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Noonan syndro me is a rare autosomal dominant congenital abnormality associated with a gene defect located on the short arm of chromosome 12. It is characterized by dysmorphic facies, webbed neck, short stature, lymphatic obstruction, cardiac anomalies, and intellectual disability. Prenatal diagnosis of Noonan syndrome is rare because there are no pathognomonic sonographic signs. Studies on the prenatal sonographic features of Noonan syndrome have been reported in very limited numbers. This case series of severe fetal Noonan syndrome, together with a literature review, was conducted to establish prenatal sonographic features highly suggestive of Noonan syndrome to facilitate early detection by clinicians. This study reveals that Noonan syndrome has a relatively specific pattern, which facilitates prenatal molecular genetic diagnosis. Increased nuchal translucency (NT) in the late first trimester and fluid collection in the early second trimester could be warning signs for follow-up, prompting further investigation to detect late-onset features and leading to molecular genetic confirmation. Most structural abnormalities appear in the second trimester, with progressive changes noted throughout gestation. This review better characterizes the sonographic features of fetal Noonan syndrome based on a larger sample size, illustrating a wider spectrum of prenatal phenotypes, including lymphatic drainage disorders, cardiac abnormalities, polyhydramnios, and absent ductus venosus. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich syndrome (WAS)/X-linked thrombocytopenia (XLT) is a rare X-linked disease characterized by thrombocytopenia, eczema, and recurrent infection. In addition, WAS/XLT increases incidence of autoimmune diseases and malignancies. We reported 7 male patients, 2 with WAS and 5 with XLT, from 6 different families. Two novel mutations, p.Gly387GlufsTer58 and p.Ala134Asp, were identified in patients with WAS. Both patients had severe clinical phenotypes compatible with classic WAS and developed lethal outcomes with intracranial hemorrhage. Other than that, one patient with XLT developed pineoblastoma. [ABSTRACT FROM AUTHOR]

X-linked agammaglobulinemia is caused by mutations in the human BTK gene, leading to recurrent pyogenic infections. We describe four novel and three known BTK-mutations in seven patients from seven (six Thai and one Burmese) families. All but one were sporadic cases. Patients 1 and 2 had recurrent mutations in exon 10 (R288W) and exon 17 (R562W), respectively. Patient 3, a previously healthy individual who presented with pseudomonas sepsis with ecthyma gangrenosum had a known mutation in exon 17 (1749delT), leading to frameshift effect (F583fsX586). Patient 4 manifested with sepsis and concurrent acute appendicitis and pneumonia. He had a mutation, IVS8 + 1G > A, which led to an insertion of intron 8 into the transcripts. In Patient 5, a novel change in exon 7, c.588G > C, initially presumed Q196H, was found to cause a leaky splicing mutation, resulting in three distinct transcripts containing 17, 108, and 190 bp of the 5′-terminal of intron 7, which led to truncated peptides consisting of 203 and 211 amino acid residues (or Q196fsX204 and Q196fsX212, respectively). Patient 6 had a mutation in exon 14 (W421X), while patient 7 had a newly defined large deletion of exons 6–9. All of the mothers tested were mutation carriers. Transcript analysis in three mothers who were heterozygous for frameshift mutations revealed a minimal amount of aberrant transcripts, while their affected children had full expression of the mutant alleles, suggesting rapid degradation due to nonsense-mediated mRNA decay in the mothers. This is the first report of mutations of BTK from Thailand. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I Hurler syndrome (MPS IH) is a severe lysosomal storage disorder caused by alpha- l -iduronidase (IDUA) deficiency. Premature truncation mutations (PTC) are the most common (50%–70%) type of IDUA mutations and correlate with MPS IH. Nonsense suppression therapy is a therapeutic approach that aims to induce stop codon readthrough. The different ability of gentamicin to bind mutant mRNA in readthrough is determined by nucleotide sequence (PTC context: UGA > UAG > UAA) and inserted amino acid including the nucleotide position +4 of the PTC, as well as the mRNA secondary structure. We used COS-7 cells to investigate the functional characteristics of p.Q500X and p.R619X, IDUA variants and the effects of gentamicin in inducing stop codon readthrough of seven IDUA variants including p.Q500X, p.R619X, p.Q70X, p.E299X, p.W312X, p.Q380X, and p.W402X. Moreover, we performed prediction of RNA secondary structure using the online tool RNAfold. We found that cells treated with gentamicin showed significantly enhanced full-length IDUA expression and restored IDUA activity, in a dose-dependent manner, only in cells expressing cDNA with W312X, Q380X, W402X, and R619X. Among the readthrough-responsive variants, we observed UGA PTC in W312X, W402X and R619X; and UAG PTC with C at nucleotide +4 in Q380X. Changes of RNA secondary structure were noted only in mutants with readthrough-responsive variants including W312X, Q380X, W402X, and R619X. Additional preclinical studies of selected PTCs with potential readthrough, using drugs with less oto-nephrotoxicity, in patient's skin fibroblasts and animal model are necessary for the premise of personalized medicine. • IDUA PTC variants showed difference readthrough response to gentamicin. • Only readthrough-responsive variants showed changes of RNA secondary structure. • Suppression of PTC variants is dependent on nucleotide sequence context of PTC. [ABSTRACT FROM AUTHOR]

Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by variants in any of the following genes: BCKDHA, BCKDHB, and DBT gene. Previous reports have highlighted a variety of common causing genes and variants among different ethnic groups affected by MSUD. This study is the first to describe the molecular characteristics, potential common variants, clinical phenotypes, and treatment outcomes of 20 Thai MSUD patients before the implementation of expanded newborn screening in Thailand. Results: A cross-sectional, multicenter study was conducted, including twenty Thai MSUD patients from 1997 to 2023. Most of the patients presented with classic neonatal onset (95%). The mortality rate was 20%, while global developmental delay was observed in 40% of the patients. Variants in the BCKDHB gene were detected in 85% (17/20) of the patients, while the BCKDHA gene accounted for 15% (3/20). The study identified the 11-kb deletion involving 5'UTR, exon 1, and intron 1 in the BCKDHB gene, from a position of g.80102385 to g.80113453 (NC_000006.12), accounting for 50% of all variants (20/40 alleles) in Thai MSUD patients. All patients with the 11-kb deletion in BCKDHB presented with the classic type. The gap-PCR for this common deletion was established in the study. Conclusion: This study is the first to describe the clinical and molecular spectrum of Thai MSUD patients before the implementation of expanded NBS. The 11-kb deletion involving exon 1 in the BCKDHB emerges as the most common variant among Thai individuals with MSUD. Furthermore, the gap-PCR test for detecting the 11-kb exon 1 deletion status holds the potential for integration into stepwise molecular analysis following positive expanded newborn screening. [ABSTRACT FROM AUTHOR]

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle α-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA. [ABSTRACT FROM AUTHOR]

Abstract: A total of 664 high school students having ≥1 episode of syncope and 560 students without syncope (controls) underwent 12-lead ECG. A significant QT prolongation was defined as corrected QT (QTc) >470 ms in male and >480 ms in female. A diagnosis of LQTS was made by Schwartz''s score. Most students had only 1 episode of syncope (66.1%), 2 (16.9%), 3 (11.6%), and ≥4 (5.4%). Most syncopal episodes were related to non-exertional events with only 11.4% related to exertion. The QTc distribution of the study group was almost identical to controls with mean QTc of 405.1±23.2 vs 402.5±23.4 ms, respectively. Only one male (0.15%) in the study group had significant QTc prolongation. None met the criteria for diagnosis of LQTS (score ≥4). In conclusion, the prevalence of LQTS in adolescents having syncope seems to be low in this cohort study. [Copyright &y& Elsevier]

Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase (EC. 3.2.1.20) due to mutations in human GAA gene. The objective of the present study was to examine clinical and molecular characteristics of infantile-onset Pompe disease (IOPD) in Thailand. Methods: Twelve patients with infantile-onset Pompe disease (IOPD) including 10 Thai and two other Asian ethnicities were enrolled. To examine the molecular characteristics of Pompe patients, GAA gene was analyzed by PCR amplification and direct Sanger-sequencing of 20 exons coding region. The novel mutations were transiently transfected in COS-7 cells for functional verification. The severity of the mutation was rated by study of the GAA enzyme activity detected in transfected cells and culture media, as well as the quantity and quality of the proper sized GAA protein demonstrated by western blot analysis. The GAA three dimensional structures were visualized by PyMol software tool. Results: All patients had hypertrophic cardiomyopathy, generalized muscle weakness, and undetectable or < 1% of GAA normal activity. Three patients received enzyme replacement therapy with variable outcome depending on the age of the start of enzyme replacement therapy (ERT). Seventeen pathogenic mutations including four novel variants: c.876C > G (p.Tyr292X), c.1226insG (p.Asp409GlyfsX95), c.1538G > A (p.Asp513Gly), c.1895 T > G (p.Leu632Arg), and a previously reported rare allele of unknown significance: c.781G > A (p.Ala261Thr) were identified. The rating system ranked p.Tyr292X, p. Asp513Gly and p. Leu632Arg as class "B" and p. Ala261Thr as class "D" or "E". These novel mutations were located in the N-terminal beta-sheet domain and the catalytic domain. Conclusions: The present study provides useful information on the mutations of GAA gene in the underrepresented population of Asia which are more diverse than previously described and showing the hotspots in exons 14 and 5, accounting for 62% of mutant alleles. Almost all mutations identified are in class A/B. These data can benefit rapid molecular diagnosis of IOPD and severity rating of the mutations can serve as a partial substitute for cross reactive immunological material (CRIM) study. [ABSTRACT FROM AUTHOR]

