Browsing by Author "Sanmaneechai O."

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    Axonal-demyelinating differences in functional change in pediatric Charcot–Marie–Tooth and related neuropathies
    (2026-12-01) Inmongkol C.; Vorasan N.; Limpaninlachat S.; Sereephaowong N.; Kulsirichawaroj P.; Sanmaneechai O.; Burns J.; Inmongkol C.; Mahidol University
    Background: Charcot–Marie–Tooth disease and related neuropathies (CMTR) are heterogeneous inherited neuropathies with variable progression, yet data on pediatric disease progression by neurophysiological subtype are limited. We evaluated 1-year clinical and functional changes in children with CMTR and compared axonal versus demyelinating trajectories. Methods: We conducted a prospective cohort study of 20 Thai children with CMTR who were aged 3–20 years. Participants were assessed at baseline and after 1 year using the Rasch-modified Charcot–Marie–Tooth Examination Score (CMTES-R), Charcot–Marie–Tooth Pediatric Scale (CMTPedS), manual muscle testing (MMT), Foot Posture Index, and muscle length testing. Within-subject changes in clinical outcomes over time were assessed using appropriate paired statistical tests. Results: Thirteen patients had axonal forms and seven had demyelinating forms; the patients’ mean age was 13.0 ± 4.9 years. The axonal variants involved MFN2 (n = 3), GDAP1 (n = 2), and GAN, GJB1, IGHMBP2, KIF1A, PRDM12 (n = 1 each); 3 axonal variants were genetically undiagnosed. The demyelinating variants comprised MPZ (n = 2), PMP22 duplication (n = 2), EGR2 (n = 1), NEFL (n = 1), and PMP22 deletion (n = 1). At both time points, 85% of the patients were ambulatory, 15% used a wheelchair, and 65% used an ankle-foot orthosis. CMTPedS increased by 1.0 ± 3.4 points over 1 year (p = 0.271), with a larger change in axonal versus demyelinating cases (+ 1.1 ± 3.2 vs. + 0.7 ± 4.0). CMTES-R changed minimally (median + 0.5), and MMT showed stable strength. Conclusion: The clinical progression in pediatric CMTR was heterogeneous and differed by neurophysiological subtype, with more pronounced 1-year functional decline in axonal disease. These findings support vigilant longitudinal monitoring of pediatric CMTR, particularly where genetic testing access is limited.
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    Comparative Costs and Diagnostic Yields of Next-Generation Sequencing Versus Muscle Biopsy for Multiplex Ligation-Dependent Probe Amplification-Negative Duchenne Muscular Dystrophy
    (2026-01-01) Meepolprapai M.; Vorasan N.; Leelahavarong P.; Kulsirichawaroj P.; Sanmaneechai O.; Meepolprapai M.; Mahidol University
    Objectives To compare diagnostic sensitivity, time to diagnosis, and costs of next-generation sequencing (NGS) with biopsy in multiplex-ligation-dependent-probe-amplification-negative Duchenne muscular dystrophy. Methods This retrospective, observational study was conducted at a major tertiary care hospital in Bangkok, Thailand. We reviewed medical records of affected children managed between June 2003 and April 2023. Data collected included the time from first clinical presentation to definitive diagnosis and total hospital charges. Hospital charges were converted to 2024 United States Dollars (USD) an exchange rate of 1 USD = 36.74 Thai Baht (THB) for standardized comparison. Medians for continuous variables were compared using the Mann-Whitney U test. Results Of 52 included patients; 35 underwent biopsy and 17 underwent NGS. Biopsy confirmed Duchenne muscular dystrophy in 32 cases (91.4 %), whereas NGS identified pathogenic variants in all 17 (100 %). The median diagnostic interval was identical (3.0 years; biopsy interquartile range [IQR] 2.0-5.0, NGS IQR 3.0-5.0; P = .593). For investigations from 2013 onward, the median direct cost per patient was higher for biopsy (USD 1031.8; IQR 937.7-1185.6) than for NGS (USD 711.8; IQR 537.8-981.4; P = .0004). Cost per confirmed case likewise favored NGS (USD 952.6 versus USD 756.9). Conclusions NGS delivers superior diagnostic accuracy and was more cost-effective, demonstrating a lower cost per detected case without prolonging the time to diagnosis. Despite limited numbers and the absence of a full economic model, these real-world data suggest that NGS may be a cost-effective diagnostic strategy in this setting and support consideration of reimbursement within Thailand’s healthcare system.
