18 results on '"Boonsimma P"'
Search Results
2. Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum
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Summa, Sarinya, Ittiwut, Chupong, Kulsirichawaroj, Pimchanok, Paprad, Tanitnun, Likasitwattanakul, Surachai, Sanmaneechai, Oranee, Boonsimma, Ponghatai, Suphapeetiporn, Kanya, and Shotelersuk, Vorasuk
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- 2023
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3. Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact
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Boonsimma, Ponghatai, Ittiwut, Chupong, Kamolvisit, Wuttichart, Ittiwut, Rungnapa, Chetruengchai, Wanna, Phokaew, Chureerat, Srichonthong, Chalurmpon, Poonmaksatit, Sathida, Desudchit, Tayard, Suphapeetiporn, Kanya, and Shotelersuk, Vorasuk
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- 2023
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4. Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants
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Suphalak Chokvithaya, Natarin Caengprasath, Aayalida Buasong, Supavadee Jantasuwan, Kanokwan Santawong, Netchanok Leela-adisorn, Siraprapa Tongkobpetch, Chupong Ittiwut, Vitchayaporn Emarach Saengow, Wuttichart Kamolvisit, Ponghatai Boonsimma, Saknan Bongsebandhu-phubhakdi, and Vorasuk Shotelersuk
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Medicine ,Science - Abstract
Abstract Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype–phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.
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- 2023
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5. Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum
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Sarinya Summa, Chupong Ittiwut, Pimchanok Kulsirichawaroj, Tanitnun Paprad, Surachai Likasitwattanakul, Oranee Sanmaneechai, Ponghatai Boonsimma, Kanya Suphapeetiporn, and Vorasuk Shotelersuk
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Medicine ,Science - Abstract
Abstract Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, single gene testing, and gene panels. The remaining 43 patients from 42 families could be classified into three groups: Group 1, MLPA-negative Duchenne muscular dystrophy (DMD) with 9 patients (9/43; 21%), Group 2, other muscular dystrophies (MD) with 18 patients (18/43; 42%) and Group 3, congenital myopathies (CM) with 16 patients (16/43; 37%). All underwent exome sequencing which could identify pathogenic variants in 8/9 (89%), 14/18 (78%), and 8/16 (50%), for each Group, respectively. Overall, the diagnostic yield of ES was 70% (30/43) and 36 pathogenic/likely pathogenic variants in 14 genes were identified. 18 variants have never been previously reported. Molecular diagnoses provided by ES changed management in 22/30 (73%) of the patients. Our study demonstrates the clinical utility and implications of ES in inherited myopathies.
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- 2023
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6. Using an experiment among clinical experts to determine the cost and clinical impact of rapid whole exome sequencing in acute pediatric settings
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Nattiya Kapol, Wuttichart Kamolvisit, Lalida Kongkiattikul, Evan Huang-Ku, Namfon Sribundit, Surasit Lochid-Amnuay, Nathapol Samprasit, Thamonwan Dulsamphan, Parntip Juntama, Chotika Suwanpanich, Ponghathai Boonsimma, Vorasuk Shotelersuk, and Yot Teerawattananon
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rapid whole-exome sequencing ,cost-effectiveness ,next-generation sequencing ,low- and middle-income countries ,acute pediatrics ,Pediatrics ,RJ1-570 - Abstract
ObjectiveEvaluate the cost and clinical impacts of rapid whole-exome sequencing (rWES) for managing pediatric patients with unknown etiologies of critical illnesses through an expert elicitation experiment.MethodPhysicians in the intervention group (n = 10) could order rWES to complete three real-world case studies, while physicians in the control group (n = 8) could not. Costs and health outcomes between and within groups were compared.ResultsThe cost incurred in the intervention group was consistently higher than the control by 60,000–70,000 THB. Fewer other investigation costs were incurred when rWES could provide a diagnosis. Less cost was incurred when an rWES that could lead to a change in management was ordered earlier. Diagnostic accuracy and the quality of non-pharmaceutical interventions were superior when rWES was available.ConclusionIn acute pediatric settings, rWES offered clinical benefits at the average cost of 60,000–70,000 THB. Whether this test is cost-effective warrants further investigations. Several challenges, including cost and ethical concerns for assessing high-cost technology for rare diseases in resource-limited settings, were potentially overcome by our study design using expert elicitation methods.
