Browsing by Author "Tim-Aroon T."
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Item Metadata only A generation of human induced pluripotent stem cell line (MUi031-A) from a type-3 Gaucher disease patient carrying homozygous mutation on GBA1 gene(2022-04-01) Pornsukjantra T.; Kangboonruang K.; Tong-Ngam P.; Tim-Aroon T.; Wattanasirichaigoon D.; Anurathapan U.; Hongeng S.; Tubsuwan A.; Bhukhai K.; Asavapanumas N.; Mahidol UniversityGaucher disease (GD) is one of the most prevalent lysosomal storage diseases caused by mutation of glucocerebrosidase (GBA1) gene. GD patients develop symptoms in various organs of the body; however, the underlying mechanisms causing pathology are still elusive. Thus, a suitable disease model is important in order to facilitate subsequent investigations. Here, we established MUi031-A human induced pluripotent stem cell (hiPSC) line from CD34+ hematopoietic stem cells of a female type-3 GD patient with homozygous c.1448 T > C (L444P) mutation. The cells exhibited embryonic stem cell-like characteristics and expressed pluripotency markers with capability to differentiate into three germ layers.Item Metadata only A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability(2024-01-01) Noojarern S.; Tim-Aroon T.; Anurat K.; Phetthong T.; Khongkraparn A.; Wattanasirichaigoon D.; Noojarern S.; Mahidol UniversityPettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.Item Metadata only A novel TCN2 mutation with unusual clinical manifestations of hemolytic crisis and unexplained metabolic acidosis: expanding the genotype and phenotype of transcobalamin II deficiency(2022-12-01) Pongphitcha P.; Sirachainan N.; Khongkraparn A.; Tim-Aroon T.; Songdej D.; Wattanasirichaigoon D.; Mahidol UniversityBackground: Transcobalamin deficiency is a rare inborn metabolic disorder, characterized by pancytopenia, megaloblastic anemia, failure to thrive, diarrhea, and psychomotor retardation. Case presentation: We describe a patient who first presented at 3 months of age, with pancytopenia, hepatosplenomegaly, recurrent infection, metabolic acidosis, and acute hemolytic crisis. Extensive hematologic and immunologic investigations did not identify inherited bone marrow failure syndrome, acute leukemia or its related disorders. Whole exome sequencing identified a novel homozygous TCN2 mutation, c.428-2A > G and mRNA study confirmed an aberrant transcription of exon 4 skipping. The mutant protein is predicted to have an in-fame 51 amino acids deletion (NP_000346:p.Gly143_Val193del). The patient exhibited marked clinical improvement following hydroxocobalamin treatment. Conclusions: Transcobalamin deficiency should be investigated in infants with unexplained pancytopenia and acute hemolytic crisis with or without typical evidence of vitamin B12 deficiency.Item Metadata only An increase in ER stress and unfolded protein response in iPSCs-derived neuronal cells from neuronopathic Gaucher disease patients(2024-12-01) Pornsukjantra T.; Saikachain N.; Sutjarit N.; Khongkrapan A.; Tubsuwan A.; Bhukhai K.; Tim-Aroon T.; Anurathapan U.; Hongeng S.; Asavapanumas N.; Pornsukjantra T.; Mahidol UniversityGaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the GBA1 gene, responsible for encoding the enzyme Glucocerebrosidase (GCase). Although neuronal death and neuroinflammation have been observed in the brains of individuals with neuronopathic Gaucher disease (nGD), the exact mechanism underlying neurodegeneration in nGD remains unclear. In this study, we used two induced pluripotent stem cells (iPSCs)-derived neuronal cell lines acquired from two type-3 GD patients (GD3-1 and GD3-2) to investigate the mechanisms underlying nGD by biochemical analyses. These iPSCs-derived neuronal cells from GD3-1 and GD3-2 exhibit an impairment in endoplasmic reticulum (ER) calcium homeostasis and an increase in unfolded protein response markers (BiP and CHOP), indicating the presence of ER stress in nGD. A significant increase in the BAX/BCL-2 ratio and an increase in Annexin V-positive cells demonstrate a notable increase in apoptotic cell death in GD iPSCs-derived neurons, suggesting downstream signaling after an increase in the unfolded protein response. Our study involves the establishment of iPSCs-derived neuronal models for GD and proposes a possible mechanism underlying nGD. This mechanism involves the activation of ER stress and the unfolded protein response, ultimately leading to apoptotic cell death in neurons.Item Metadata only Assessing the Value for Money of Enzyme Replacement Therapy in Gaucher Disease Types 1 and 3b: Can Expanded Coverage Be Justified?