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Baseline demographic and phenotypic characteristics of patients aged ≥ 50 years in the Fabry Outcome Survey (Shire; data extracted June 2014) were compared with younger adults to investigate potential factors influencing treatment decisions in later life. Age groups were defined using age at treatment initiation or at FOS entry for untreated patients: 18–49 ( n = 1344; 49.5% male; 64.6% received agalsidase alfa enzyme replacement therapy [ERT]); 50–64 ( n = 537; 35.4% male; 74.3% treated); 65–74 ( n = 137; 32.1% male; 68.6% treated); and ≥ 75 years ( n = 26; 26.9% male; 50.0% treated). Successive age groups showed higher median age at first symptom and diagnosis. Median alpha-galactosidase A activity, measured as percentage activity of the midpoint of the normal range, was much greater in females than males of all groups except ≥ 75 years (33.4% in females; 27.8% in males). Patients aged ≥ 75 years showed greater values than patients aged 18–49 years for median left ventricular mass indexed to height (62.7 vs 42.4 g/m 2.7 ), mean ventricular wall thickness (15.0 vs 10.0 mm) and prevalence of hypertension (57.7% vs 21.8%), and lower median estimated glomerular filtration rate (Modification of Diet in Renal Disease: 65.6 vs 98.5 mL/min/1.73 m 2 ). Larger proportions in the groups aged ≥ 50 exhibited cardiac and/or cerebrovascular manifestations compared with patients aged 18–49 years. The smaller proportion of patients receiving ERT aged ≥ 75 years compared with the younger groups might reflect relatively milder disease burden or physician/patient reluctance to initiate/continue ERT at this age. Further studies are needed to increase knowledge of Fabry disease and ERT in later life. [ABSTRACT FROM AUTHOR]

Abstract: CYP21A2 mutations resulting from microconversions of the CYP21A1P sequence in congenital adrenal hyperplasia (CAH) commonly appear in all populations. However, it has not often been described as being due to the gene founder effect. Herein, we investigated two spontaneous mutations of IVS2+1G>A and R316X in ethnic Chinese (Taiwanese) CAH patients to determine whether they share the same haplotype of ancient origin by the analysis of sequence-specific oligonucleotide (SSO) for HLA class I B and sequence-based typing (SBT) for HLA class II DRB1 gene-typing methods. From over 200 CAH families, eight unrelated CAH patients were found and examined: five had the IVS2+1G>A mutation and three had the R316X mutation. Based on HLA typing data, five alleles in five patients with the IVS2+1G>A mutation were consistent with a shared haplotype of the B∗3909–DRB1∗160201 allele, and the three alleles in the three patients with the R316X mutation were all the B∗460101–DRB1∗080302 allele. The evidence indicates that the haplotype of single-base substitutions of either the IVS2+1G>A or R316X mutation came from the same allele rather than a mutational hot spot, suggesting that the gene founder effect has occurred in the Taiwanese population. This is the first report of the gene founder effect of the CYP21A2 mutation occurring in ethnic Chinese (Taiwanese) CAH patients with 21-hydroxylase deficiency. [Copyright &y& Elsevier]

Objectives The level of 8-hydroxy-2-deoxyguanosise (8-OHdG) is a marker of oxidative stress. The objective of this study was to evaluate the effect of enzyme replacement therapy (ERT) on the level of 8-OHdG in patients with Fabry cardiomyopathy and the clinical evolution of Fabry cardiomyopathy. Methods We measured the serum levels of 8-OHdG in 20 healthy control and 22 patients with Fabry cardiomyopathy before and after ERT. Results The mean lysoGb3 and 8-OHdG levels was significantly increased in patients with Fabry cardiomyopathy compared with that of control subjects (lysoGb3, 3.6 ± 1.1 nM vs. 0.4 ± 0.1 nM, p < 0.01 ; 8-OHdG, 4.5 ± 0.5 ng/mL vs. 3.4 ± 0.4 ng/mL, P < 0.05 ). The mean lysoGb3 and 8-OHdG levels was significantly reduced after ERT for 14.2 months (lysoGb3, 3.6 ± 1.1 nM vs. 2.9 ± 1.1 nM, P < 0.05 ; 8-OHdG, 4.5 ± 0.5 ng/mL to 4 ± 0.4 ng/mL, P < 0.05 ). These changes were accompanied by decreases in LVM and LVMI. Conclusions We demonstrated that the serum 8-OHdG levels is increased in patients with Fabry cardiomyopathy (FC) and that successful management of FC with ERT is associated with a decrease in this oxidative stress marker. Serum 8-OHdG levels can be used not only as a noninvasive biomarker of oxidative stress in patients with FC but also an objective and quantitative parameter in the follow-up of patients during ERT. [ABSTRACT FROM AUTHOR]