Background: In developing countries, pregnant women have insufficient knowledge about cell-free DNA screening. Reports from developed countries have found that various tools in prenatal genetic counseling can improve the knowledge of pregnant women who undergo cell-free DNA screening. Data are limited from developing countries where women have different baseline socio-educational backgrounds. The objective of this study was to compare the effects of an animated educational video combined with traditional counseling versus traditional counseling alone in changing pregnant women's knowledge of cell-free DNA screening. Methods: This study was a randomized control trial at an antenatal clinic. Eligible subjects who were Thai pregnant women, were randomized to either view or not view the 4-minute animated educational video explaining cell-free DNA screening. Both groups received traditional counseling. The women were asked to complete a Thai questionnaire assessing knowledge of the screening before and after intervention. The questionnaire consisted of three sections: demographic data of the research participants and their existing awareness about cell-free DNA testing; performance and limitations of cell-free DNA screening; and participants' attitudes toward the positive screening. Primary outcome was the change in knowledge scores. Secondary outcomes were attitudes toward positive screening test, levels of satisfaction with counseling, and screening acceptance rates. Results: Data from 83 women in the video group and 82 in the non-video group were analyzed. The knowledge score (range 0–18) change after counseling was significantly higher in the video group than the non-video group (+ 7.1 ± 3.3 vs + 4.2 ± 2.5; p = 0.03). There were no significant differences in attitudes toward positive screening test (p = 0.83), levels of satisfaction (p = 0.24), or screening acceptance rates (p = 0.15) between the groups. Conclusions: Adding the video to traditional counseling was better than traditional counseling alone in improving pregnant women's knowledge about cell-free DNA screening. Trial registration: The study was retrospectively registered with the Thai Clinical Trials Registry (TCTR20210917001, 17/09/2021). [ABSTRACT FROM AUTHOR]

Background: Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. Method: A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. Results: The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. Conclusion: At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem. [ABSTRACT FROM AUTHOR]

The mutations of bone morphogenetic protein receptor type 2 (BMPR2) in patients with idiopathic pulmonary hypertension has been well defined. We investigated the occurrence of BMPR2 mutation and genetic polymorphisms in children with pulmonary hypertension associated with congenital heart disease (aPH/CHD) and correlated with the pulmonary haemodynamic and vasoreactivity. Methods: BMPR2 mutation/polymorphisms were determined in 30 aPH/CHD children. All children underwent cardiac catheterisation to obtain baseline haemodynamic data. The 5′UTR containing promoter region and all the exons [1–13] of BMPR2 gene were genotyped for possible genetic variants that may be related to the aPH/CHD. Results: None of our 30 patients (median-age 90 months) with aPH/CHD (mean PAP 48±17mmHg, PVR 6.7±4.2WUm2) has had any BMPR2 mutation. Fifteen of them had single nucleotide polymorphism, rs1061157 and/or 5′UTR-polymorphism, specifically GGC repeat variant in seven patients; AGC repeat variant in one patient; and nine base pairs duplication (CTTCTTCGG) in one patient. The GGC repeat ≥13 was found in three out of six of children with aPH/CHD with normal PVR vs. two out of 24 children with aPH/CHD with high PVR. The odd ratio between these two subgroups of aPH/CHD is 0.09 (95% CI 0.02–0.34). Conclusions: In our cohort, there was no BMPR2 mutation in children with aPH/CHD while nine out of 30 of them have 5′UTR repeat polymorphisms. Our data suggests the occurrence of GGC repeat ≥13 at the 5′UTR region may have some protective effect towards pulmonary vasculopathy in children who have been exposed to high pulmonary blood flow due to CHD. [ABSTRACT FROM AUTHOR]

Background: Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010-2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before.Results: There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa.Conclusions: Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD. [ABSTRACT FROM AUTHOR]

The use of rapid DNA sequencing technology in severely ill children in developed countries can accurately identify diagnoses and positively impact patient outcomes. This study sought to evaluate the outcome of Thai children and adults with unknown etiologies of critical illnesses with the deployment of rapid whole exome sequencing (rWES) in Thailand. We recruited 54 unrelated patients from 11 hospitals throughout Thailand. The median age was 3 months (range, 2 days–55 years) including 47 children and 7 adults with 52% males. The median time from obtaining blood samples to issuing the rWES report was 12 days (range, 5–27 days). A molecular diagnosis was established in 25 patients (46%), resulting in a change in clinical management for 24 patients (44%) resulting in improved clinical outcomes in 16 patients (30%). Four out of seven adult patients (57%) received the molecular diagnosis which led to a change in management. The 25 diagnoses comprised 23 different diseases. Of the 34 identified variants, 15 had never been previously reported. This study suggests that use of rWES as a first‐tier investigation tool can provide tremendous benefits in critically ill patients with unknown etiology across age groups in Thailand. [ABSTRACT FROM AUTHOR]

The presence of pelvic pain, a pelvic/paravaginal mass, and purulent vaginal discharge in primigravida should raise the possibility of obstructed hemivagina and uterine didelphys. Though conservative management could result in successful pregnancy outcomes, early excision of vaginal septum and adequate drainage offer a shorter course of management and complication avoidance. [ABSTRACT FROM AUTHOR]