(2025-01-01) Rattanavipapong W.; Anothaisintawee T.; Isaranuwatchai W.; Wattanasirichaigoon D.; Tim-Aroon T.; Wichajarn K.; Sathienkijkanchai A.; Charoenkwan P.; Suphapeetiporn K.; Traivaree C.; Kuptanon C.; Teerawattananon Y.; Rattanavipapong W.; Mahidol UniversityBackground and Objectives: The Health Intervention and Technology Assessment Program was commissioned to conduct a cost–utility and budget impact analysis of enzyme replacement therapy (ERT) for Gaucher disease types 1 and 3b. The findings from this assessment are to support the decision-making process regarding the potential expansion of ERT coverage within Thailand’s public health system. Methods: The analysis compared the current policy, which provides treatment with imiglucerase only for patients with Gaucher disease type 1, as listed in the National List of Essential Medicine, with a proposed policy that extends coverage to include Gaucher disease types 1 and 3b with either imiglucerase or velaglucerase. Cost–utility analysis of these policy options was performed using decision tree and Markov models over a lifetime horizon from a societal perspective. The financial implications for the relevant budgetary authority over 5 years were estimated. The research methodology adheres rigorously to Thailand’s health technology assessment guidelines. Results: The study found that the incremental cost-effectiveness ratios for treating both Gaucher disease types 1 and 3b are 6,769,000 and 9,359,000 baht per quality-adjusted life year (QALY) for imiglucerase and velaglucerase, respectively, which is well beyond Thailand’s cost-effectiveness threshold of 160,000 baht per QALY. Such an expansion would incur an additional budgetary burden of approximately 81 million baht for imiglucerase and 138 million baht for velaglucerase. Increasing the rate of hematopoietic stem cell transplantation (HSCT) can improve the cost-effectiveness of the expansion. Conclusions: The study concludes that expanding ERT with either imiglucerase or velaglucerase to treat both Gaucher disease types 1 and 3b is not cost-effective at current prices in Thailand; however, it could become cost-effective with a reduction of approximately 60% in drug prices or if all eligible patients undergo HSCT.Item Metadata only Association of Mitochondrial DNA Polymorphisms With Pediatric-Onset Cyclic Vomiting Syndrome(2022-05-24) Veenin K.; Wattanasirichaigoon D.; Suktitipat B.; Noojarern S.; Lertrit P.; Tim-Aroon T.; Kaewsutthi S.; Treepongkaruna S.; Mahidol UniversityBackground: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder characterized by recurrent stereotypic episodes of vomiting. The pathophysiology of CVS remains obscure. Previous studies have supported the hypotheses of mitochondrial dysfunction. However, data on association studies between mitochondrial DNA (mtDNA) polymorphisms and pediatric-onset CVS are limited and inconsistent. The aims of this study were to describe clinical characteristics, evaluate association of mtDNA polymorphisms 16519T and 3010A with pediatric-onset CVS and identify new mtDNA candidate variants. Methods: This study involved Thai patients diagnosed with CVS according to the Rome III or IV criteria before the age of 15 years. Patients' demographic data, clinical characteristics, previous investigations and treatment outcomes were obtained. Blood samples were collected for next-generation (whole exome) sequencing, followed by analysis of chromosome M (mitochondrial. Variants were filtered according to clinical significance using ClinVar and MITOMAP. mtDNA polymorphisms in 148 normal Thai individuals were used as controls. Results: Forty-eight children were enrolled in the clinical study, and 30 participated in the genetic analysis. The median age at onset and median age at diagnosis was 3.0 (1.5–5.6) and 6.3 (3.0–8.6) years, respectively. Maternal history of migraine was positive in 16.7%. About 45.7% (21 of 46) of the patients achieved complete clinical remission, with the mean symptom duration of 5.9 ± 3.3 years. The prevalence of mtDNA variants 16519T and 3010A among the patient group and Thai general population (control) were as follows: 40.0% (12/30) vs. 27.7% (P = 0.18) and 6.7% (2/30) vs. 0.7% (P = 0.07), respectively. Five known pathogenic