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Abstract
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.
- Neurology
- Rehabilitation
Data availability statement
Data are available upon reasonable request. Data supporting the findings of this study are available from the corresponding author upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Spinal muscular atrophy (SMA) is a progressive autosomal recessive neuromuscular disorder resulting in muscle weakness and respiratory impairment. It is a major cause of infant mortality.
SMA ranks as the second most common neuromuscular disease in Thai children; however, comprehensive data about natural progression, standard of care (SoC) and patient outcomes in Thailand are still scant.
WHAT THIS STUDY ADDS
The multi-centre study revealed delayed diagnosis leading to delayed access to the SoC and disease-modifying therapies for SMA in Thailand.
These unmet needs underscore the potential gaps in improving SMA care plans and SMA patient outcomes.
The multi-centre data source makes the findings more generalisable to a large portion of the Thai population and may also represent the broader middle-income Southeast Asian community.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The study sheds light on a significant diagnostic delay that might affect the outcomes associated with DMTs and SoC. Improved care plans for SMA patients in Thailand are urgently needed.
Achieving optimal outcomes hinges on early detection, timely intervention and the administration of DMTs. Newborn screening offers an opportunity for early diagnosis, which can expedite and streamline the diagnostic process.
Introduction
Spinal muscular atrophy (SMA) is a progressive autosomal recessive neuromuscular disorder manifesting in muscle weakness and respiratory impairment. It is a major cause of infant mortality.1 2 The disease is caused by a deletion or mutation in the survival motor neuron 1 (SMN1) gene, culminating in motor neuron deterioration.3 4 The recommended first-line diagnostic test for SMA is molecular genetic testing of the SMN1/SMN2 genes.5 The number of copies of the SMN2 gene is highly correlated to disease severity, with a higher number of copies associated with milder symptoms.6 SMA is classified into subtypes based on the age at onset and the attainment of motor milestones.7
The previous standard of care (SoC) for SMA included supportive measures such as nutritional aids and respiratory assistance. This approach has been widely implemented worldwide.5 8
In Thailand, SMA ranks as the second most common neuromuscular disease in children.9 10 Despite being an upper-middle-income country,11 Thailand has not yet establish a national newborn screening (NBS) protocol for SMA. This situation contrasts with nations such as the USA, Germany, Australia, Italy and Belgium, where screening systems are operative.12 Additionally, Thailand’s Universal Coverage Scheme does not cover genetic testing for SMA. Genetic testing is also only available at three laboratory centres, with a waiting period of 1 month for results. Although DMTs have been available in Thailand since 2021, they are not covered by the country’s Universal Coverage Scheme. Some patients were previously enrolled in early access programmes and received DMTs; however, all programmes have now been discontinued.
SMA patients require substantial healthcare resources, have high hospitalisation rates and are at risk of mortality due to respiratory failure. Understanding the situation of SMA in Thailand, including the time of diagnosis and the provided SoC, is crucial for identifying unmet needs and formulating strategies to improve the healthcare system. This multi-centre study in Thailand aimed to describe the clinical characteristics, the natural course of the disease and the implementation of the SoC for SMA patients in real-world clinical practice.
Materials and methods
Study design and patient population
This retrospective observational study was conducted across seven tertiary-level hospitals in Thailand: Siriraj Hospital, Queen Sirikit National Institute of Child Health, Ramathibodi Hospital, Chiang Mai University Hospital, Songklanagarind Hospital, Phramongkutklao Hospital and Chulalongkorn Hospital. The study included patients aged 0–25 years with genetically confirmed SMA diagnosis. The testing method was quantitative PCR, PCR-restriction fragment length polymorphism (RFLP) or multiplex ligation-dependent probe amplification (MLPA). Patients who were diagnosed with SMA with genetic confirmation from 1 January 2012 to 31 December 2021 in participating sites were included. The exclusion criteria were patients whose SMA diagnosis changed during the follow-up period. SMA subtypes were determined based on the age at onset and maximum motor function/milestone achievement. SMA0 was classified by the onset at birth. SMA1 was further segmented into type 1B (onset <3 months) and 1C (onset 
3 months).13 Motor milestones were assessed using the established WHO scale.14
The research was conducted per the principles outlined in the Declaration of Helsinki. Approval for the study was obtained from the Institutional Review Board and approved COA number as follow: 1) Siriraj Institutional Review Board Approved, Si 268/2022; (2) the Research Ethics Review Committee of Queen Sirikit National Institute of Child Health, REC.046/2565; (3) Institutional Review Boards, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, COA-CREC024/2022; (4) Research Ethics Committee, Faculty of Medicine, Chiang Mai University, 063/2022; (5) Human Research Ethics Committee, Faculty of Medicine, Prince of Songkla University, REC-65-159; (6) the Institutional Review Board, Royal Thai Army Medical Department, IRBRTA 0279/2022; and (7) Institutional Review Board, Faculty of Medicine, Chulalongkorn University, 0515/2022.