• Dystrophin gene sequencing should be performed as guideline-based investigation in developing country because it is essential for gene-based therapies that are anticipated to be introduced in the near future. • Only 40% patients in our study tested positive for DMD by MLPA technique. • Eight patients were found novel frameshift mutation by dystrophin gene sequencing. • No significant genotype and phenotype correlation. Gene-based therapy is a treatment for Duchenne muscular dystrophy (DMD) has become lately available; limited use for specific of mutation and percentages of the patients. Diagnosis in Thailand is made by muscle biopsy or multiplex ligation-dependent probe amplification (MLPA). Appropriate treatment in developing countries is difficult because gene sequencing is expensive and has limited availability. We aimed to identify the clinical and genetic characteristics of Thai DMD. Patients aged 0–22 years were recruited from the pediatric neuromuscular clinic of Siriraj Hospital during 2017–2019. Ninety-four charts were reviewed for clinical and laboratory data. Patients with negative MLPA who underwent next generation sequencing were consented. The mean age at onset and diagnosis was 4 and 7 years, respectively. Approximately 70% of patients had loss of ambulation by the mean age of 9.6 ± 1.8 years. Eighty percent were treated with glucocorticoids. Genetic testing was performed in 70 patients. Molecular analysis revealed mutations in 90% of cases, including exon deletions in 48.57%, nonsense mutations in 20%, frameshift mutations in 12.86%, splice site in 7.14%, exon duplications in 5.71%, and in-frame deletion in 2.86%. Gene sequencing should be performed because baseline genetic mutation data is essential for gene-based therapies that will become available in the future. [ABSTRACT FROM AUTHOR]

MITF is a known gene underlying autosomal dominant hearing loss, Waardenburg syndrome (WS). Biallelic MITF mutations have been found associated with a rare hearing loss syndrome consisting eye abnormalities and albinism; and a more severe type of WS whose heterozygous parents were affected with classic WS in both cases. The aims of this study were to identify a new candidate gene causing autosomal recessive nonsyndromic hearing loss (ARNSHL) and confirm its causation by finding additional families affected with the candidate gene and supporting evidences from functional analyses. By using whole exome sequencing, we identified a homozygous c.1022G>A: p.Arg341His variant of MITF, which co-segregated with the hearing loss in five affected children of a consanguineous hearing couple. Targeted exome sequencing in a cohort of 130 NSHL individuals, using our in-house gene panel revealed a second family with c.1021C>T: p.Arg341Cys MITF variant. Functional studies confirmed that the Arg341His and Arg341Cys alleles yielded a normal sized MITF protein, with aberrant cytosolic localization as supported by the molecular model and the reporter assay. In conclusion, we demonstrate MITF as a new cause of ARNSHL, with heterozygous individuals free of symptoms. MITF should be included in clinical testing for NSHL, though it is rare. [ABSTRACT FROM AUTHOR]

Background: Prader-Willi syndrome (PWS) is a multisystem genetic disorder, which has a typical eating behavior and growth pattern. In the infancy period, children with PWS have low body weight followed by hyperphagia in later childhood. Disease-specific growth charts have been recommended for monitoring PWS patients. Previous literature demonstrated growth differences among individuals with PWS of different ethnicity.Methods: A retrospective multicenter study was performed in PWS patients from different areas of Thailand included collaboration with the Thai PWS support group during 2000-2017. Baseline characteristics and anthropometric data were reviewed. Both growth hormone and non-growth hormone received patients were included, but the data after receiving GH were excluded before curve construction. Growth charts for Thai PWS compared to the 50th normative centile were constructed using Generalized Least Squares (GLS) methods. Curve smoothing was performed by Fractional Polynomials and Exponential Transformation.Result: One hundred and thirteen patients with genetically confirmed PWS (55 males and 58 females) were enrolled. Fifty percent of patients were diagnosed less than 6 months of age. We developed growth charts for non-growth hormone treated Thai children with PWS aged between 0 and 18 years. A growth pattern was similar to other ethnicities while there were some differences. Mean birth weight of PWS patients was less than that of typical newborns. Mean adult height at 18 years of age in Thai children with PWS was lower than that in American children, but taller than Japanese. Mean weight of Thai PWS males at 18 years of age was more than those from other countries.Conclusion: This study is the first to document PWS-specific growth charts in Southeast Asian population. These growth charts will be useful in improving the quality of patient care and in evaluating the impact of growth hormone treatment in the future. [ABSTRACT FROM AUTHOR]

Pediatric primary cardiomyopathy is rare but serious, having high mortality; hypertrophic and dilated types are the most common. Its etiology has been mainly considered idiopathic; however, next generation sequencing techniques have revealed nearly half of idiopathic pediatric cases arose from specific genetic mutations. Therefore, our study aimed to identify the genetic causes of primary idiopathic cardiomyopathy. Newborns to 15-year old patients with this condition were recruited between March 2016 and May 2017 at Thammasat University Hospital. Complete patient history and physical examination data were collected by a geneticist with cardiac examinations and echocardiograms by pediatric cardiologists. Whole exome sequencing was performed for all. Of the 12 patients enrolled, 5 cases were dilated type and 7 hypertrophic. Two with dilated type were excluded during follow-up as cause was determined (hypocalcemia and pacemaker induced). A list of 118 genes for cardiomyopathy was analyzed in the remaining 10 cases. Pathogenic and likely pathogenic mutations were identified in 5 patients: HRAS, PTPN11, SOS1, FLNC and TXNRD2; half our patients were not actually idiopathic. Despite its high cost, genetic testing is useful for determining familial risk as well as predicting patient cardiomyopathy progress. [ABSTRACT FROM AUTHOR]

Successful parathyroidectomy with intra-operative parathyroid hormone monitoring in a neonate with severe primary hyperparathyroidism caused by homozygous mutation in CASR gene Neonatal severe primary hyperparathyroidism is a cause of malignant neonatal hypercalcaemia, caused by inactivating mutation in I CASR i gene. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca 2+ -sensing receptor gene: Normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. [Extracted from the article]