variants were identified in 6 patients, including mtDNA 8528C in one patient who also had infantile hypertrophic cardiomyopathy. Six likely pathogenic variants were found but without statistical significance. We identified 11 variants with significant prevalence in the patient group. Though, these variants were classified as variants of unknown significance (VUS), several of them were located in mt functional regions and therefore they deserve further investigations as new candidates for association with pediatric CVS. Conclusion: There were no associations of mtDNA polymorphisms 16519T and 3010A with CVS in our pediatric cohort. Five pathogenic variants and 11 VUS were found associated with pediatric-onset CVS.Item Metadata only Case report of a novel variant in SMPD1 of Niemann-Pick disease type A with a liver histology from Thailand(2024-03-01) Ngoenmak T.; Somran J.; Foonoi M.; Srisingh K.; Singpan N.; Tim-Aroon T.; Ngoenmak T.; Mahidol UniversityWe report a 7-month-old Thai girl diagnosed with a Niemann-Pick Disease (NPD) Type A. Hepatosplenomegaly was initially noticed at the age of 2 months. She developed progressive neurodevelopmental delay at 5 months. Other typical manifestations include coarse facies, cherry red spot of macula, hypotonia, and failure to thrive. A liver biopsy demonstrated an accumulation of enlarged histiocytes with foamy appearance in hepatic sinusoids. An acid sphingomyelinase activity from dried blood spot showed low activity. A novel c.1241T>C variant in SMPD1 was identified. The patient died at 4 years of age due to neurological decline and respiratory failure. Even in type A, onset of systemic symptoms occurs before neurodevelopmental delay. NPD type A is exceptionally rare in Thailand. Infantile neurovisceral ASMD prognosis is poor, often fatal by age 3. No specific NPD type A treatment exists; supportive care is offered. Therefore, the case reveals a novel SMPD1 variant in typical NPD type A symptoms. Early progressive neurodevelopmental delay challenges treatment study.Item Metadata only Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3(2023-03-01) Anurathapan U.; Tim-Aroon T.; Zhang W.; Sanpote W.; Wongrungsri S.; Khunin N.; Chutipongtanate S.; Chirdkiatgumchai V.; Ngiwsara L.; Jaovisidha S.; Khongkraparn A.; Pakakasama S.; Svasti J.; Setchell K.D.R.; Wattanasirichaigoon D.; Hongeng S.; Mahidol UniversityBackground: Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population. Methods: We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3). Results: Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment. Conclusions: ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.Item Metadata only Diagnostic yield of whole exome sequencing with targeted gene analysis in prelingual sensorineural hearing loss in Thailand(2025-09-25) Damrongchietanon T.; Wattanasirichaigoon D.; Khongkraparn A.; Noojarern S.; Tiravanitchakul R.; Kasemkosin N.; Kiatthanabumrung S.; Tim-Aroon T.; Wongkittichote P.; Damrongchietanon T.; Mahidol UniversityPrelingual sensorineural hearing loss (SNHL) represents about 80% of genetic SNHL, with at least 90 causative genes identified. In order to identify the genetic diagnosis of prelingual SNHL, we performed a prospective study by systematic history-taking and phenotyping, followed by whole-exome sequencing (WES) with target gene analysis in 100 Thai patients. We found an overall diagnostic yield of 46%, 58.3% for familial cases, and 39.0% for sporadic cases. These included 41 cases with nonsyndromic SNHL(nsSNHL) and 5 cases with syndromic SNHL (sSNHL). We identified 41 P/LP and 4 VUS variants of 15 genes. Of those sSNHL, the causative genes were PAX3, SOX10, MITF (Waardenburg and Teitz syndromes), and SLC26A4 (Pendred syndrome). The genetic defects identified among those with nsSNHL were GJB2 and SLC26A4 as the most prevalent causes, followed by MYO15A, MYO7A, POU3F4, OTOF, PCDH15, GSDME, PTEN, ACTG1, TMPRSS3, MITF, and MPZL2. The inheritance of these nsSNHL genes involved X-linked recessive (n = 3), autosomal dominant (n = 3), and autosomal recessive in the remainder (n = 36). Patients with positive mutations underwent surveillance for associated symptoms like goiter and retinitis pigmentosa. In conclusion, most prelingual SNHL was nsSNHL with autosomal recessive inheritance. Identifying the causative gene benefits patients for specific management and genetic counseling.Item Metadata only Effects of gentamicin