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- 2023
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7. ATP1A3-related epilepsy: Report of seven cases and literature-based analysis of treatment response.
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Gasser, Marius, Boonsimma, Ponghatai, Netbaramee, Wiracha, Wechapinan, Thanin, Srichomthomg, Chalurmpon, Ittiwut, Chupong, Krenn, Martin, Zimprich, Fritz, Milenkovic, Ivan, Abicht, Angela, Biskup, Saskia, Roser, Timo, Shotelersuk, Vorasuk, Tacke, Moritz, Kuersten, Marianne, Wagner, Matias, Borggraefe, Ingo, Suphapeetiporn, Kanya, and von Stülpnagel, Celina
- Abstract
• ATP1A3 gene is related to difficult-to-treat epilepsy. • Information on anti-epileptic drug (AED) treatment is rare. • Most used AEDs: levetiracetam, phenobarbital, valproic acid and topiramate. • No most effective AED; and 45% of patients did not show any seizure relief. • Median onset of symptoms was 2 months of age. ATP1A3 related disease is a clinically heterogeneous condition currently classified as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Recently, it has become apparent that a remarkably large subgroup is suffering from often difficult-to-treat epilepsy. The aim of the present study was to assess the prevalence and efficacy of commonly used anti-epileptic-drugs (AEDs) in patients with ATP1A3 r elated seizures. Therefore, we performed a retrospective study of patients in combination with a systematic literature-based review. Inclusion criteria were: verified ATP1A3 mutation, seizures and information about AED treatment. The literature review yielded records for 188 epileptic ATP1A3 patients. For 14/188 cases, information about anti-epileptic treatment was available. Combined with seven unpublished records of ATP1A 3 patients, a sample size of 21 patients was reached. Most used AED were levetiracetam (n = 9), phenobarbital (n = 8), valproic acid (n = 7), and topiramate (n = 5). Seizure reduction was reported for 57% of patients (n = 12). No individual AEDs used (either alone or combined) had a success rate over 50%. There was no significant difference in the response rate between various AEDs. Ketogenic diet was effective in 2/4 patients. 43% of patients (n = 9) did not show any seizure relief. Even though Epilepsy is a significant clinical issue in ATP1A3 patients, only a minority of publications provide any information about patients' anti-epileptic treatment. The findings of treatment effectiveness in only 57% (or lower) of patients, and the non-existence of a clear first-line AED in ATP1A3 related epilepsy stresses the need for further research. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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8. Detection and characterisation of a sixth Candida auris clade in Singapore: a genomic and phenotypic study.
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Suphavilai C, Ko KKK, Lim KM, Tan MG, Boonsimma P, Chu JJK, Goh SS, Rajandran P, Lee LC, Tan KY, Shaik Ismail BB, Aung MK, Yang Y, Sim JXY, Venkatachalam I, Cherng BPZ, Spruijtenburg B, Chan KS, Oon LLE, Tan AL, Tan YE, Wijaya L, Tan BH, Ling ML, Koh TH, Meis JF, Tsui CKM, and Nagarajan N
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- Singapore epidemiology, Humans, Phenotype, Candidiasis microbiology, Candidiasis epidemiology, Candidiasis drug therapy, Polymorphism, Single Nucleotide genetics, Phylogeny, Genomics methods, Genotype, Drug Resistance, Fungal genetics, Candida genetics, Candida drug effects, Candida isolation & purification, Antifungal Agents pharmacology, Whole Genome Sequencing, Candida auris genetics, Candida auris drug effects, Microbial Sensitivity Tests, Genome, Fungal genetics
- Abstract
Background: The emerging fungal pathogen Candida auris poses a serious threat to global public health due to its worldwide distribution, multidrug resistance, high transmissibility, propensity to cause outbreaks, and high mortality. We aimed to characterise three unusual C auris isolates detected in Singapore, and to determine whether they constitute a novel clade distinct from all previously known C auris clades (I-V)., Methods: In this genotypic and phenotypic study, we characterised three C auris clinical isolates, which were cultured from epidemiologically unlinked inpatients at a large tertiary hospital in Singapore. The index isolate was detected in April, 2023. We performed whole-genome sequencing (WGS) and obtained hybrid assemblies of these C auris isolates. The complete genomes were compared with representative genomes of all known C auris clades. To provide a global context, 3651 