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    Expanding the Genetic Landscape of Congenital Insensitivity to Pain
    (2026-02-01) Pho-iam T.; Kulsirichawaroj P.; Likasitwattanakul S.; Ridchuayrod N.; Sanmaneechai O.; Limwongse C.; Zuchner S.; Pho-iam T.; Mahidol University
    Objectives – Congenital insensitivity to pain (CIP) is a rare sensory neuropathy marked by absent nociception that predisposes patients to injuries and complications. Variants in genes, particularly PRDM12, underlie the condition. We investigated the molecular basis of CIP in 2 unrelated families.Methods – Trio whole-exome sequencing was performed for 3 CIP patients from 2 unrelated families and their parents; 1 family with negative results subsequently underwent whole genome sequencing. Sanger sequencing and fluorescent PCR confirmed and sized a GCC repeat expansion.Results – PRDM12 variants explained CIP in both families, each manifesting infantile-onset neuropathic keratopathy and self-mutilation. In Family 1, 2 siblings born to consanguineous parents were homozygous for a 19-GCC repeat expansion in the last exon, resulting in a polyalanine tract of 20 alanines—the largest PRDM12 polyalanine expansion reported to date. In Family 2, the proband carried 2 compound-heterozygous variants c.570+2T > G and c.796A > C (p.Thr266Pro) classified as pathogenic and likely pathogenic, respectively, and both previously undescribed.Discussion – These data broaden the genetic spectrum of CIP and reinforce PRDM12 as a key gene in pain perception. They also emphasize that diagnostic analysis should target both single-nucleotide variants and polyalanine expansions, which are often underrepresented in whole-exome or whole-genome sequencing data.
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    Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy
    (2025-01-01) Pongsakornkullachart P.; Kulsirichawaroj P.; Kongkasuwan R.; Tovichien P.; Jitwongwai S.; Kanjanauthai S.; Preeprem N.; Limpaninlachat S.; Sermpon N.; Sanmaneechai O.; Pongsakornkullachart P.; Mahidol University
    Supported by encouraging trial outcomes, onasemnogene abeparvovec (OA) was authorized for spinal muscular atrophy (SMA). Nevertheless, efficacy of OA in advanced SMA patients remains underexplored. This investigation assessed clinical effectiveness and adverse effects of OA in a cohort including advanced SMA, and compared to historical survival data for SMA type 1 patients in Thailand. We conducted observational cohort study at Siriraj Hospital, Thailand, from May 2019 to April 2022. The study enrolled eight SMA patients receiving OA therapy. The cohort comprised five SMA type 1 patients treated at 16.7 months (6.5–24.9 months) and three SMA type 2 patients treated at 20.3 months (19–31.5 months). Before receiving OA, all Type 1 patients required 24-hour invasive ventilation and feeding support. Post-treatment, Three of five showed gradual improvement in motor scores, but none achieved new motor milestones. Survival rate was not improved, with all experiencing fatalities. Conversely, Type 2 patients exhibited motor score improvement without serious adverse events. OA did not significantly improve clinical outcomes or survival rates in advanced Type 1 SMA. These findings highlight need for additional caution when administering OA to severe SMA Type 1 and more specific guidelines in selecting subgroups for treatment.