inducing readthrough premature stop Codons: A study of alpha-L-iduronidase nonsense variants in COS-7 Cells(2022-12-25) Ngiwsara L.; Sawangareetrakul P.; Wattanasirichaigoon D.; Tim-Aroon T.; Dejkhamron P.; Champattanachai V.; Ketudat-Cairns J.R.; Svasti J.; Mahidol UniversityMucopolysaccharidosis 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.Item Metadata only Epidermolysis Bullosa With Congenital Absence of Skin: Congenital Corneal Cloudiness and Esophagogastric Obstruction Including Extended Genotypic Spectrum of PLEC, LAMC2, ITGB4 and COL7A1(2022-04-01) Pongmee P.; Wittayakornrerk S.; Lekwuttikarn R.; Pakdeeto S.; Watcharakuldilok P.; Prempunpong C.; Tim-Aroon T.; Puttanapitak C.; Wattanasoontornsakul P.; Junhasavasdikul T.; Wongkittichote P.; Noojarern S.; Wattanasirichaigoon D.; Mahidol UniversityEpidermolysis bullosa (EB) is a rare and genetically heterogeneous disorder characterized by skin fragility and blister formation occurring spontaneously or after minor trauma. EB is accompanied by congenital absence of skin (EB with CAS) in some patients. Pathogenic variants of COL7A1 are responsible for EB with CAS in the vast majority of cases. Type and subtype diagnosis of EB with CAS generally requires specific immunohistological examinations that are not widely available plus targeted gene analysis. The present study aimed to determine the clinical features of five patients affected by EB with CAS and to identify the underlying genetic defects using whole exome sequencing (WES) followed by focused analysis of the target genes. Four patients had generalized skin involvement and one had localized defects. Two patients exhibited extremely severe skin manifestations and congenital cloudy cornea along with pyloric atresia, and one had partial esophagogastric obstruction and anuria due to vesicoureteric obstruction. In the WES analysis, the average coverage of the target exons was 99.05% (726 of 733 exons), with a range of 96.4–100% for individual genes. We identified four novel and two known pathogenic/likely pathogenic variants of five distinct genes in the examined families: PLEC:c.2536G > T (p.Glu846Ter); LAMC2:c.3385C > T (p.Arg1129Ter); KRT5:c.429G > A (p.Glu477Lys); ITGB4:c.794dupC (p.Ala266SerfsTer5); COL7A1:c.5440C > T (p.Arg1814Cys); and COL7A1:c.6103delG. All alleles were inherited from the parents, except for the KRT5 variant as a de novo finding. The findings reveal extremely rare phenotypes found in EB with CAS, namely congenital cloudy cornea, esophagogastric obstruction, and anuria, and extend the genotypic spectrum of EB-related genes. The data confirm that WES provides very high coverage of coding exons/genes and support its use as a reasonable alternative method for diagnosis of EB. The present data from an underrepresented population in Southeast Asia could further broaden the knowledge and research on EB.Item Metadata only Establishment of MUi030-A: A human induced pluripotent stem cell line carrying homozygous L444P mutation in the GBA1 gene to study type-3 Gaucher disease(2023-12-01) Kangboonruang K.; Pornsukjantra T.; Tong-Ngam P.; Chokpanuwat T.; Tim-Aroon T.; Wattanasirichaigoon D.; Anurathapan U.; Hongeng S.; Asavapanumas N.; Bhukhai K.; Tubsuwan A.; Mahidol UniversityGaucher disease (GD) is a common lysosomal storage disease resulting from mutations in the glucocerebrosidase (GBA1) gene. This genetic disorder manifests with symptoms affecting multiple organs, yet the underlying mechanisms leading to pathology remain elusive. In this study, we successfully generated the MUi030-A human induced pluripotent stem cell (hiPSC) line using a non-integration method from a male type-3 GD patient with a homozygous c.1448T>C (L444P) mutation. These hiPSCs displayed a normal karyotype and pluripotency markers and the remarkable ability to differentiate into cells representing all three germ layers. This resourceful model holds significant promise for illuminating GD's underlying pathogenesis.Item Metadata only Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review(2025-01-01) Eiumtrakul W.; Tim-Aroon T.; Wuthisiri W.; Sujirakul T.; Chansakul T.; Khongkraparn A.; Noojarern S.; Wattanasirichaigoon D.; Wongkittichote P.; Eiumtrakul W.; Mahidol UniversityGenetic defects in primary cilia-related genes are associated with a heterogeneous group of disorders known as ciliopathies. TBC1D32-related ciliopathy presents with a broad phenotypic spectrum, ranging