Abstract: Background: Mucopolysaccharidosis type I (MPS I) is a rare autosomal‐recessive disorder caused by defects in alpha‐L‐iduronidase (IDUA), a lysosomal enzyme encoded by the IDUA gene. Herein, we characterized IDUA mutations underlying mucopolysaccharidosis type I intermediate form (Hurler–Scheie syndrome) and its molecular pathogenic mechanisms. Methods: Clinical data, activity of the IDUA enzyme in leukocytes, and a mutation of the IDUA gene were analyzed. Pathogenesis associated with an IDUA mutation was further investigated by evaluating the mutant cDNA sequence, protein expression and activity in COS‐7 cells. Results: Five unrelated patients were identified to have clinical diagnosis of intermediate form of MPS I (Hurler–Scheie) and exhibited low‐to‐absent levels of leukocyte IDUA activity. Genetic analysis revealed homozygous c.*1T>C (p.X654R) mutation in two patients and compound heterozygosity between the c.*1T>C and another allele including c.265G>A (p.R89Q), c.935G>A (p.W312X), or c.1138 C>T (p.Q380X), each in a single patient. Sequencing the 3′RACE product of the c.*1T>C (p.X654R) allele indicated a 38‐amino acids elongation of the mutant protein. COS‐7 cells expressing IDUA with the mutations exhibited extremely low levels or complete absence of enzyme activity compared to wild‐type IDUA. Western blot analysis detected no protein in p.W312X and p.Q380X samples, while an elevated molecular mass and a different pattern of protein bands were found in p.X654R specimen compared with the wild type IDUA. Conclusions: Mutational spectrum underlying intermediate MPS I is expanded. Our data suggest that the p.X654R is an intermediate IDUA mutant allele with residual enzyme activity. It can lead to intermediate or milder form of MPS I depending on another associated allele. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) is caused by mutations on the GBA1 gene leading to deficiency in acid β-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GlcC) and glucosylsphingosine (GlcS). GlcS in plasma has been proposed as a highly sensitive and specific biomarker for the diagnosis of GD and for monitoring disease progression and response to therapy. Here we report a novel robust and accurate hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) for the direct measurement of glucosylsphingosine (GlcS) in dried plasma spots (DPS). The method was also capable of resolving the isomeric pair, glucosylsphingosine and galactosylsphingosine, the latter of which was proposed as a promising biomarker for Krabbe disease. The method was fully validated and applied to the analysis of 19 GD patients and carriers. The GlcS levels in 9 GD type I patients who have been on enzyme replacement therapy (ERT) were reduced to a mean of 31.0 nM, much lower compared to a pre-treated specimen at a level of 85.8 nM, but still significantly elevated compared to healthy controls. GlcS concentrations in three treated type III GD patients were much lower compared to an untreated patient. In our preclinical GD studies, 4L;C* mice (subacute nGD model) exhibited comparable levels of plasma GlcS, but had much higher GlcS accumulation in the brain than those of 9V/null mice (chronic neuropathic GD model). Our method for the measurement of GlcS in DPS proved to be a very convenient approach for sample collection, storage and shipping nationwide and internationally. [ABSTRACT FROM AUTHOR]

Introduction: Due to the economic downturn in Thailand, two baby girls with congenital central hypoventilation syndrome had to wait for several months to obtain definite diagnosis and long-term mechanical ventilation. Genetic investigation later revealed 20/25 polyalanine expansion of PHOX2B gene in both girls. In this report we highlight the use of non-invasive bi-level positive airway pressure ventilators via tracheostomy, overnight end-tidal carbon dioxide trend graphs and outcomes of the patients whose diagnosis and treatment were delayed. Case presentation: Case 1: A Thai baby girl showed symptoms of apnea and cyanosis from birth and required invasive mechanical ventilation via tracheostomy during sleep. At 5 months, she unfortunately was discharged from the hospital without any ventilatory support due to financial problems. She subsequently developed cor pulmonale, respiratory failure and generalized edema and was referred to us when she was 9-months old. An overnight polysomnogram was consistent with a central hypoventilation disorder, in which the severity of oxygen desaturation and hypercapnia was worsening during non-rapid eye movement compared to rapid eye movement sleep. At 12 months she was allowed to go home with a conventional home ventilator. The ventilator was changed to bi-level positive airway pressure when she was 4-years old. After she received adequate home ventilation, she thrived with normal growth and development. Case 2: A Thai baby girl developed apnea and cyanosis from the age of 5 weeks, requiring ventilatory support (on and off) for 5 months. After being extubated, she had been put on supplemental oxygen via nasal cannula for 2 months. She was then referred to us when she was 7-months old. An overnight end-tidal carbon dioxide trend graph revealed marked hypercapnia without increase in respiratory rate. An overnight polysomnogram was consistent with a central hypoventilation disorder. Since 9 months of age she has been on home bi-level positive airway pressure via tracheostomy without any complications. Genetic testing confirmed 20/25 polyalanine expansions of PHOX2B gene in both girls. Conclusions: Bi-level positive airway pressure, originally designed as a non-invasive ventilator, was found to work effectively and safely, and may be used as an invasive ventilator via tracheostomy in young children with congenital central hypoventilation syndrome. [ABSTRACT FROM AUTHOR]

Reports on the absence of actin-binding proteins in muscle biopsies of patients with muscular dystrophy. Identification of actinin deficiency by immunocytochemistry; Determination of the frequency and ethnic distribution in the general population; Reevaluation of previous studies on the loss actinin in patients with Duchenne muscular dystrophy.