international WGS data from the National Center for Biotechnology Information (NCBI) database were included in a high-resolution single nucleotide polymorphism (SNP) analysis. Antifungal susceptibility testing was done and antifungal resistance genes, mating-type locus, and chromosomal rearrangements were characterised from the WGS data of the three investigated isolates. We further implemented Bayesian logistic regression models to classify isolates into known clades and simulate the automatic detection of isolates belonging to novel clades as their WGS data became available., Findings: The three investigated isolates were separated by at least 37 000 SNPs (range 37 000-236 900) from all existing C auris clades. These isolates had opposite mating-type allele and different chromosomal rearrangements when compared with their closest clade IV relatives. The isolates were susceptible to all tested antifungals. Therefore, we propose that these isolates represent a new clade of C auris, clade VI. Furthermore, an independent WGS dataset from Bangladesh, accessed via the NCBI Sequence Read Archive, was found to belong to this new clade. As a proof-of-concept, our Bayesian logistic regression model was able to flag these outlier genomes as a potential new clade., Interpretation: The discovery of a new C auris clade in Singapore and Bangladesh in the Indomalayan zone, showing a close relationship to clade IV members most commonly found in South America, highlights the unknown genetic diversity and origin of C auris, particularly in under-resourced regions. Active surveillance in clinical settings, along with effective sequencing strategies and downstream analysis, will be essential in the identification of novel strains, tracking of transmission, and containment of adverse clinical effects of C auris infections., Funding: Duke-NUS Academic Medical Center Nurturing Clinician Researcher Scheme, and the Genedant-GIS Innovation Program., Competing Interests: Declaration of interests BHT declares that he serves on the advisory boards for Pfizer (for respiratory syncytial virus vaccine) and MSD (for letermovir). ALT declares that she serves on the Chapter of Pathologists, Singapore. She also received an honorarium (to her institution) for a lecture delivered to the Singapore Association of Pharmaceutical Industries. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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9. Can knowledgeable experts assess costs and outcomes as if they were ignorant? An experiment within precision medicine evaluation.
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Dulsamphan T, Juntama P, Suwanpanich C, Isaranuwatchai W, Silzle M, Poonmaksatit S, Boonsimma P, Shotelersuk V, Visudtibhan A, Lusawat A, Kamolvisit W, Kapol N, Lochid-Amnuay S, Sribundit N, Samprasit N, Morton A, and Teerawattananon Y
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- Humans, Child, Thailand, Precision Medicine, Judgment
- Abstract
Objectives: The purpose of this study is to evaluate the validity of the standard approach in expert judgment for evaluating precision medicines, in which experts are required to estimate outcomes as if they did not have access to diagnostic information, whereas in fact, they do., Methods: Fourteen clinicians participated in an expert judgment task to estimate the cost and medical outcomes of the use of exome sequencing in pediatric patients with intractable epilepsy in Thailand. Experts were randomly assigned to either an "unblind" or "blind" group; the former was provided with the exome sequencing results for each patient case prior to the judgment task, whereas the latter was not provided with the exome sequencing results. Both groups were asked to estimate the outcomes for the counterfactual scenario, in which patients had not been tested by exome sequencing., Results: Our study did not show significant results, possibly due to the small sample size of both participants and case studies., Conclusions: A comparison of the unblind and blind approach did not show conclusive evidence that there is a difference in outcomes. However, until further evidence suggests otherwise, we recommend the blind approach as preferable when using expert judgment to evaluate precision medicines because this approach is more representative of the counterfactual scenario than the unblind approach.
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- 2023
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10. Using an experiment among clinical experts to determine the cost and clinical impact of rapid whole exome sequencing in acute pediatric settings.