from isolated retinal diseases to severe multisystemic involvement, including fetal demise. We report two unrelated patients with retinal disease and hypopituitarism, with one also exhibiting facial dysmorphism, developmental delay, and unilateral oculomotor nerve palsy. Whole genome sequencing identified biallelic TBC1D32 variants in both patients, including two splice-site variants. RNA analysis revealed exon skipping, leading to frameshift and premature protein truncation. A review of previously reported cases highlighted facial dysmorphism, retinal disease, and hypopituitarism as major clinical features of TBC1D32-related ciliopathy. Additionally, we propose oculomotor nerve palsy as an extended clinical feature of this disorder. This study expands the clinical and molecular spectrum of TBC1D32-related ciliopathy.Item Metadata only Exploring molecular spectrum in thai patients with maple syrup urine disease: unveiling a common variant(2024-12-01) Lakkhana P.; Tim-Aroon T.; Khongkraparn A.; Noojarern S.; Wongkittichote P.; Wichajarn K.; Kuptanon C.; Boonyawat B.; Suphapeetiporn K.; Wejaphikul K.; Seo G.H.; Wattanasirichaigoon D.; Lakkhana P.; Mahidol UniversityBackground: 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.Item Metadata only High depth targeted next-generation sequencing in vascular malformations(2026-02-08) Pakhathirathien P.; Wongkittichote P.; Wittayakornrerk S.; Treesit T.; Feinggumloon S.; Pichipichatkul K.; Bua-Ngam C.; Sarovath A.; Thanachatchairattana P.; Dumrongwongsiri S.; Bowling K.M.; Corliss M.M.; Cao Y.; Tim-Aroon T.; Khongkraparn A.; Noojaroen S.; Wattanasirichaigoon D.; Pakhathirathien P.; Mahidol UniversityA vascular anomaly could be a vascular tumor or a vascular malformation. Vascular malformation is subclassified into fast-flow, including arteriovenous malformation and portwine stain, and slow-flow group comprising venous malformation, lymphatic malformation, and venolymphatic malformation. Recent data have shown that somatic mutations of genes in PIK3/AKT/mTOR and RAS/MAPK/ERK pathways are a major cause of this disorder. We conducted a gene panel testing (129 genes) with high-depth next-generation sequencing (NGS), which can detect very low-level mosaicism (~ 1%), on the tissue obtained from 26 patients in a cohort of mixed types of vascular malformation, comprising 2 fast-flow and 24 slow-flow malformations. Pathogenic/likely pathogenic (P/LP) variants were identified in 21 of 26 patients, yielding the overall diagnostic rate of 80.8%. The leading causes identified were PIK3CA (57.1%) and TEK (33.3%), especially in the slow-flow group, whereas HRAS and GNAQ were found positive in patients with fast-flow malformations. Three of 11 P/LP variants were previously unreported in vascular malformation, including those from HRAS, PIK3CA, and TEK. Most variants were detected as a solo, except for double mutations of TEK in patients with blue rubber bleb nevus syndrome (BRBNS) and a non-syndromic venous malformation. The level of mosaicism in the tissue ranged from 0.93% to 16.53%, with 60% (15/25) of the variants having ≥ 5% mosaicism. Three variant of uncertain significance of IDH1 and NACC1 were found and deserve further investigation for their pathogenic role. Data from the present study suggest the potential benefit of targeted therapy, in particular drugs in the mTOR pathway, for these patients.Item Metadata only HMG-CoA Synthase-2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease(2025-07-01) Vaseenon H.; Tim-Aroon T.; Saengow V.E.; Sangcakul A.; Wongkittichote P.; Khongkraparn A.; Wattanasirichaigoon D.; Vaseenon H.; Mahidol UniversityMitochondrial HMG-CoA synthase-2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency. Patient 1 presented on day of life 7 with a sepsis-like condition, coma, metabolic acidosis, and marked elevation of ammonium level at 1081 μmol/L. Metabolic screening demonstrated elevated valine and leucine/isoleucine concentrations, resembling maple syrup urine disease (MSUD). The patient received a blood exchange transfusion, which lowered the ammonium level to 92 μmol/L. Urine organic acid analysis did not confirm MSUD. At 1 year and 4 months, the patient experienced acute decompensation again. Exome sequencing revealed a homozygous HMGCS2 variant, c.1502G>C (p.Arg501Pro). Patient 2, an older sibling of Patient 1, was healthy but diagnosed through genetic testing. Both patients exhibited abnormal biochemical