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    Gene Distribution in Pediatric-Onset Inherited Peripheral Neuropathy: A Single Tertiary Center in Thailand
    (2024-01-02) Kulsirichawaroj P.; Suksangkharn Y.; Nam D.E.; Pho-Iam T.; Limwongse C.; Chung K.W.; Sanmaneechai O.; Zuchner S.L.; Choi B.O.; Kulsirichawaroj P.; Mahidol University
    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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    Gene-based therapy for the treatment of spinal muscular atrophy types 1 and 2 : a systematic review and meta-analysis
    (2024-01-01) Chongmelaxme B.; Yodsurang V.; Vichayachaipat P.; Srimatimanon T.; Sanmaneechai O.; Chongmelaxme B.; Mahidol University
    Despite numerous studies identifying the advantages of therapies for spinal muscular atrophy (SMA), healthcare professionals encounter obstacles in determining the most effective treatment. This study aimed to investigate the effects of gene-based therapy for SMA. A systematic search was conducted from inception to May 2024 across databases, and all studies assessing the effects of gene-based therapy on patients with SMA types 1 and 2 were included. The outcomes measured were survival, the need for ventilatory support, improvements in motor function, and the occurrence of adverse drug reactions. Meta-analyses were performed using a random-effects model. A total of 57 studies (n = 3418) were included, and the meta-analyses revealed that onasemnogene abeparvovec showed the highest survival rate (95% [95% CI: 88, 100]), followed by risdiplam (86% [95% CI: 76, 94]) and nusinersen (60% [95% CI: 50, 70]). The number of patients needing ventilatory support was reduced after treatment with onasemnogene abeparvovec (risk ratio = 0·10 [95% CI: 0·02, 0·53]). Onasemnogene abeparvovec and risdiplam had similar proportions of patients with improvements in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders score of ≥4 points (92% [95% CI: 62, 100] vs 90% [95% CI: 77, 97]). In contrast, nusinersen had the smallest improvement (74% [95% CI: 66, 81]). The most frequently observed adverse drug reactions were headaches, vomiting, and gastrointestinal disorders. Gene-based therapy benefits patient survival and improves motor function. Onasemnogene abeparvovec and risdiplam appear highly effective, whereas nusinersen exhibits moderate effectiveness.
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    Health-related quality of life in Thai children with spinal muscular atrophy
    (2022-05-01) Aksaralikitsunti M.; Sanmaneechai O.; Mahidol University
    Background: Spinal muscular atrophy (SMA) is a chronic genetic disease that causes varying degrees of disability. There is currently no data specific to the health-related quality of life (HRQoL) of Thai children and adolescents with SMA. Accordingly, this study aimed to evaluate the HRQoL of Thai pediatric SMA, and to identify factors significantly associated with HRQoL and other aspects of quality of life. The findings of this study will help to improve overall care in this vulnerable pediatric population. Methods: This prospective cross-sectional descriptive study was conducted at the Division of Neurology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during 2015–2018. HRQoL was measured using the Thai language version of the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scale (PedsQL™). The PedsQL™ was administered to SMA children aged 2–18 years and their parents. Disease severity was evaluated by pediatric neurologists, and patients were classified according to their SMA subtype. Results: Forty-two Thai pediatric SMA (mean age: 9.8 ± 5.0 years, 25 males) and their families were recruited. The mean PedsQL™ total score was 57.3 ± 13.6 by child self-report, and 54.3 ± 14.8 by parent proxy-report. The PedsQL™ scores of Thai SMA children were found to be significantly lower than those reported in healthy Thai children. The mean PedsQL™ total score among healthy Thai children was 78.7 ± 9.3 by child self-report, and 79.0 ± 12.8 by parent proxy-report. Factors independently associated with lower HRQoL were non-ambulation, household income less than 18,500 Thai baht/month, mechanical ventilation, and inability to attend school. Conclusion: HRQoL score was found to be an accurate reflection of patient and parent perception of SMA, which suggests the value of this tool for prioritizing interventions to improve the quality of life of Thai SMA. The results of this study also provide a baseline measurement of quality of life among Thai SMA.
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    Intrathecal onasemnogene abeparvovec in treatment-naive patients with spinal muscular atrophy: a phase 3, randomized controlled trial
    (2025-01-01) Proud C.M.; Vũ D.C.; Wilmshurst J.M.; Sanmaneechai O.; Gulati S.; Xiong H.; Moreno H.C.; Tay S.K.H.; Thong M.K.; Born A.P.; Banzzatto Ortega A.; Jong Y.J.; Al-Muhaizea M.A.; Lee A.W.; Visootsak J.; Tauscher-Wisniewski S.; Alecu I.; Parlikar R.; Finkel R.S.; Jong Y.J.; Ortega A.B.; Thong M.K.; Vũ D.C.; Proud C.M.; Mahidol University
    STEER (NCT05089656) was a 52-week, phase 3, multicenter, randomized, sham-controlled, double-blind trial evaluating intrathecal onasemnogene abeparvovec (OAV101 IT), a one-time gene transfer therapy, in patients with spinal muscular atrophy (SMA). Participants ranged in age from 2 years to <18 years, were treatment-naive and were able to sit but never walked independently. Primary efficacy endpoint was change from baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) score. In total, 126 patients received OAV101 IT (n = 75) or a sham procedure (n = 51). The primary endpoint was met: patients treated with OAV101 IT demonstrated a significant increase in HFMSE score compared with sham (least squares mean difference, 1.88 (95% confidence interval: 0.51−3.25); P = 0.0074). Overall incidence of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI) was similar between groups. Transaminase increases were infrequent; most were low grade and transient. Two participants in the OAV101 IT arm and one participant in the sham arm developed sensory symptoms. One-time OAV101 IT demonstrated a statistically significant improvement in motor function compared with sham control. The overall safety findings were acceptable, with similar incidences of AEs, SAEs and AESI in the OAV101 IT and sham groups. Trial registration: ClinicalTrials.gov identifier: NCT05089656.