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Kapol N, Kamolvisit W, Kongkiattikul L, Huang-Ku E, Sribundit N, Lochid-Amnuay S, Samprasit N, Dulsamphan T, Juntama P, Suwanpanich C, Boonsimma P, Shotelersuk V, and Teerawattananon Y
- Abstract
Objective: Evaluate the cost and clinical impacts of rapid whole-exome sequencing (rWES) for managing pediatric patients with unknown etiologies of critical illnesses through an expert elicitation experiment., Method: Physicians in the intervention group ( n = 10) could order rWES to complete three real-world case studies, while physicians in the control group ( n = 8) could not. Costs and health outcomes between and within groups were compared., Results: The cost incurred in the intervention group was consistently higher than the control by 60,000-70,000 THB. Fewer other investigation costs were incurred when rWES could provide a diagnosis. Less cost was incurred when an rWES that could lead to a change in management was ordered earlier. Diagnostic accuracy and the quality of non-pharmaceutical interventions were superior when rWES was available., Conclusion: In acute pediatric settings, rWES offered clinical benefits at the average cost of 60,000-70,000 THB. Whether this test is cost-effective warrants further investigations. Several challenges, including cost and ethical concerns for assessing high-cost technology for rare diseases in resource-limited settings, were potentially overcome by our study design using expert elicitation methods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kapol, Kamolvisit, Kongkiattikul, Huang-Ku, Sribundit, Lochid-amnuay, Samprasit, Dulsamphan, Juntama, Suwanpanich, Boonsimma, Shotelersuk and Teerawattananon.)
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- 2023
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11. Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand.
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Kulsirichawaroj P, Likasitwattanakul S, Boonsimma P, Prangphan K, and Chanvanichtrakool M
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- Child, Homozygote, Humans, Membrane Proteins genetics, Mutation, Phenotype, Thailand, Neuronal Ceroid-Lipofuscinoses diagnosis, Neuronal Ceroid-Lipofuscinoses genetics, Rett Syndrome
- Abstract
Background: Neuronal ceroid lipofuscinoses (NCLs) (hereafter described as CLN disease) comprise a rare and life-limiting set of genetically inherited neurodegenerative disorders that are characterized by abnormal lysosomal storage. The NCL disorders are, collectively, the most common group of degenerative brain disorders in children., Patient Descriptions: We report two cases of CLN disease that were diagnosed and treated at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Both cases of CLN disease (CLN1 and CLN6 diagnosed in 2016 and 2017, respectively) profiled in this report presented with clinical features of Rett syndrome. In the first case, a 2-year-old girl presented with Rett-like clinical features, including global developmental regression and hand-wringing action. Single-gene analysis of the MECP2 gene was negative. However, PPT1 gene sequencing revealed a novel homozygous frameshift mutation, c.629_630dupGT (p.Ile211Valfs∗10). In the second case, a 7.5-year-old girl presented with ataxia, progressive myoclonic epilepsy, and Rett-like hand-wringing. A c.794_796delCCT variant in the CLN6 gene was identified by whole-exome sequencing. Fingerprint bodies from electron microscopy of the skin also supported a diagnosis of CLN disease in our second case., Discussion: Presentation with clinical features of Rett syndrome has only been reported in patients diagnosed with CLN1 and CLN7 disease, and never in those with CLN6., Conclusions: Physicians should suspect and investigate for CLN disease in patients with Rett-like phenotype who are negative for MECP2 mutation, especially in patients with visual impairment and early prominent brain atrophy., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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12. Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10.
