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BACKGROUND: Inherited peripheral neuropathy presents a diagnostic and therapeutic challenge due to its association with mutations in over 100 genes. This condition leads to long-term disability and poses a substantial healthcare burden on society. OBJECTIVE: This study aimed to investigate the distribution of genes and establish the genotype-phenotype correlations, focusing on pediatric-onset cases. METHODS: Exome sequencing and other analytical techniques were employed to identify pathogenic variants, including duplication analysis of the PMP22 gene. Each patient underwent physical examination and electrophysiological studies. Genotypes were correlated with phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. RESULTS: We identified 35 patients with pediatric-onset inherited peripheral neuropathy. Pathogenic or likely pathogenic variants were confirmed in 24 out of 35 (68.6%) patients, with 4 of these variants being novel. A confirmed molecular diagnosis was achieved in 90.9% (10/11) of patients with demyelinating Charcot-Marie-Tooth disease (CMT) and 56.3% (9/16) of patients with axonal CMT. Among patients with infantile-onset CMT (≤2 years), the most common causative genes were MFN2 and NEFL, while GDAP1 and MFN2 were frequent causes among patients with childhood- or adolescent-onset CMT (3-9 years). CONCLUSIONS: The MFN2 gene was the most commonly implicated gene, and the axonal type was predominant in this cohort of Thai patients with pediatric-onset inherited peripheral neuropathy.

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Hepatocellular carcinoma (HCC) is one of the most common cancers and is a leading cause of death. Delivery of therapeutic molecules, e.g., siRNA, to HCC cells could potentially be an alternative treatment for HCC. In this study, the siRNA targeting α-fetoprotein (AFP) mRNA was found to specifically induce apoptosis and significant cell death in HepG2 cells. It also enhanced the cytotoxic effects of doxorubicin by about two-fold, making it the candidate therapeutic molecule for HCC treatment. To deliver the siRNAs into HCC cells, the AFP siRNAs were loaded into the nanoparticles based on poly (lactic-co-glycolic) acid (PLGA). These nanoparticles induced apoptosis in HepG2 cells and synergistically increased the cytotoxicity of doxorubicin. In summary, the delivery of the AFP siRNA-loaded PLGA nanoparticles in combination with doxorubicin could be a very promising approach for the treatment of HCC.

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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 ±â€¯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.

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Case series reports on clinical features of pediatric hereditary neuropathy in Thailand is scarce. Subtype and clinical presentation in childhood-onset CMT differ from adult-onset. The aim of this study is to investigate the CMT phenotype in Thai children. We retrospectively reviewed children diagnosed with CMT who followed up with Pediatric Neurology, Siriraj Hospital from January 1999 to June 2016. CMT subtypes determined by clinical presentation and neurophysiologic studies. Mutation analysis of PMP22 genes was performed in all demyelinating cases. The disease burden was assessed by CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score (CMTES) and CMT Pediatric Scale (CMTPedS). 30 patients from 29 families with Hereditary Neuropathies, 25 diagnosed with CMT and 5 with HSAN. 8-year-old was the average age at first medical visit with disease-related problems. Twenty (67%) were male. Twenty-three were sporadic (77%). 16.7% was autosomal dominant and 6.7% was autosomal recessive. Clinical presentations in CMT children were walking difficulty and foot deformities. Nine (36%) CMT patients had demyelinating and sixteen (64%) had axonal. Forty percent had a history of delayed walking after 15-month-old. Foot deformities presented in all CMT patients, and twelve had foot surgery. 2 axonal CMT patients were wheelchair-dependence. Mean (SD) CMTNSv2, CMTES and CMTPedS were 15.44(9), 11.05(7) and 34(4) respectively. Our findings suggest Thai CMT children are predominantly axonal type. Patients with low socioeconomic status and mild symptoms may not seek healthcare. International collaboration in genetic testing is crucial in diagnosis and initiation of clinical trials in future.

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Dysferlinopathy refers to a variety of autosomal recessive, skeletal muscle disorders due to the mutations of dysferlin-encoding gene, DYSF. It encompasses limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), distal myopathy with anterior tibial onset (DMAT), isolated hyperCKemia, rigid spine syndrome and congenital muscular dystrophy. Herein, we report five Thai patients with distal myopathy due to dysferlinopathy including four MM and one DMAT patients. Muscle biopsy from one MM patient depicted numerous ring fibers which is an atypical finding in dysferlinopathy. Mutation analysis of DYSF revealed novel compound heterozygous mutations of p.Tyr309X and c.236+1G>T in two related MM patients, known homozygous mutations, p.Arg89X and p.Gln176X, in two MM patients and a heterozygous missense mutation, p.Arg555Trp, in a DMAT patient. Most of the previously reported DMAT patients were Hispanic. To the best of our knowledge, this is the first report of genetically confirmed patients with dysferlinopathy in Thailand.

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Distal myopathy with rimmed vacuoles (DMRV) is an early-adult-onset, distal myopathy caused by a mutation of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE) gene. We herein report four Thai patients with DMRV who carried compound heterozygous mutations of the GNE gene including three novel (p.G89R, p.P511T, and p.I656N) and two known mutations (p.A524V and p.V696M). All patients shared p.V696M in one allele. Our study demonstrates the mutation spectrum of the GNE gene in Thai patients with DMRV.

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AIM: To investigate mutation of serine protease 1-cationic trypsinogen (CT, PRSS1) gene in members of a Thai family with hereditary pancreatitis and pancreatic cancer. METHODS: Polymerase chain reaction and direct sequencing were performed to analyze the PRSS1 gene in two members of the family affected by pancreatitis. Allele specific amplification (ASA) method was then developed to detect the mutation of the PRSS1 gene in all available members of the family and normal control subjects. RESULTS: A cytosine (C) to thymine (T) mutation at position 2441 (g.2441C>T) of the PRSS1 gene, which results in a substitution of arginine by cysteine at position 116 (R116C) of CT, was identified by direct sequencing in both clinically affected members of the family but was not found in the unaffected member. This mutation, which might be arising from deamination of methylated cytosine in CpG dinucleotide of codon 116 (CGT>TGT), was also detected by the ASA method in the two affected members and a proband's brother but was not observed in unaffected members and 54 normal control subjects. CONCLUSION: Autosomal dominant pancreatitis with increased cancer risk in the studied Thai family is most likely due to missense (R116C) mutation in the PRSS1 gene.

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A Thai girl with a unique combination of limb and craniofacial anomalies is reported. Manifestations include blepharoptosis; prominent nose; hypodontia; multiple, hyperplastic frenula; and dysplastic ears. Limb anomalies include short stature, postaxial polydactyly of both hands and the left foot, proximal and distal symphalangism of fingers, and congenital absence of the distal phalanges of toes 2-5. Mutation analyses of NOG and GDF5, the genes responsible for symphalangism-related syndromes, were negative.

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