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    Next-generation sequencing for pediatric-onset neuromuscular disorders unresolved by conventional diagnostic methods
    (2025-01-01) Kulsirichawaroj P.; Chanvanichtrakool M.; Wattanadilokchatkun P.; Pho-iam T.; Limwongse C.; Likasitwattanakul S.; Boonyapisit K.; Sanmaneechai O.; Nishino I.; Shotelersuk V.; Han J.; Zuchner S.; Kulsirichawaroj P.; Mahidol University
    Background: Neuromuscular disorders (NMDs), rare diseases affecting the peripheral nervous system, often cause progressive weakness and systemic complications. Despite advances in genetic diagnostics, data from Southeast Asia remain limited. Ancestral variation may influence mutation spectra, revealing novel alleles and phenotypic diversity. Methods: We evaluated the diagnostic yield and clinical impact of targeted gene panel testing and exome sequencing in pediatric-onset NMDs at Siriraj Hospital, Thailand (2020‒2024). Patients with suspected genetic NMDs and negative single-gene tests underwent gene panel testing or exome sequencing. Genetic findings were classified as positive, probable, possible, or negative. Results: Among 135 patients, the overall diagnostic yield was 69.6% (94/135). Subgroup yields were 70.7% for inherited myopathies (53/75), 63.3% for inherited neuropathies (31/49), 90.0% for congenital myasthenic syndromes (9/10), and 100% for motor neuron diseases (1/1). Excluding patients with Duchenne muscular dystrophy, the diagnostic yield of inherited myopathies was 63.2% (36/57). Genetic diagnoses influenced clinical care in 87.2% of cases, prompting revised diagnoses, personalized treatments, enhanced surveillance, informed family planning, and accurate prognostication. Conclusions: NGS substantially enhances diagnostic accuracy and clinical management for pediatric NMDs. These findings support incorporating NGS into diagnostic workflows for suspected genetic NMDs, thereby optimizing patient care and advancing genetic insights. Impact: Gene panel testing and exome sequencing demonstrate an approximately 70% diagnostic yield for pediatric neuromuscular disorders, exceeding yields reported in many other hereditary diseases. Genetic findings underscore potential differences in mutation spectra among Southeast Asian populations, which remain under-investigated relative to Western cohorts. Clinical implementation of next-generation sequencing confers substantial benefits, including more accurate diagnoses, personalized management, and informed family planning, ultimately improving care for pediatric neuromuscular disorders.
