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Uniparental disomy (UPD) represents an imbalance in the distribution of paternal and maternal chromosomes in the offspring. It is defined as a condition in which both homologues of a chromosome are inherited from only one parent. UPD for some chromosomes does not exert any adverse effect on an individual. However, for certain chromosomes, it can result in abnormality through aberrant genomic imprinting, when the chromosomes contain imprinted genes. In isodisomy, not only is there a risk for a disturbance due to imprinting, but there is also risk that the two pairs of homologs are identical creating homozygosity for a large region of a certain chromosome, with an associated increased risk for recessive disorders. In this report, we will demonstrate two rare autosomal recessive diseases, argininosuccinic aciduria and recessive congenital methemoglobinemia, were caused by uniparental isodisomy or uniparental heterodisomy with segmental isodisomy. The molecular studies of this mechanism and literatures reviewed will be presented in this report.

All of the current newborn screening studies of Fabry disease revealed that the incidences of later-onset Fabry disease in their studied populations were much higher than the previous expectancy. It reveals that later-onset Fabry disease could be an important hidden health issue in some populations or even a lot of populations. However, the natural course of later-onset Fabry disease is still largely unknown. A total of 792,247 newborns have been screened for Fabry disease by our team in Taiwan. Through this screening and pedigree study, more than 900 individuals were found to have a later-onset type mutation, IVS4+919G > A. The left ventricular hypertrophy (LVH) onset rate was analyzed through our patient database and gadolinium-enhanced cardiac magnetic resonance imaging (GE-CMRI) was performed in 73 IVS4 adults. LVH onset rate were 77% in male and 35% in female adults who were older than 40 years old. GE-CMRI revealed that 43% of males and 14.3% of females hadn’t LVH but had already developed significant myocardial delayed enhancement (MDE). Ten of patients who hadn’t LVH with MDE underwent endomyocardial biopsy and all revealed typical Fabry myocardial pathological findings with significant globotriaosylceramide accumulation in their cardiomyocytes. Our findings indicate that the current common consensus when to start ERT for cardiac Fabry patients might be inappropriately focusing on the existence of hypertrophic cardiomyopathy and its related symptoms/signs. An earlier intervention before significant cardiac manifestations have occurred in these later-onset Fabry patients might be necessary for a better outcome of enzyme replacement therapy.

Since 2001, tandem mass spectrometry was introduced for newborn screening by two Taiwan national newborn screening centers: Taipei Institute of Pathology and Chinese Foundation of Health, in Taiwan, respectively. A total of 24 metabolic disorders, including 6 amino acidopathies, 8 organic acid disorders and 9 fatty acid disorders, etc., were screened and the newborns with positive screening result were referred to Taipei Veterans General Hospital for confirmatory diagnosis. Until Dec 2014, a total of 1,391,583 newborns have been screened by these two newborn screening centers. The overall incidence of inborn errors of metabolism identified by tandem mass was approximately 1/6,000. The most common inborn errors were defects of phenylalanine metabolism (phenylketonuria: 1/60,000; 6-pyruvoyltertrahydropterin synthase (PTPS): 1/110,000). Maple syrup urine disease was the second most common amino acidopathy (1/100,000) and, significantly, most MSUD patients (75%) belonged to the Austronesian aboriginal tribes of southern Taiwan. The most frequently detected organic acid disorder was 3-methylcrotonyl-CoA carboxylase deficiency (1/35,000). Glutaric aciduria type 1 and methylmalonic academia were the second most common organic acid disorders (1/100,000 for each disease). The incidence of fatty acid disorder is relatively less than most western countries. Out of them, carnitine transport defect was the most common fatty acid disease (1/100,000). In this report we will present this large population study of tandem mass newborn screening in Chinese population.

Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). A total of 71 PAH-deficient Taiwanese families were included for PAH gene analysis. A total 34 different mutations, including 20 missense mutations, 4 nonsense mutations, 4 deletion/insertion within structural gene, 1 deletion in enhancer region and 5 affecting splicing were identified. The most prevalent mutations in Taiwan are R241C, R408Q and Ex6- 96A4G accounting for 23.2%, 12.0% and 9.2% of the 142 mutant chromosomes, respectively. A total of 18 patients were regular follow up in our clinics and good responsive to high dose of BH4 (10 mg/kg/day). Their genotypes and phenotypes were analysis and the correlation between the proposed mutant PAH structures and functions regarding BH4 responsiveness are suggested.

Pompe disease is a lysosomal storage disease caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase (GAA) enzyme. Our team has started newborn screening of Pompe disease since 2008. Until now, around 800,000 newborns have been screening. Rapid diagnostic criteria for the newborns with infantile-onset Pompe disease (IOPD) has been established by our team. Through this effective program, IOPD infants can receive their first ERT within 4 hours of admission and at an average of 11.56±3.4 days of age. However, for late onset Pompe disease (LOPD) newborns, it is very difficult to distinguish them from the newborns with low GAA enzyme activity caused pseudo-deficiency allele (G576S) by clinical manifestations or enzyme activity. Therefore, we try to find a reliable biomarker to distinguish LOPD newborns from pseudo-deficiency. In this study, we analyzed urinary Glc4 levels of the newborns who have pseudo-deficiency (G576S), suspected LOPD (suspected by their genotypes), or IOPD. We found that all the pseudo-deficiency newborns and suspected LOPD newborns had normal urinary Glc4 level, while IOPD had very high urinary Glc4 level before they got ERT. The urinary Glc4 level decreased rapidly after ERT in these IOPD newborns. For long-term ERT follow up, the urinary Glc4 level elevated gradually after longer-term follow-up in some patients, especially in who received ERT later. We also found that urinary Glc4 level was correlated with serum creatine kinase (CK) level in our patients. Our data suggested that urinary Glc4 level is a good biomarker for IOPD newborns, but not LOPD, especially for the pre-symptomatic LOPD patients.