profiles, including dicarboxylic aciduria and increased urinary excretion of 4-hydroxy-6-methyl-2-pyrone (4-HMP) after 8 h of fasting, suggesting that a clinically asymptomatic patient, like Patient 2, may eventually develop acute decompensation. Therefore, preemptive treatment with fasting avoidance with or without l-carnitine during intercurrent illness should be advised. The present cases were the second and third patients of p.Arg501Pro homozygosity. The elevated branched-chain amino acids in the metabolic screening (without including alloisoleucine) and the described organic acid profile can be found during the catabolic state, resembling MSUD, and severe hyperammonemia is an uncommon phenotype and an exception to neonatal decompensation in HMGCS2 deficiency. Our findings demonstrated intrafamilial variability and expanded the clinical and biochemical spectrum of HMGCS2 deficiency.Item Metadata only Impacts and Economic Burden of Pompe Disease on Patients and Families in Thailand: A Mixed Method Study(2026-01-01) Youngkong S.; Thavorncharoensap M.; Chaikledkaew U.; Luangsinsiri C.; Tim-Aroon T.; Kuptanon C.; Sathienkijkanchai A.; Rojnueangnit K.; Wichajarn K.; Boonyawat B.; Suphapeetiporn K.; Wattanasirichaigoon D.; Youngkong S.; Mahidol UniversityPurpose: This study aimed to explore the impacts and economic burden experienced by patients and families affected by Pompe disease in Thailand. Patients and Methods: A mixed-methods analysis was employed. To estimate the direct medical cost, databases and/or medical records of the seven rare disease (RD) centers in Thailand from 2010 to 2021 were reviewed. Structured interviews were also conducted to examine direct non-medical and indirect costs. The economic burden was presented in 2024 US dollars (USD) value (1 USD = 35.29 THB). In-depth interviews were conducted with four patients and two caregivers to explore the impacts of this disease. Results: Frequently reported symptoms included fatigue, muscle weakness, and difficulty breathing during sleep. These symptoms had significant and profound impacts on patients’ functioning, family and social roles, self-esteem, emotion, and financial status. Frequent visits to the RD centers, along with the referral process, were reported as a substantial burden to the patients and families. The mean annual direct medical cost per patient, excluding the cost of enzyme replacement therapy, ranged between 2,505 and 14,042 USD from the provider’s perspective and 1,484 USD from the patient’s perspective. Direct non-medical costs were highly significant, with the annual cost of informal care of 1,878–1,992 USD per patient. Around 43% of the patients reported requiring informal care. On average, each patient required 2.6 ± 3.5 hours of informal care per day. Conclusion: Our findings revealed substantial impacts of Pompe disease on individuals’ physical, social, emotional, and functional capacities as a result of its symptoms. Coordinated care, where patients can be treated by clinicians at local hospitals who operate in close liaison with specialists from the RD centers, is warranted. Psychosocial, welfare, and transportation supports are clearly justified to alleviate the burden and improve the quality of life of the patients.Item Metadata only Parental Awareness, Knowledge, and Attitudes Regarding Current and Future Newborn Bloodspot Screening: The First Report from Thailand(2023-06-01) Wilaiwongsathien K.; Wattanasirichaigoon D.; Rattanasiri S.; Aonnuam C.; Tangshewinsirikul C.; Tim-Aroon T.; Mahidol UniversityNewborn screening (NBS) is a public health service that is used to screen for treatable conditions in many countries, including Thailand. Several reports have revealed low levels of parental awareness and knowledge about NBS. Because of limited data on parental perspectives toward NBS in Asia and the differences in socio-cultural and economic contexts between Western and Asian countries, we conducted a study to explore parental perspectives on NBS in Thailand. A Thai questionnaire to assess awareness, knowledge, and attitudes regarding NBS was constructed. The final questionnaire was distributed to pregnant women, with or without their spouses, and to parents of children aged up to one year who visited the study sites in 2022. A total of 717 participants were enrolled. Up to 60% of parents were identified as having good awareness, which was significantly associated with gender, age, and