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    Nitrous oxide-induced myeloneuropathy in a Thai adolescent: a case report
    (2024-01-01) Puetpaiboon S.; Meepolprapai M.; Saengpanit P.; Laohathai P.; Prasertsup W.; Khiewbanyang S.; Charupash R.; Sanmaneechai O.; Kriengsoontornkij W.; Puetpaiboon S.; Mahidol University
    Nitrous oxide, an inhalational anaesthetic, is popular with adolescents worldwide as an accessible recreational drug which induces a euphoric effect. However, chronic abuse leads to serious complications such as myeloneuropathy and bone marrow suppression by inactivation of vitamin B12. A 17-year-old girl presented with nitrous oxide-induced myeloneuropathy. She reported chronic nitrous oxide inhalation for 10 months and was admitted to the emergency department on account of repeated falls for 2 weeks. She also had ascending paraesthesia in both legs and urinary incontinence. Neurological examination demonstrated bilateral lower extremity weakness [motor power: proximal muscles 4/5, plantar flexion and extensor hallucis longus (EHL) 3/5], decreased sensation, proprioception and vibration of the lower extremities. Deep tendon reflexes were absent in the ankles and knees. Laboratory results demonstrated mild anaemia [Hb 11.2 g/dL (12.0–16.0), haematocrit 35.4% (36–50), MCV 89.4 fl (78–102)] with significant hypersegmented neutrophils in a peripheral blood smear. Serum vitamin B12 was 340 pg/mL (197–771), but serum homocysteine was increased at 65.8 µmol/L (5–15). A nerve conduction study was prolonged, and F-waves were absent from the bilateral perineal and tibial nerves, indicating diffuse demyelinating motor polyneuropathy. Magnetic resonance imaging of the whole spine demonstrated faint T2 hypersignal intensity and an inverted V-shape appearance at the posterior column of the upper thoracic cord (around T2–T6), a pathognomonic sign of vitamin B12 deficiency or subacute combined degeneration of the nitrous oxide-induced myeloneuropathy. A 7-day course of 1000 µg cyanocobalamin was given intramuscularly, followed by weekly doses for 4 weeks. Supplements of daily oral vitamin B1, B6 and B12 (65 µg vitamin B12) were administered, along with rehabilitation. At the 6-months outpatient follow-up, there were a few residual neurological abnormalities: weakness of the left EHL (grade 4/5) and an absent deep tendon reflex in the left ankle. This case emphasises the significant health consequences of chronic abuse of nitrous oxide, myeloneuropathy and megaloblastic anaemia, by inactivation of vitamin B12. The myelopathy is noticeably improved by cyanocobalamin. Abbreviations: EHL: extensor hallucis longus; MRI: magnetic resonance imaging; NCS: nerve conduction study.
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    Onasemnogene Abeparvovec Gene Therapy and Risdiplam for the Treatment of Spinal Muscular Atrophy in Thailand: A Cost-Utility Analysis
    (2024-01-01) Khuntha S.; Prawjaeng J.; Ponragdee K.; Sanmaneechai O.; Srinonprasert V.; Leelahavarong P.; Khuntha S.; Mahidol University
    Objectives: Caring for individuals with spinal muscular atrophy (SMA), a rare genetic disorder, poses tremendous challenges for the economy and healthcare system. This study evaluated the cost-utility of onasemnogene abeparvovec-xioi gene therapy and risdiplam for SMA in Thailand. Methods: A Markov model was used to analyze the lifetime costs and outcomes of these treatments compared with standard of care for symptomatic SMA types 1 and 2–3. SMA type 1 patients were treated with one of either onasemnogene or risdiplam, while SMA types 2–3 patients received risdiplam. Data on disease progression and medical costs were sourced from hospital databases, while treatment efficacy was based on clinical trials. Interviews with patients and caregivers provided data on non-medical costs and utilities. Base case cost-effectiveness and sensitivity analyses were conducted, with the incremental cost-effectiveness ratio (ICER) calculated in US dollars (USD) per quality-adjusted life year (QALY) gained, against a willingness-to-pay threshold of 4444 USD/QALY gained. Results: For SMA type 1, the ICERs for onasemnogene and risdiplam were 163,102 and 158,357 USD/QALY gained, respectively. For SMA types 2–3, the ICER for risdiplam was 496,704 USD/QALY gained. Conclusions: While onasemnogene and risdiplam exceeded the value-for-money threshold of the Thai healthcare system, they yielded the highest QALY gains among all approved medications. Policy-makers should incorporate various pieces of evidence alongside the cost-effectiveness results for rare diseases with costly drugs. Additionally, cost-effectiveness findings are useful for price negotiations and alternative financial funding, which allows policy-makers to seek solutions to ensure patient access, aligning with universal health coverage principles in Thailand.
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    Polyneuritis Cranialis Associated with BNT162b2 mRNA COVID-19 Vaccine in a Healthy Adolescent
    (2022-01-01) Kulsirichawaroj P.; Sanmaneechai O.; Wittawatmongkol O.; Chokephaibulkit K.; Mahidol University
    A 16-year-old Thai girl developed right facial palsy, a lower motor neuron lesion, and numbness 3 h after receiving the first dose of the BNT162b2 mRNA vaccine. Neurological examination showed the involvement of the right cranial nerves (CN) V, VII, IX, and X. Electrophysiological tests revealed the absence of an F wave response, suggesting a proximal demyelinating process. Magnetic resonance imaging of the brain demonstrated abnormal enhancement of the right CN VII. The cerebrospinal fluid profile on day 7 after the onset of symptoms was normal. The patient was diagnosed with polyneuritis cranialis, a rare variant of Guillain-Barre syndrome. She was successfully treated with intravenous immunoglobulin therapy.
