Kanya Suphapeetiporn

Blau syndrome is a rare granulomatous autoinflammatory disease typically characterized by a triad of polyarthritis, uveitis, and dermatitis. It is caused by either an inherited autosomal dominant pathogenic variant or a de novo pathogenic variant in NOD2. In this report, we present an 11-month-old boy with Blau syndrome who initially presented with calcitriol-mediated hypercalcemia. Severe hypercalcemia was controlled with intravenous fluids, diuretics, calcitonin, and a short course of corticosteroids. Following resolution of the hypercalcemic episode, the patient gradually developed the full clinical spectrum of Blau syndrome, including the classic triad, along with hepatosplenomegaly, lymphadenopathy, and bone marrow involvement. Trio genome sequencing identified a de novo heterozygous pathogenic variant in NOD2. Following the genetic diagnosis, corticosteroids and methotrexate were initiated to control the disease. This is the first reported case of Blau syndrome presenting with hypercalcemia as an initial manifestation, preceding the development of the classic triad. This case underscores the importance of considering Blau syndrome in the differential diagnosis of early-onset hypercalcemia of unknown etiology. Molecular genetic testing should be pursued in such cases to facilitate an accurate and timely diagnosis and appropriate management.

Purpose: 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.

Background 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.

Purpose: To describe the demographic profile, clinical characteristics, and treatment trends of Fuchs endothelial corneal dystrophy (FECD) in Thai patients, reflecting the evolving landscape of corneal transplantation in this region. Patients and Methods: This retrospective cohort study included 900 patients (1,743 eyes) diagnosed with FECD at a tertiary referral center in Thailand between January 2017 and June 2023. Demographic, clinical, and surgical data were analyzed, focusing on best-corrected visual acuity (BCVA), central corneal thickness (CCT), endothelial cell density (ECD), surgical interventions, and graft survival rate. Results: The mean age was 63.9 years, with 77.2% of patients being female. Most eyes were classified as Adamis grade I (83.7%). Diabetes mellitus and hypertension were prevalent in 17.4% and 38.6% of patients, respectively. The rate of corneal transplantation was 8.1%, with DMEK accounting for 69.3% of transplants. Graft survival rates were 94.3% at 1 year and 76.2% at 5 years. The average post-operative ECD declined from 1667.8 ± 668.0 cells/mm² at 1 year to 1140.7 ± 684.4 cells/mm² at 5 years. Cataract surgery was performed in 20.4% of phakic eyes, with only 2.2% requiring corneal transplantation within five years. Conclusion: FECD in Thailand, as reflected by this large cohort, predominantly presents at an early stage, allowing for conservative management. The growing use of DMEK highlights the shift towards less invasive procedures, mirroring global trends in Southeast Asia. These findings emphasize the importance of advancing surgical techniques and improving eye banking practices in the region.

Wiskott–Aldrich syndrome (WAS) is a severe X-linked disorder caused by loss-of-function mutations in the WAS gene, responsible for encoding WAS protein (WASP), a key regulator of the actin cytoskeleton in all hematopoietic cells, except red blood cells. The mechanism underlying microthrombocytopenia, a distinctive feature of WAS and a major contributor to mortality, remains not fully elucidated. In this study, using different gene-editing strategies, we corrected mutations in patient-derived WAS-induced pluripotent stem cell (iPSC) lines, generating isogeneic WAS-iPSC lines. These included lines with direct mutation-specific correction and lines incorporating a WASP transgene cassette regulated by the MND or WAS1.6 kb promoter integrated at the safe harbor AAV1 site. Our results demonstrated that direct mutation correction successfully restored WASP levels to the equivalent of the wild-type in iPSC-derived megakaryocytes (MKs). In contrast, the AAV1-targeted strategy using the MND and WAS1.6 promoters yielded a lower level of WASP. Notably, only the mutation-specific correction lines exhibited improvements in proplatelet structures and generated larger-sized platelets. Our findings underscore the crucial roles of WASP during human thrombopoiesis and suggest that therapeutic approaches, such as direct gene correction, which can achieve physiologic levels of WASP in MKs, hold promise for ameliorating platelet defects in individuals with WAS.

Plectin is a cytoskeletal linker of intermediate filaments, encoded by the PLEC gene. Recently, plectin mutations have been identified in a pair of siblings with progressive familial intrahepatic cholestasis. Here, we reported two unrelated infants with plectinopathy causing cholestatic jaundice with novel variants in the PLEC gene. Trio exome sequencing identified compound heterozygous variants in the PLEC gene for each patient: c.71‐11768C>T and c.4331G>T (p.Arg1444Leu) in Patient 1, and c.592C>T (p.Arg198Trp) and c.4322G>A (p.Arg1441His) in Patient 2. Immunofluorescence staining of liver samples from both patients revealed scattered signals of plectin in the cytoplasm of hepatocytes and reduced colocalization of plectin and cytokeratin 8. This study not only underscores the involvement of plectin in cholestasis but also highlights the utility of exome sequencing as a powerful diagnostic tool in identifying genetic underpinnings of infantile cholestasis.

Background: The prognosis for relapsed or refractory childhood cancer is approximately 20%. Genetic alterations are one of the significant contributing factors to the prognosis of patients. Objective: To investigate the molecular profile of relapsed or refractory childhood cancers in Thai cases. Methods: The study design is a descriptive study of patients NCOR2 , COL6A3 , TP53 , and SMAD4 genes. These alterations were found to be associated with tumor aggressiveness. Conclusion: This study is the first one to demonstrate genetic alterations by using WES in relapsed or refractory childhood cancer in Thai cases.

Aims: Analysis of the F8 gene helps predict the risk of developing factor VIII (FVIII) inhibitors and the depth of phenotype in haemophilia A (HA) patients. Since data in Southeast Asian countries remain scarce, we aim to study F8 variation correlated with HA phenotypes in Thailand. Methods: Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022–2023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for F8 -intron 22 inversion (Inv22) and F8 -intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22/Inv1. Results: Of 124 patients with HA, 91.9% were detected with a causative F8 variant, including Inv22 (30.6%), Inv1 (1.6%), missense (23.4%), nonsense (16.9%) and small insertion/deletion (16.1%) mutations. Inv22, small insertion/deletion and nonsense were associated with severe HA, compared with missense variants, by the ORs of 13.9 (95% CI, 4.2 to 56.7), 14.7 (95% CI, 3.4 to 104.7) and 15.6 (95% CI, 3.6 to 110.2), respectively. While nonsense variants affecting the light chain increased the risk of developing FVIII inhibitors (OR, 6.8; 95% CI, 1.5 to 32.6) compared with the low-risk (small insertion/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel F8 variants, comprising five missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), five small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA) and one nonsense mutations (p.Glu1292Ter). Conclusions: IS-PCR followed by WES successfully assesses F8 alterations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion and nonsense, whereas missense variants are more responsible for nonsevere HA phenotypes.

Aims: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES). Methods: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing. Results: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively. Conclusions: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.

The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.