occupation. Only 10% of parents were classified as having good knowledge relative to their education level and occupation. Providing appropriate NBS education should be initiated during antenatal care, focusing on both parents. This study noted a positive attitude toward expanded NBS for treatable inborn metabolic diseases, incurable disorders, and adult-onset diseases. However, modernized NBS should be holistically evaluated by multiple stakeholders in each country because of different socio-cultural and economic contexts.Item Metadata only Pharmacogenomic landscape of the Thai population from genome sequencing of 949 individuals(2024-12-01) Piriyapongsa J.; Chumnumwat S.; Kaewprommal P.; Triparn K.; Suvichapanich S.; Udomsinprasert W.; Jittikoon J.; Shaw P.J.; Nakhonsri V.; Ngamphiw C.; Wangkumhang P.; Pithukpakorn M.; Roothumnong E.; Wiboonthanasarn S.; Kuptanon C.; Jinawath N.; Porntaveetus T.; Suriyaphol P.; Viprakasit V.; Pisitkun P.; Kantaputra P.; Tim-Aroon T.; Wattanasirichaigoon D.; Sura T.; Suphapeetiporn K.; Sripichai O.; Khongphatthanayothin A.; Fucharoen S.; Ngamphaiboon N.; Shotelersuk V.; Mahasirimongkol S.; Tongsima S.; Piriyapongsa J.; Mahidol UniversityInter-individual variability in drug responses is significantly influenced by genetic factors, underscoring the importance of population-specific pharmacogenomic studies to optimize clinical outcomes. In this study, we analyzed whole genome sequencing data from 949 unrelated Thai individuals and conducted an in-depth analysis of 3239 genes involved in drug pharmacokinetics, pharmacodynamics, or immune-mediated adverse drug reactions. We identified 43 single nucleotide polymorphisms (SNPs), 134 diplotypes, and 15 human leukocyte antigen (HLA) alleles, all with moderate to high clinical significance. On average, each Thai individual carried 14 SNPs, one to two HLA alleles, and six diplotypes with actionable phenotypic associations. Clinically important diplotypes were present in over 20% of individuals for seven genes (CYP2A6, CYP2B6, CYP2C19, CYP3A5, NAT2, SLCO1B1, and VKORC1). In addition, clinically significant SNPs with allele frequencies exceeding 20% were identified among 15 genes, including VKORC1, CYP4F2, and ABCG2. We also identified 21,211 potentially deleterious variants among 3239 genes. Of these variants, 3746 were novel. The comprehensive dataset from this study serves as a valuable resource of pharmacogenomic variants in the Thai population, which will facilitate the development of personalized drug therapies and enhance patient care in Thailand.Item Metadata only Phenotypic and molecular features of Thai patients with primary carnitine deficiency(2023-01-01) Liammongkolkul S.; Boonyawat B.; Vijarnsorn C.; Tim-Aroon T.; Wasant P.; Vatanavicharn N.; Mahidol UniversityBACKGROUND: Primary carnitine deficiency (PCD) is screened by expanded newborn screening (NBS) using tandem mass spectrometry (MS/MS) that can detect both affected neonates and mothers. This study aimed to delineate the clinical, biochemical, and molecular findings of Thai PCD patients. METHODS: Expanded NBS using MS/MS was implemented in Bangkok and 146,757 neonates were screened between 2014 and 2018. PCD was screened by low free carnitine (C0) levels in dried blood spots. Plasma C0 levels and C0 clearance values were measured in neonates and their mothers with positive screening results. Clinically diagnosed cases were described. The coding regions and intron-exon boundaries of the SLC22A5 gene were sequenced in all cases with low plasma C0 levels. RESULTS: There were 14 cases with confirmed PCD: two clinically diagnosed cases, and 12 cases identified through NBS including five newborns, six mothers, and one older sibling. Thus, the incidence of PCD in neonates was 1:29,351. All affected neonates and mothers were asymptomatic except one mother with dilated cardiomyopathy. SLC22A5 gene sequencing identified biallelic causative variants in all cases, comprising 10 different variants of which four were novel. c.51C > G (p.Phe17Leu) and c.760C > T (p.Arg254Ter) were the most prevalent variants in this study. Cases with significant clinical features tended to have higher C0 clearance values. CONCLUSIONS: Primary carnitine deficiency is a common inherited metabolic disorder (IMD) in Thailand. Our findings broaden the spectrum of SLC22A5 variants. The future national NBS program will shed more light on PCD and other IMDs in Thailand.