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the glucocerebrosidase (GBA) gene, leading to a deficiency of lysosomal β-glucosidase and accumulation of glycosphingolipids in macrophages. We studied five Thai families with GD (four with GD type 1 and one with GD type 2). Using long-template PCR, PCR using specific primers for the functional gene, direct sequencing of all coding regions of GBA and restriction enzyme digestions, all 10 mutant alleles were successfully identified. The common c.1448T>C (p.L483P or L444P) mutation was identified in 60% of mutant alleles. Of the two patients homozygous for the p.L483P (L444P) mutation, one died from hepatic failure at age 16 years and the other died from sepsis at age 12 years. This p.L483P (L444P) mutation was found in four different haplotypes, suggesting that it was a recurrent mutation, not caused by a founder effect. Two novel mutations, a missense (c.1204T>C, p.Y402H), and a termination codon mutation (c.1609T>C, p.X537A) were found. Studies to determine the molecular pathomechanism of the p.X537A mutation, the first of its kind in this gene, showed that it decreased the amount of protein being expressed and the enzymatic activity, while it was still correctly localized. [ABSTRACT FROM AUTHOR]

Background: Injection skill is one of procedural skills usually taught to medical students. Lack of experience and confidence in their ability creates nervousness, anxiety, and leads to poor performance in giving an injection to patient. Aims: To evaluate the satisfaction on teaching method, perceptions of confidence and feeling of empathy to the patients, and performance in injection skill of medical students toward practicing injection skill using manikin only compared to additional training using themselves as surrogate patients. Methods: Control group consisted of year 5 medical students, who completed studying injection skill from computer assistant instruction, demonstration, and practicing with manikin. The intervention group in addition to those conventional learning methods, directly experienced injection skill using themselves as surrogate patients and received direct feedback from their peers. Both group had a chance to perform injection to actual children and were assessed while performing the injection for their performance of injection procedures. Upon completion of the entire learning process, the students were asked to answer questionnaire presented with Likert-type scales. Results: There were 57 students in the control group and 32 in the intervention group who completed the study. The intervention group reported significantly higher satisfaction on the teaching method, higher level of confidence and empathy to the children who were given injection, and had significantly better performance in preparing the children and giving injection. Both groups are not different in checking accuracy of order, preparing vaccine, selecting injection site, sterile techniques, handling of instruments and injection site, documentation, and explaining to children/parents. Conclusions: Direct experience by medical students themselves as surrogate patients is an appropriate option for learning injection skill and can enhance the student performance, and therefore should be encouraged. [ABSTRACT FROM AUTHOR]

The article discusses the mutations among iduronate-2-sulfatase (IDS) that catabolizes dermatan sulfate and heparan sulfate. It informs that the mutations cause X-linked recessive lysosomal storage disorder called Hunter syndrome. The mutants alter the protein folding of IDS that finally alters the three dimensional structure and protein processing.

Abstract: Introduction: Mucopolysaccharidosis (MPS) type VI (Maroteaux–Lamy syndrome) is a clinically heterogeneous lysosomal storage disorder. It presents significant diagnostic and treatment challenges due to the rarity of the disease and complexity of the phenotype. As information about MPS VI in Asia-Pacific countries is limited, a survey was conducted to assess current practices for diagnosis and management of MPS VI in this region. The participants were selected based on their experience in diagnosing and managing MPS patients. Methods: The survey comprised 29 structured quantitative or qualitative questions. Follow-up consultations were undertaken to discuss the data further. Results: Thirteen physicians from eight countries or regions (Australia, China, Hong Kong, Japan, Malaysia, Philippines, Taiwan and Thailand) were surveyed. At the time of the survey twenty-two patients with MPS VI were directly treated by the respondents and most (~80%) had rapidly progressing disease. A wide range of medical specialists are involved in managing patients with MPS VI, the most common being orthopedic surgeons, pediatricians and geneticists. The availability/accessibility of diagnostic tools, therapies and national insurance coverage vary greatly across the countries/regions and, in some cases, between different regions within the same country. Currently, there are national MPS management groups in Australia and Japan. Australia, Taiwan and Hong Kong have local guidelines for managing MPS and local MPS registries are available in Australia, Taiwan, and Japan. Conclusions: This survey highlights differences in the diagnosis and management of MPS VI between Asia-Pacific countries/regions. Important barriers to advancing the identification, understanding and treatment of MPS VI include the paucity of epidemiological information, limited access to laboratory diagnostics and therapies, low disease awareness, and a lack of monitoring and treatment guidelines. There is a clear need to facilitate communications between physicians and establish regional or national disease registries, a multidisciplinary referral network, and a centralized diagnostic and management framework. [Copyright &y& Elsevier]