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    Prognostic model for time to achieve independent walking in children with Guillain-Barré syndrome
    (2022-11-01) Chaweekulrat P.; Sanmaneechai O.; Mahidol University
    Background: Guillain-Barré Syndrome (GBS) is an immune-mediated peripheral neuropathy. Clinical features and outcomes in children differ from adults. Currently, there is no prognostic model to predict outcomes in children and existing models for adults are not suitable. Objectives: To identify factors that are associated with outcomes and develop clinical model to predict time to independent walking in children with GBS. Methods: Between 2005 and 2018, 41 patients with GBS were identified by retrospective chart review. Factors associated with independent walking were analyzed with the Kaplan–Meier method. A prediction model was developed based on regression coefficients from Cox’s proportional hazard model. Results: The disability score at maximum weakness and nerve conduction study results were associated with independent walking and included in the model. Scores range from 0 to 5. A score of 5 predicts 34 days to independent walking while a score of 0 predicts 5 months (mean 158 days, p = 0.008). Conclusion: This scoring system for pediatric patients provides predicts the time needed to achieve independent walking, an important milestone of recovery for communication with parents, and to assist clinicians to optimize treatment. Further studies of predictive factors and external validation are needed to improve precision of the model. Impact: This is the first study to create a prognostic scoring system for individual outcomes in children with GBS.A clinical prognostic model can predict time to achieve independent walking in individual pediatric patients with GBS.This model can assist clinicians to optimize treatment and guide decisions on rehabilitation to prevent long-term disability.
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    Spinal muscular atrophy in an upper-middle-income nation before the advent of reimbursed disease-modifying therapies
    (2024-08-30) Sakpichaisakul K.; Katanyuwong K.; Intusoma U.; Paprad T.; Suwanpakdee P.; Khongkhatithum C.; Sanmaneechai O.; Sakpichaisakul K.; Mahidol University
    Objective To elucidate the clinical characteristics and standard of care (SoC) of spinal muscular atrophy (SMA) patients in Thailand, focusing on primary endpoints: age at death and a composite of death or tracheostomy need. Design Retrospective observational study. Setting Seven tertiary centres across Thailand. Patients Records of 110 patients with genetically confirmed SMA, spanning 2012-2021. Interventions Historical data review; no active interventions. Main outcome measures Age at death and a composite measure of death or tracheostomy necessity. Results The cohort included 1 SMA0, 50 SMA1, 40 SMA2 and 19 SMA3 cases. Median ages at the onset and diagnosis of SMA1 were 3 and 6.2 months. Of SMA1 patients, 63% required ventilators, and eight received dimethyltryptamines (DMTs) at a median of 15 months (range 6.4-24.5 months). The median time from onset to DMT was 11 months (range 4.2-20.5 months). Among SMA1 patients, 73% died by the study's end. SMA2 and SMA3 patients' median onset ages were 11 and 24 months, respectively, with diagnosis at 24.8 and 68.7 months. Half of all types received physical therapy. Conclusions Significant delays in diagnosis and SoC access, including DMTs, were observed, underscoring urgent needs for improved diagnostic and care strategies to enhance SMA patient outcomes in Thailand.
