Results: Mean total WeeFIM score was 75.4 of a potential score of 126. Mean total WeeFIM scores of each type (MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI) were 103.8, 76.2, 41.6, 92.2, and 113.6, respectively. Mean scores for self‐care, mobility, and cognition domains were 30 (maximum 56), 23 (maximum 35), and 22 (maximum 35), respectively. MPS type IIIB patients had the lowest scores in self‐care, mobility, cognition, and total domains compared to other types of MPS. All patients with ERT in MPS I, II, and IVA had higher scores in self‐care and mobility domains than patients without ERT. Most patients required assistance for self‐care skills, especially in grooming and bathing. Conclusion: MPS patients require support and supervision in self‐care tasks. For cognition tasks, MPS IIIB patients also require help. This questionnaire is useful to identify the strengths and limitations of MPS patients. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans in various tissues and organs. Ocular problems that affect the cornea, trabecular meshwork, sclera, retina, and optic nerve are very common in these patients. However, there was limited literature focusing on comprehensive ocular findings in different types of MPS. Methods: We retrospectively reviewed the clinical ophthalmologic features and electrodiagnostic results of 50 Taiwanese patients with a diagnosis of MPS (34 males and 16 females; age range, 1.1–34.9 years; nine with MPS I, 17 with MPS II, 17 with MPS IV, and seven with MPS VI). Results: Among 44 patients with available data for visual acuity, 15 patients (34%) had a visual acuity of less than 0.5 (6/12) equivalent in their better eye, including 71% of those with MPS VI, 38% with MPS IV, 29% with MPS I, and 14% with MPS II. Severe corneal opacities existed in 57% of MPS VI patients and 11% of MPS I patients, compared with none for MPS II and MPS IV patients. Among 80 eyes with available data of refraction, 11 eyes (14%) had myopia (≦−0.50 D), 55 eyes (69%) had hyperopia (≧0.50 D), and 55 eyes (69%) had high astigmatism (≧1.50 D). Ocular hypertension was found in 45% (28/62) of eyes. There were 16% (14/90), 11% (10/90), 13% (12/90), 31% (27/86), and 79% (30/38) of MPS eyes with lens opacities, optic disc swelling, optic disc cupped, retinopathy, and visual pathway dysfunction, respectively. Intraocular pressure was positively correlated with the severity of corneal opacity (p < 0.01). Conclusions: Ocular complications with significant reduction in visual acuity are common in MPS patients. Diagnostic problems may arise in these patients with severe corneal opacification, especially for those with MPS VI and MPS I. [ABSTRACT FROM AUTHOR]

Background A previously underrecognized phenotype of left ventricular apical aneurysm (LVAA) has been increasingly identified in Fabry disease. This study explored LVAA's clinical prevalence and its prognostic implications over a long-term follow-up. Methods and Results We retrospectively analyzed 268 consecutive patients with Fabry disease at a tertiary medical center. Patients with increased left ventricular mass index were recognized as having left ventricular hypertrophy (LVH). LVAA was identified using either echocardiography or cardiovascular magnetic resonance imaging. Two patients with ischemic LVAA were excluded. The primary end point was a composite of cardiovascular events, including heart failure hospitalization, sustained ventricular tachycardia, ischemic stroke, and all-cause mortality. Of 266 enrolled patients, 105 (39.5%) had LVH (age 58.5±11.9 years, 48.6% men), and 11 (10.5%) had LVAA. Over 49.3±34.8 months of follow-up, 25 patients with LVH experienced composite events, including 9 heart failure hospitalizations, 4 sustained ventricular tachycardia, 6 ischemic strokes, and 15 mortalities. In patients with LVH, those with LVAA had a significantly higher risk of composite events and lower event-free survival than those without LVAA (8 [72.7%] versus 17 [18.1%], log-rank P <0.001). LVAA was independently associated with an increased risk of composite events (hazard ratio, 3.59 [95% CI, 1.30-9.91]; P =0.01) after adjusting for age, sex, advanced heart failure, renal function, dyslipidemia, atrial fibrillation, left ventricular ejection fraction, left ventricular diastolic function, and left ventricular mass index. Conclusions LVAA is present in approximately 10% of patients with Fabry disease and LVH. It is associated with an increased risk of adverse cardiovascular events and may necessitate aggressive treatment.