Abstract: Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous organic acid disorder caused by either deficiency of the enzyme methylmalonyl-CoA mutase (MCM), or a defect in the biosynthesis of its cofactor, adenosyl-cobalamin (AdoCbl). Herein, we report and review the genotypes and phenotypes of 14 Thai patients with isolated MMA. Between 1997 and 2011, we identified 6 mut patients, 2 cblA patients, and 6 cblB patients. The mut and cblB patients had relatively severe phenotypes compared to relatively mild phenotypes of the cblA patients. The MUT and MMAB genotypes were also correlated to the severity of the phenotypes. Three mutations in the MUT gene: c.788G>T (p.G263V), c.809_812dupGGGC (p.D272Gfs*2), and c.1426C>T (p.Q476*); one mutation in the MMAA gene: c.292A>G (p.R98G); and three mutations in the MMAB gene: c.682delG (p.A228Pfs*2), c.435delC (p.F145Lfs*69), and c.585-1G>A, have not been previously reported. RT-PCR analysis of a common intron 6 polymorphism (c.520-159C>T) of the MMAB gene revealed that it correlates to deep intronic exonization leading to premature termination of the open reading frame. This could decrease the ATP:cobalamin adenosyltransferase (ATR) activity resulting in abnormal phenotypes if found in a compound heterozygous state with a null mutation. We confirm the genotype–phenotype correlation of isolated MMA in the study population, and identified a new molecular basis of the cblB disorder. [Copyright &y& Elsevier]

Background: The most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH). Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s) of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2). To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error.Results: Five out of 39 (12.8%) unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel) and two compound heterozygous 851del4/IVS16ins3kb and 851del4/ 1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q) of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) and lower level of alanine aminotransferase (ALT) than those in non-NICCD patients (p< 0.05). NICCD patients showed higher citrulline level and threonine/serine ratio than non-NICCD infants (p< 0.05). Fatty liver was found in 2 NICCD patients. Jaundice resolved in all NICCD and in 87.5% of non-NICCD infants at the median age of 9.5 and 4.0 months, respectively. Conclusion: NICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among Thai infants. However, this number may be underestimated and required further analysis with mutation screening in larger control population to establish the true prevalence of NICCD and AGC2 deficiency. [ABSTRACT FROM AUTHOR]

Polymorphic variability in immune response genes, such as IL12B, encoding the IL-12p40 subunit is associated with susceptibility to severe malaria in African populations. Since the role of genetic variation in conditioning severe malaria in Thai adults is largely unexplored, the functional association between IL12B polymorphisms [i.e. IL12Bpro (rs17860508) and IL12B 3′ UTR T/G (rs3212227)], severe malaria and cytokine production was examined in patients with Plasmodium falciparum infections ( n = 355) recruited from malaria endemic areas along the Thai–Myanmar border in northwest Thailand. Circulating IL-12p40 ( p = 0.049) and IFN-γ ( p = 0.051) were elevated in patients with severe malaria, while only IL-12p40 was significantly higher in severe malaria patients with hyperparasitaemia ( p = 0.046). Carriage of the IL12Bpro1.1 genotype was associated with enhanced severity of malaria (OR, 2.34; 95% CI, 0.94–5.81; p = 0.066) and hyperparasitaemia (OR, 3.42; 95% CI, 1.17–9.87; p = 0.025) relative to the IL12Bpro2.2 genotype (wild type). Individuals with the IL12Bpro1.1 genotype also had the lowest IL-12p40 ( p = 0.002) and the highest IFN-γ ( p = 0.004) levels. Construction of haplotypes revealed that carriage of the IL12Bpro-2/3′ UTR-T haplotype was associated with protection against severe malaria (OR, 0.51; 95% CI, 0.29–0.90; p = 0.020) and reduced circulating IFN-γ ( p = 0.06). Thus, genotypic and haplotypic variation at IL12Bpro and IL12B 3′ UTR in this population influences susceptibility to severe malaria and functional changes in circulating IL-12p40 and IFN-γ levels. Results presented here suggest that protection against severe malaria in Thai adults is associated with genotypic variants that condition enhanced IL-12p40 and reduced IFN-γ levels. [ABSTRACT FROM AUTHOR]

The OTUD6B and ZMIZ1 genes were recently identified as causes of syndromic intellectual disability (ID) with shared phenotypes of facial dysmorphism, distal limb anomalies, and seizure disorders. OTUD6B- and ZMIZ1-related ID are inherited in autosomal recessive and autosomal dominant patterns, respectively. We report a 5-year-old girl with developmental delay, facial phenotypes resembling Williams syndrome, and cardiac defects. The patient also had terminal broadening of the fingers and polydactyly. Cytogenomic microarray (CMA), whole exome sequencing (WES), and mRNA analysis were performed. The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3, chr8:92084087–92202189, with OTUD6B involved. The WES identified a hemizygous OTUD6B variant, c.873delA (p.Lys291AsnfsTer3). The mother was heterozygous for this allele. The WES also demonstrated a heterozygous ZMIZ1 variant, c.1491 + 2T > C, in the patient and her father. This ZMIZ1 variant yielded exon 14 skipping, as evidenced by mRNA study. We suggest that Williams syndrome-like phenotypes, namely, periorbital edema, hanging cheek, and long and smooth philtrum represent expanded phenotypes of OTUD6B-related ID. Our data expand the genotypic spectrum of OTUD6B- and ZMIZ1-related disorders. This is the first reported case of a compound heterozygote featuring point mutation, chromosomal microdeletion of OTUD6B, and the unique event of OTUD6B, coupled with ZMIZ1 variants. [ABSTRACT FROM AUTHOR]

The article presents two case studies of two infants with abetalipoproteinemia (ABL); one with the classic manifestation and the other with an atypical predominant presentation. Topics discussed include histopathology of the duodenal biopsy in infants, the response of infants to dietary treatment, and ABL in an infant or achild with post-prandial vomiting, steatorrhea and substantial growth failure of unclear etiology.