Background Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth disorder predisposing to tumorigenesis that results from abnormal expression or function of imprinted genes of chromosome 11p15.5. Methods Forty-seven patients in Taiwan with clinical suspicion of BWS were referred for diagnostic testing based on methylation profiling of H19 -associated imprinting center (IC) 1 and KCNQ1OT1 -associated IC2 using high-resolution melting analysis, multiplex ligation-dependent probe amplification, or high-resolution quantitative methylation profiling. Results Twenty-eight patients received a clinical diagnosis of BWS (the presence of 3 major features or 2 major features and at least 1 minor feature), 18 had suspected BWS (the presence of at least 1 major feature), and 1 had isolated Wilms' tumor. Nineteen patients were identified with IC2 hypomethylation (including 1 with isolated Wilms' tumor), 1 with IC1 hypermethylation, 2 with paternal uniparental disomy, and 1 with CDKN1C mutation. Several clinical features were found to be statistically different ( P < 0.05) between the 2 groups—clinical diagnosis of BWS (n = 28) or suspected BWS (n = 18)—including macroglossia, pre- or postnatal gigantism, abdominal wall defect, ear creases, facial nevus flammeus, BWS score, and the molecular diagnosis rate. Molecular lesion was detected in 81% of patients with the presence of three major features, compared with 33% and 28% of those with two or one major feature, respectively. The mean BWS score was 5.6 for 19 subjects with “IC2 hypomethylation”, compared with 3.8 for 2 subjects with pUPD. The BWS score of one subject with CDKN1C mutation and one with IC1 hypermethylation was 6 and 7, respectively. Conclusions The BWS score was positively correlated with the molecular diagnosis rate ( P < 0.01). The BWS database of epigenotype, genotype, and phenotype is expected to promote better genetic counseling and medical care of these patients. [ABSTRACT FROM AUTHOR]

Background While enzyme replacement therapy (ERT) has been shown to improve endurance and joint mobility for patients with mucopolysaccharidoses (MPS) I, II, IVA and VI, the impact of ERT on cardiac abnormalities remains uncertain. Methods Medical records and echocardiograms of 28 Taiwanese MPS patients (9 with MPS I, 7 with MPS II, 7 with MPS IVA, and 5 with MPS VI) treated with ERT for 1–10.8 years were retrospectively reviewed. Results At start of ERT, z scores > 2 were identified in 46% and 75% for left ventricular mass index (LVMI) and interventricular septum thickness in diastole (IVSd) in these patients, respectively. Twenty-four patients (86%) had valvular heart disease. After ERT, the mean IVSd z score of all patients decreased significantly from 3.87 to 2.57 ( p = 0.016). For 11 patients starting ERT before 12 years of age, z scores for both LVMI and IVSd decreased significantly ( p < 0.01) after ERT. However, the condition of valve regurgitation or stenosis did not show improvement despite ERT. Conclusions ERT was shown to be an effective therapy for reducing cardiac hypertrophy, with best results seen when ERT was started at an early age. ERT, however, had little impact on valvular heart disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with mucopolysaccharidoses (MPS) often have hearing loss. However, the characterization of hearing loss by pure-tone audiometry (PTA) in this rare disease population and its relationship to age and treatment is limited. Methods: PTA was performed in 39 patients with MPS (29 males and 10 females; 3 with MPS I, 21 with MPS II, 9 with MPS IVA, and 6 with MPS VI; median age, 11.9years; age range, 4.4–34.2years). The degree of hearing loss was classified by the age-independent World Health Organization (WHO) clinical guidelines. Results: Hearing loss by PTA was present in 85% (33/39) of patients and was categorized as mild (26–40dB) in 18%, moderate (41–60dB) in 36%, severe (61–80dB) in 23%, and profound (≥81dB) in 5%. Among the patients with hearing loss, 33% were classified as mixed type (conductive and sensorineural), 30% as pure conductive type, 27% as pure sensorineural type, and 9% were undefined. The means of the right and left ear hearing thresholds at 2000 and 4000Hz by air conduction (AC) and at 500, 1000, 2000, and 4000Hz by bone conduction (BC) were all positively correlated with age (p <0.05). In the 6 patients with MPS II or VI who underwent follow-up PTA after ventilation tube insertion and enzyme replacement therapy for 1.9 to 8.5years, all showed improvements in AC and BC of the better ear, as well as in the air-bone gap. Conclusions: Hearing impairment is common in MPS. Early otolaryngological evaluation and intervention are recommended. These findings and the follow-up data can be used to develop quality of care strategies for patients with MPS. [Copyright &y& Elsevier]