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous congenital disorder characterized by severe growth retardation. Hypomethylation of the differentially methylated region (DMR) of the H19 gene and uniparental disomy of maternal chromosome 7 is present in ∼45% of the patients with SRS so more than half of these patients have no known genetic etiology. We combined several molecular technologies including multiplex methylation polymerase chain reaction, methylation-sensitive multiple ligation probe-dependent amplification, and methylation-sensitive high-resolution melting to assess the epigenetic status of 34 patients with SRS. Additionally, we applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Thirteen patients (38.2%) had hypomethylation of the DMR of the H19 gene and none had uniparental disomy of maternal chromosome 7. The whole genome arrays identified five patients (14.7%) with microdeletions on chromosomes 1q23q24.3, 7p15.3, 13q31.3, 14q32.31, and 15q26.2qter, respectively. The overall mutation detection rate was 52.9% by the epigenetic study and the whole genome strategy. Although epimutation may be the major cause of SRS and can be identified by multiplex methylation polymerase chain reaction, the whole genome approach also provides information on the etiology of SRS. If no epimutation is identified in the patients with typical SRS, microdeletions should be suspected., (Copyright © 2010 Wiley-Liss, Inc.)

The aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.

Aim: Mode of delivery may influence the innate immune system in newborns. We investigated the effect of maternal labour on the expression of two Toll-like receptors, TLR2 and TLR4, in monocytes obtained from healthy full-term newborns., Methods: Monocytes were obtained from cord blood of 48 newborns that have been vaginally delivered (VD) and 14 newborns delivered by elective caesarean section (CS) without labour. Peripheral blood was also obtained from 17 healthy adults. Surface expression of TLR2 and TLR4 in the monocytes was measured by antihuman TLR2 or TLR4 monoclonal antibody and immunofluorescence flow cytometry. TLR2 and TLR4 mRNA levels were evaluated by real-time PCR., Results: CS newborns had a significantly lower level of TLR2 and TLR4 surface expression on monocytes than VD newborns. No significant difference was found between the surface expression of VD newborns and healthy adults. TLR2 and TLR4 mRNA levels in monocytes did not vary among the three study groups., Conclusion: Labour may up-regulate TLR2 and TLR4 on the cord blood monocytes of newborns at the protein level. Since TLRs are an important part of the innate immune system, our findings suggest that labour may be immunologically beneficial to normal newborns.

Previous studies on the incidence of the various types of mucopolysaccharidoses (MPS) in different populations have shown considerable variation. However, information regarding the incidence of MPS in the Asian population is lacking. An epidemiological study of the MPS disorders in Taiwan using multiple ascertainment sources was undertaken, and incidences of different types of MPS during the period of 1984-2004 were estimated. We compared our data with previous reports in different populations. The combined birth incidence for all MPS cases was 2.04 per 100,000 live births. MPS II (Hunter syndrome) had the highest calculated birth incidence of 1.07 per 100,000 live births (2.05 per 100,000 male live births), comprising 52% of all MPS cases diagnosed. The birth incidences of MPS I (Hurler syndrome), III (Sanfilippo syndrome), IV (Morquio syndrome), and VI (Maroteaux-Lamy syndrome) were 0.11, 0.39, 0.33, and 0.14 per 100,000 live births, respectively, which accounted for 6%, 19%, 16%, and 7% of all MPS, respectively. No cases of MPS III D (Sanfilippo syndrome type D), MPS IV B (Morquio syndrome type B), MPS VII (Sly syndrome) or MPS IX were ascertained during the study period. Overall incidence of MPS in Taiwan was consistent with that reported in Western populations. However, in contrast to the higher incidence of MPS I in most Western populations, this study showed a higher incidence of MPS II in Taiwan. It remains to be investigated whether this discrepancy is attributed to the under-diagnosis of MPS I in Taiwan or to ethnic differences.

Aim: Several different genetic defects have been found to result in the characteristic phenotypic expression of Prader-Willi syndrome (PWS)., Methods: We performed a retrospective analysis of 67 cases of molecularly confirmed PWS diagnosed from January 1980 through July 2006 in five medical centres in Taiwan. Clinical manifestations were compared between patients with deletion and those with maternal uniparental disomy (UPD)., Results: Deletion was present in 56 (84%), UPD in 10 (15%), and a probable imprinting centre deletion or imprinting defect in 1 (1%). PWS with deletion was more likely than that with UPD to be characterized by hypogonadism (p < 0.001), small hands and feet (p < 0.001), and hypopigmentation (p < 0.002). Both maternal (p = 0.015) and paternal age (p = 0.021) were higher in the UPD group. No other clinical features differed significantly different between the two groups., Conclusion: In contrast to most Western populations with a higher incidence of UPD, this study of PWS in Taiwan shows a higher incidence of deletion. There may be subtle phenotypic differences between the UPD and deletion genotypes, but its not clear that these are important clinically.