PEX34 , encoding a peroxisomal protein implicated in regulating peroxisome numbers, was identified as a high copy suppressor, capable of bypassing impaired acetate utilization of agc1 ∆ yeast. However, improved growth of agc1 ∆ yeast on acetate is not mediated through peroxisome proliferation. Instead, stress to the endoplasmic reticulum and mitochondria from PEX34 overexpression appears to contribute to enhanced acetate utilization of agc1 ∆ yeast. The citrate/2-oxoglutarate carrier Yhm2p is required for PEX34 stimulated growth of agc1 ∆ yeast on acetate medium, suggesting that the suppressor effect is mediated through increased activity of a redox shuttle involving mitochondrial citrate export. Metabolomic analysis also revealed redirection of acetyl-coenzyme A (CoA) from synthetic reactions for amino acids in PEX34 overexpressing yeast. We propose a model in which increased formation of products from the glyoxylate shunt, together with enhanced utilization of acetyl-CoA, promotes the activity of an alternative mitochondrial redox shuttle, partially substituting for loss of yeast AGC1. [ABSTRACT FROM AUTHOR]

Background: Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome 18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2‐q21.1 region. Methods: We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11‐q12 (band 1 only; 17.2–43.5 Mb position) deletion. Results: Common presentations of 18q11‐q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non‐specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype–phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11‐q12 deletion syndrome could be narrowed down as follows: 38.8–43.5 Mb for moderate to severe DD/ID, 19.6–24.4 Mb and 26.9–28.6 Mb for conotruncal heart defect. Conclusion: The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype–phenotype correlations and better long‐term care of patients with this rare syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Due to the economic downturn in Thailand, two baby girls with congenital central hypoventilation syndrome had to wait for several months to obtain definite diagnosis and long-term mechanical ventilation. Genetic investigation later revealed 20/25 polyalanine expansion of PHOX2B gene in both girls. In this report we highlight the use of non-invasive bi-level positive airway pressure ventilators via tracheostomy, overnight end-tidal carbon dioxide trend graphs and outcomes of the patients whose diagnosis and treatment were delayed.Case Presentation: Case 1: A Thai baby girl showed symptoms of apnea and cyanosis from birth and required invasive mechanical ventilation via tracheostomy during sleep. At 5 months, she unfortunately was discharged from the hospital without any ventilatory support due to financial problems. She subsequently developed cor pulmonale, respiratory failure and generalized edema and was referred to us when she was 9-months old. An overnight polysomnogram was consistent with a central hypoventilation disorder, in which the severity of oxygen desaturation and hypercapnia was worsening during non-rapid eye movement compared to rapid eye movement sleep. At 12 months she was allowed to go home with a conventional home ventilator. The ventilator was changed to bi-level positive airway pressure when she was 4-years old. After she received adequate home ventilation, she thrived with normal growth and development. Case 2: A Thai baby girl developed apnea and cyanosis from the age of 5 weeks, requiring ventilatory support (on and off) for 5 months. After being extubated, she had been put on supplemental oxygen via nasal cannula for 2 months. She was then referred to us when she was 7-months old. An overnight end-tidal carbon dioxide trend graph revealed marked hypercapnia without increase in respiratory rate. An overnight polysomnogram was consistent with a central hypoventilation disorder. Since 9 months of age she has been on home bi-level positive airway pressure via tracheostomy without any complications. Genetic testing confirmed 20/25 polyalanine expansions of PHOX2B gene in both girls.Conclusions: Bi-level positive airway pressure, originally designed as a non-invasive ventilator, was found to work effectively and safely, and may be used as an invasive ventilator via tracheostomy in young children with congenital central hypoventilation syndrome. [ABSTRACT FROM AUTHOR]

Background: The most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH). Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s) of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2). To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error.Results: Five out of 39 (12.8%) unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel) and two compound heterozygous 851del4/IVS16ins3kb and 851del4/1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q) of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) and lower level of alanine aminotransferase (ALT) than those in non-NICCD patients (p< 0.05). NICCD patients showed higher citrulline level and threonine/serine ratio than non-NICCD infants (p< 0.05). Fatty liver was found in 2 NICCD patients. Jaundice resolved in all NICCD and in 87.5% of non-NICCD infants at the median age of 9.5 and 4.0 months, respectively.Conclusion: NICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among Thai infants. However, this number may be underestimated and required further analysis with mutation screening in larger control population to establish the true prevalence of NICCD and AGC2 deficiency. [ABSTRACT FROM AUTHOR]