Abstract: Background: In view of the therapeutic benefits resulting from early intervention for Fabry disease, our team has implemented an enzyme-based newborn screening in Taiwan since 2008. However, we found that most heterozygous females cannot be detected. To improve the screening efficiency, a more effective method for GLA gene genotyping is necessary. Methods: As the suspected mutations are limited to only 29 different spots in Taiwanese, a panel of Sequenom iPLEX assay was designed for rapid screening of GLA variations. To determine the accuracy and sensitivity of this assay, previously diagnosed and undiagnosed DNA samples were analyzed by this genotyping assay and Sanger sequencing. In addition, DNA extracted from dried blood spots was also tested. Results: Sequenom iPLEX assay is accurate and cost-effective, identifying the sequence variations, which were designated in the panel. It identified common GLA variants in DNA samples extracted from whole blood or dried blood spots with 100% accuracy and sensitivity. Conclusions: Sequenom iPLEX assay is suitable for Fabry newborn screening when hotspot mutations and common variations are known in a well-studied population. In addition, this assay can also be applied for first-line determination of GLA variant sequences in suspected subjects of high-risk patients, or newborns. [Copyright &y& Elsevier]

Abstract: Recessive congenital methemoglobinemia (RCM) is a very rare disorder caused by NADH-cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, caused by cb5r deficiency have been recognized. In type I, the enzyme deficiency is restricted only to erythrocytes with cyanosis being the only major symptom. In contrast, in type II, the enzyme deficiency is generalized to all tissues and associated with neurological impairment, mental and growth retardation and reduced life expectancy, in addition to cyanosis. Recently, we conducted a study on an 11-year-old boy with cb5r deficiency type I. The mutational analysis of the CYB5R3 gene revealed that the boy is homozygous for L72P mutation. Surprisingly, his mother is heterozygous for this L72P mutant, but not his father. Thirteen microsatellite markers of chromosome 22 were selected to analyze the origins of the patient''s chromosome 22. The result showed that both of the chromosome 22(s) of this patient came from the maternal side (uniparental heterodisomy of chromosome 22 with segmental isodisomy). This is the first case report of a patient with cb5r deficiency type I resulting from uniparental disomy and also discloses an alternate mechanism whereby this enzymatic disorder can be derived from a single parent. [Copyright &y& Elsevier]

Abstract: The newborn screening of homocystinuria in Taiwan has never been formally reported before. Since 1984, out of 5million newborns screened, only 3 newborns (Han Taiwanese) suffering from homocystinuria were detected in this newborn screening program. Four mutations (p.R121L [c.362G>T], p.E176K [c.526G>A], p.V320G [c.959T>G] and p.G259D [c.776G>A]) were identified in these 3 patients. Unexpectedly, we recently found 8 patients presenting with homocystinuria in an Austronesian Taiwanese Tao tribe. Out of them, three patients participated in the newborn screening program but were unidentified by the current newborn homocystinuria (using methionine as a marker) screening. All the Tao patients are homozygous for a new p.D47E (c.141T>A) mutation. Among the 428 adult islanders screened for the D47E mutation, approximately 1 in 7.78 is a carrier of the mutation, and an estimated 1 in 240 islanders suffered from homocystinuria. This is the highest known prevalence of homocystinuria worldwide. The result of expression studies of all the mutations identified in Taiwan revealed that, except for p.D47E mutation, all mutations were severely limited in their ability to form functional tetramers. The clinical manifestations of the Tao patients varied widely, despite sharing the same mutation and very similar genetic and environmental backgrounds. Comparisons of clinical and biochemical phenotypes of these patients were presented in this report. [Copyright &y& Elsevier]