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Manaspon C, Boonsimma P, Phokaew C, Theerapanon T, Sriwattanapong K, Porntaveetus T, and Shotelersuk V
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- Adolescent, Alleles, Amino Acid Transport Systems, Acidic genetics, Antiporters genetics, Child, Child, Preschool, Developmental Disabilities complications, Developmental Disabilities pathology, Female, Genotype, Haplotypes genetics, Hereditary Central Nervous System Demyelinating Diseases complications, Hereditary Central Nervous System Demyelinating Diseases pathology, Homozygote, Humans, Male, Microcephaly complications, Microcephaly pathology, Mitochondrial Diseases complications, Mitochondrial Diseases pathology, Movement Disorders complications, Movement Disorders pathology, Mutation, Pedigree, Phenotype, Psychomotor Disorders complications, Psychomotor Disorders pathology, Young Adult, Amino Acid Transport Systems, Acidic deficiency, Antiporters deficiency, Developmental Disabilities genetics, Hereditary Central Nervous System Demyelinating Diseases genetics, Microcephaly genetics, Mitochondrial Diseases genetics, Movement Disorders genetics, Psychomotor Disorders genetics, Pyrroline Carboxylate Reductases genetics
- Abstract
PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three out of four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay. Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients., (© 2021 Wiley Periodicals LLC.)
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- 2021
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13. Rapid exome sequencing as the first-tier investigation for diagnosis of acutely and severely ill children and adults in Thailand.
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Kamolvisit W, Phowthongkum P, Boonsimma P, Kuptanon C, Rojnueangnit K, Wattanasirichaigoon D, Chanvanichtrakool M, Phuaksaman C, Wiromrat P, Srichomthong C, Ittiwut C, Phokaew C, Ittiwut R, Assawapitaksakul A, Chetruengchai W, Buasong A, Suphapeetiporn K, and Shotelersuk V
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- Adolescent, Adult, Child, Child, Preschool, Critical Illness, Female, Genetic Testing methods, Humans, Infant, Infant, Newborn, Male, Middle Aged, Thailand, Exome Sequencing methods, Young Adult, Exome genetics, Pathology, Molecular methods
- Abstract
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., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
- Published
- 2021
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14. Novel de novo mutation substantiates ATP6V0C as a gene causing epilepsy with intellectual disability.
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Ittiwut C, Poonmaksatit S, Boonsimma P, Desudchit T, Suphapeetiporn K, Ittiwut R, and Shotelersuk V
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- Female, Humans, Mutation, Epilepsy genetics, Intellectual Disability genetics, Vacuolar Proton-Translocating ATPases genetics
- Abstract
Background: In approximately half of patients with epilepsy and intellectual disability (ID), the cause is unidentified and could be a mutation in a new disease gene., Patient Description: To determine the discovery of disease-causing mutation in a female patient with epilepsy and ID, we performed trio whole-exome sequencing, reverse transcription polymerase chain reaction (RT-PCR) followed by Sanger sequencing., Results: Trio whole-exome sequencing was performed and revealed a novel de novo heterozygous stop-loss c.467A > T (p.*156Leuext*35) mutation in the ATP6V0C gene. Using RNA from leukocytes, RT-PCR followed by Sanger sequencing showed the existence of the mutant RNA, and real-time PCR demonstrated that the patient's ATP6V0C RNA level was approximately half of that in her parents, suggesting haploinsufficiency as a pathomechanism., Conclusion: These findings, along with previous reports of individuals with similar phenotypes and variants in the same gene, substantiate ATP6V0C as a gene causing epilepsy with ID., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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15. A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.
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Boonsimma P, Crosby K, Mohan P, Puscasiu E, and Tanpaiboon P
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- Autism Spectrum Disorder pathology, Child, Developmental Disabilities pathology, Fatty Liver pathology, Homozygote, Humans, Male, Mutation, Missense, Phenotype, Autism Spectrum Disorder genetics, Carnitine O-Palmitoyltransferase genetics, Developmental Disabilities genetics, Fatty Liver genetics
- Abstract
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare disorder of hepatic long-chain fatty acid oxidation. Most patients with CPT1A deficiency present with hypoketotic hypoglycemia and hepatic encephalopathy. We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis. He also had a history of developmental delay, autism spectrum disorder, and mild dysmorphic features of unknown cause. His newborn screening test suggested CPT1A deficiency, but confirmatory biochemical testing was not conclusive. The patient never experienced a metabolic crisis. At age six, hepatomegaly was detected. Further investigations showed transaminitis, hepatosteatosis and cirrhosis. Repeat acylcarnitine profile and total/free carnitine were consistent with CPT1A deficiency. The CPTI enzyme activity was 18% of normal on fibroblast enzyme assay. A novel homozygous variant in the CPT1A gene, c.1394G > A (p.Gly465Glu) was identified from whole-exome sequencing. To our knowledge, the patient is the first reported individual with CPT1A deficiency and chronic liver steatosis and fibrosis. Developmental delay and autistic spectrum disorder are not typical features of CPT1A deficiency, given that the patient never experienced any metabolic decompensation., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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16. Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations.