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    Survival analysis and life expectancy of pediatric patients with spinal muscular atrophy in Thailand
    (2024-06-15) Sittiyuno P.; Kulsirichawaroj P.; Leelahavarong P.; Sanmaneechai O.; Sittiyuno P.; Mahidol University
    Background: Survival data for Thai patients with 5q spinal muscular atrophy (SMA), the leading cause of infant mortality worldwide, are lacking. Objective: This study aimed to determine the survival rates and life expectancies of pediatric patients with SMA types 1, 2, and 3. Methods: We conducted a retrospective cohort analysis of genetically confirmed 5q SMA patients aged 0–18 years who were treated between 1999 and 2021 at the pediatric neuromuscular clinic of Siriraj Hospital, Bangkok, Thailand. Mortality data were sourced from the Civil Registration Office. Results: The study included 113 patients: 37 with SMA type 1, 53 with type 2, and 23 with type 3. Life expectancy varied significantly by SMA type: 2.2 years for type 1, 11 years for type 2, and 16.5 years for type 3. The median survival times for SMA type 1 and 2 were 1.9 and 19 years, respectively. In SMA type 2, early onset (<1 year) correlated with a shorter median survival than later onset (≥1 year) (log-rank test P = 0.009). Early onset SMA type 2 had a median survival time of 15.9 years, while 75 % of those with later onset SMA type 2 survived until the age of 19 years. Cox proportional hazards analysis revealed that each month's delay in disease onset reduced the annual mortality risk by 17 % for type 1 patients and by 20 % for type 2 patients. Compared with female patients, male patients with type 2 disease had a 12-fold increased mortality risk. Conclusions: Age at onset is a significant predictor of survival and life expectancy in patients with SMA types 1 and 2. These insights are crucial for genetic counseling and prognostic discussions in clinical settings.
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    The GENESIS database and tools: A decade of discovery in Mendelian genomics
    (2024-12-01) Danzi M.C.; Powell E.; Rebelo A.P.; Dohrn M.F.; Beijer D.; Fazal S.; Xu I.R.L.; Medina J.; Chen S.; Arcia de Jesus Y.; Schatzman J.; Hershberger R.E.; Saporta M.; Baets J.; Falk M.; Herrmann D.N.; Scherer S.S.; Reilly M.M.; Cortese A.; Marques W.; Carnejo-Olivas M.R.; Sanmaneechai O.; Kennerson M.L.; Jordanova A.; Silva T.Y.T.; Pedroso J.L.; Schierbaum L.; Ebrahimi-Fakhari D.; Peric S.; Lee Y.C.; Synofzik M.; Tekin M.; Ravenscroft G.; Shy M.; Basak N.; Schule R.; Zuchner S.; Danzi M.C.; Mahidol University
    In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.
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    Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum
    (2023-12-01) Summa S.; Ittiwut C.; Kulsirichawaroj P.; Paprad T.; Likasitwattanakul S.; Sanmaneechai O.; Boonsimma P.; Suphapeetiporn K.; Shotelersuk V.; Mahidol University
    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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    Validation and Reliability of the Thai Pediatric Charcot–Marie–Tooth Quality of Life Outcome Measure
    (2025-12-01) Kulsirichawaroj P.; Phochaisarn A.; Limpaninlachat S.; Vorasan N.; Likasitwattanakul S.; Ramchandren S.; Shy M.E.; Sanmaneechai O.; Kulsirichawaroj P.; Mahidol University
    Background and Aims: Charcot–Marie–Tooth disease (CMT) is a hereditary neuropathy that causes progressive muscle weakness, sensory deficits, and impaired mobility, significantly affecting quality of life (QoL). The Pediatric Charcot–Marie–Tooth Quality of Life (pCMT-QoL) instrument was developed specifically for children with CMT. However, a validated Thai version is not yet available. Methods: We conducted a cross-sectional study at the Pediatric Neuromuscular Clinic from July 2023 to December 2024. Using a forward–backward translation method, we adapted the pCMT-QoL into Thai. Twenty-three children with CMT and their caregivers completed the Thai questionnaire. We evaluated internal consistency using Cronbach's alpha and test–retest reliability using intraclass correlation coefficients (ICCs). Convergent validity was examined via Pearson correlation between child self-reports and parent-proxy reports across functional, mental, and physical domains. Results: The Thai pCMT-QoL demonstrated high test–retest reliability (ICC > 0.85) and satisfactory internal consistency (Cronbach's alpha > 0.7) across most domains. Convergent validity was strong for the total and mental domains but weaker for the physical domain, reflecting differences in perception between children and parents. Parents generally reported higher QoL scores than children did, a finding consistent with studies in other neuromuscular diseases. Most participants completed the questionnaire within 15 min, suggesting good feasibility. Interpretation: The Thai pCMT-QoL is a reliable, culturally adapted tool for assessing QoL in children with CMT. It is suitable for both remote and in-clinic administration. Future studies with larger cohorts are needed to confirm its responsiveness to clinical changes and to broaden its application in diverse settings.