Abstract: Marfan syndrome has been associated with approximately 562 mutations in the fibrillin-1 (FBN1) gene. Mutation scanning of the FBN1 gene with DNA direct sequencing is time-consuming and expensive because of its large size. This study analyzed the diagnostic value of high-resolution melting analysis as an alternative method for scanning of the FBN1 gene. A total of 75 polymerase chain reaction (PCR) amplicons (179–301bp, average 256bp) that covered the complete coding regions and splicing sites were evaluated on the 96-well LightCycler system. Melting curves were analyzed as fluorescence derivative plots (−dF/dT vs. temperature). To determine the sensitivity of this method, a total of 82 samples from patients with Marfan syndrome and 50 unaffected individuals were analyzed. All mutations reported in this study had been confirmed previously by direct sequencing analysis. Melting analysis identified 48 heterozygous variants. The variant c.3093 G>T (exon 25) was incorrectly identified by melting curve analysis. The sensitivity of the technique in this sample was 98.78% (81/82). This study demonstrated that high-resolution melting analysis is a reliable gene scanning method with greater speed than DNA sequencing. Our results support the use of this technology as an alternative method for the diagnosis of Marfan syndrome as well as its suitability for high-throughput mutation scanning of other large genes. [Copyright &y& Elsevier]

Abstract: Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder which causes more than 90% of CAH cases due to defects in the steroid 21-hydroxylase gene (CYP21A2). The frequency of large mutations was determined in 200 ethnic Chinese (i.e., Taiwanese) CAH patients belonging to 200 families with different clinical forms of CYP21A2 deficiency over 10 years of molecular diagnoses. For a large-gene deletion (or conversion) and the CYP21A2 deletion identification, a PCR product covering the TNXB gene and the 5′-end of the CYP21A2 gene with TaqI endonuclease digestion was analyzed by electrophoresis on agarose gels. For CYP21A2 mutational analysis, secondary PCR amplification of the amplification-created restriction site method was applied. From the results of the analysis, we found that large-gene deletions (or conversions) occurred in 7.5% of the alleles including three different types of the chimeric CYP21A1P/CYP21A2 genes and the haplotype of IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation). The CYP21A2 deletion occurred in 2.0% of the alleles which contained three types of the chimeric TNXA/TNXB genes with two novel ones. We concluded that the CYP21A2 deletion in the ethnic Chinese (Taiwanese) patients exhibits a low occurrence, with the haplotype of the IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation) being prevalent among large gene deletions or conversions. [Copyright &y& Elsevier]

Abstract: Objectives: 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most important type of BH4 deficiency related to hyperphenylalaninemia. PTPS deficiency may not only cause a typical phenylketonuric phenotype, but is also accompanied by various neurological signs and symptoms due to impaired synthesis of catecholamines and serotonin. Reports of the long-term outcomes of these patients, especially after delayed onset of therapy, are few. Study design: We reviewed the characteristics of 10 PTPS-deficient patients whose treatment onset with tetrahydrobiopterin, l-DOPA, and hydroxytryptophan had been delayed. The relationships among clinical manifestations, biochemical findings, genotypes, and long-term outcomes were analyzed. Results: We classified eight patients as having severe forms, and two as having moderate forms of PTPS deficiency. Improvements in neurological status and intelligence/developmental quotient (IQ/DQ) were observed in all patients, up to approximately 15 years of follow-up. One patient began walking and talking after 4 years of treatment. In patients with severe disease, the mean initial IQ/DQ was 45.40±13.94, and the final full-scale intelligence quotient (FIQ) score was 62.8±13.06 (p =0.042), with a mean increment of 17.4±5.27 over 15.86±4.85 years of follow-up. Two patients with moderately severe disease had FIQ increases from 75 to 77 and from 76 to 80 points, respectively. Conclusions: The administration of neurotransmitters based on clinical response and adverse effects was beneficial in patients whose treatment of PTPS deficiency was delayed. Sustained clinical improvements were observed up to 15 years of follow-up. [Copyright &y& Elsevier]