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Pattrakornkul N, Ittiwut C, Boonsimma P, Boonyapisit K, Khongkhatithum C, Sanmaneechai O, Suphapeetiporn K, and Shotelersuk V
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- Acetylcholinesterase genetics, Adolescent, Adult, Child, Child, Preschool, Collagen genetics, Cross-Sectional Studies, Electromyography, Fatty Acid Desaturases genetics, Humans, Male, Middle Aged, Muscle Proteins genetics, Pedigree, Receptors, Cholinergic genetics, Thailand, Exome Sequencing, Young Adult, Myasthenic Syndromes, Congenital diagnosis, Myasthenic Syndromes, Congenital genetics, Myasthenic Syndromes, Congenital physiopathology
- Abstract
Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718-1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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17. A case of GABRA5-related developmental and epileptic encephalopathy with response to a combination of antiepileptic drugs and a GABAering agent.
- Author
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Boonsimma P, Suwannachote S, Phokaew C, Ittiwut C, Suphapeetiporn K, and Shotelersuk V
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- Child, Preschool, Drug Therapy, Combination, Epilepsy genetics, Female, Humans, Magnetic Resonance Imaging, Microcephaly genetics, Microcephaly pathology, Mutation, Missense, White Matter diagnostic imaging, Whole Genome Sequencing, Anticonvulsants pharmacology, Developmental Disabilities genetics, Developmental Disabilities pathology, Developmental Disabilities physiopathology, Epilepsy drug therapy, GABA Agents pharmacology, Receptors, GABA-A genetics, White Matter pathology
- Abstract
Background: GABA
A receptors are ligand-gated chloride channels that regulate inhibitory neurotransmission in the central nervous system. Recently, monoallelic de novo mutations in GABRA5 resulting in altered inhibitory synapses were found in three patients with developmental and epileptic encephalopathy. Patient description: We report on a four-year and six-month-old girl with epilepsy and global developmental delay. Serial head growth measurement revealed postnatal onset microcephaly., Results: Magnetic resonance imaging (MRI) of the brain was normal at the age of eight months and subsequently showed a decrease in white matter volume and thin corpus callosum at the age of 3 years. Using whole-genome sequencing, we identified the fourth patient harboring a de novo missense mutation in GABRA5. Interestingly, the c.880G > C (p.V294F) affects the same position found in two of the three previously reported patients., Conclusion: This study suggests that the nucleotide c.880G is a mutation hotspot. Our patient also demonstrated significant seizure reduction after benzodiazepine. To our knowledge, this is the first case describing the favorable outcome of a GABAergic agent in seizure control for GABRA5-related developmental and epileptic encephalopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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18. Mutational and phenotypic expansion of ATP1A3-related disorders: Report of nine cases.
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Boonsimma P, Michael Gasser M, Netbaramee W, Wechapinan T, Srichomthong C, Ittiwut C, Wagner M, Krenn M, Zimprich F, Abicht A, Biskup S, Roser T, Borggraefe I, Suphapeetiporn K, and Shotelersuk V
- Subjects
- Adolescent, Child, Dystonic Disorders diagnosis, Dystonic Disorders genetics, Electroencephalography, Female, Hemiplegia diagnosis, Hemiplegia genetics, Humans, Male, Nervous System Diseases diagnosis, Nervous System Diseases diagnostic imaging, Neuroimaging, Young Adult, Mutation, Nervous System Diseases genetics, Phenotype, Sodium-Potassium-Exchanging ATPase genetics
- Abstract
Background: Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3-related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene., Method: The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed., Results: Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively., Conclusion: The present case series expands the clinical and genetic spectrum of ATP1A3-related disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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