Data collection, assessment and statistical analysis
Data were obtained through retrospective medical chart review, including information on symptom onset, specialist visits, diagnosis, mortality, motor milestones, SMN2 copy number, supportive treatments and hospital admissions.
Data on ventilatory support covered the use of cough assist devices, oxygen masks, oxygen cannulas, high-flow oxygen devices, bilevel positive airway pressure, continuous positive airway pressure, tracheostomies and standard ventilators. Nutritional support data included the use of nasogastric, orogastric or gastrostomy feeding tubes. The primary endpoints for the survival analysis were (1) age at death and (2) a composite of death or need for tracheostomy.
Analyses were conducted using SAS Version 9.4 TS Level 1M3 software. The data were analysed both collectively and by SMA subtypes. Descriptive statistics are presented as percentages, means (SD), or medians (IQR), as appropriate. Survival time was calculated in days from birthdate to the date of death. Survival probabilities were calculated using the Kaplan–Meier method.
For SMA1 patients with missing data on death outcomes (n=6) who did not receive ventilatory support and were older than 24 months, a review was conducted by a paediatric neurologist with expertise in neuromuscular disorders. The missing data were imputed by assuming death at the end of the study, consistent with the natural progression of SMA1.15 16 Survival probabilities were estimated using the Kaplan–Meier method.
Results
Patient demographics
The study included 110 patients, with 50 (45.5%) being male. The distribution of SMA subtypes was as follows: SMA0 (n=1, 0.9%), SMA1 (n=50, 45.5%), SMA2 (n=40, 36.4%) and SMA3 (n=19, 17.3%). As of December 2021, the median age at the most recent follow-up visit was 2 years, ranging from 0.2 to 21.6 years. The demographics and categorisation of the SMA patients are detailed in table 1.
Demographics and classification of spinal muscular atrophy patients
Clinical findings
Among the 50 SMA1 patients, the median age at symptom onset was 3 months (IQR 2–4 months), while the median duration from onset to diagnosis was 2.8 (IQR 1.5–4.7) months. Table 2 summarises the clinical characteristics and outcomes based on SMA subtypes. Eight patients received DMTs, with onasemnogene abeparvovec (OA) (n=5) administered at a median age of 16.5 (range 6.4–24.5) months and risdiplam (n=3) given at a median age of 7.8 (range 7–20.5) months. The median time from onset to received DMTs was 11 (range 4.2–20.5) months, which was 13.5 (range 5.4–20.5) months for OA and 6.7 (range 4.2–16.5) months for risdiplam. Ventilatory support was provided to 27 (63%) out of 43 patients who had respiratory status data, 22 of whom were dependent on ventilators for over 6 hours daily. Nutritional support was given to 21 out of 37 (42%) patients with available data, commencing at a median age of 6.5 (IQR 5–7.5) months. Of 44 patients who had data on physical therapy support, 22 (50%) received physical therapy, primarily involving stretching exercises and chest physical therapy. Hospitalisation was required in 30 out of 37 (81%) patients, with the median length of stay being 7(IQR 2–20) days, primarily attributed to respiratory infections.
Clinical features and outcomes of spinal muscular atrophy by type
Among the 40 patients with SMA2, the median age at onset was 11 (IQR 8–13) months, with a median duration of 15.3 (IQR 6.1–30.8) months from the onset to diagnosis. Eleven patients with SMA2 received DMTs. Risdiplam was administered to nine patients at a median age of 60.1 (range 39.5–232.4) months, while two patients received OA at 18.8 and 33.3 months. The median time from onset to received DMTs was 42.1 (range 10.8–226.4) months, which was 45.6 (range 20.5–226.4) months for risdiplam. Time from the onset to received OA was 10.8 and 22.3 months. By the end of the study, motor capabilities varied among SMA2 patients. Twenty-four (60%) patients could sit without support for at least 10 s, six (15%) patients could not sit independently, four (10%) patients were able to stand with assistance, three (7.5%) patients could walk with assistance, two (5%) patients crawled by hands and knees and one (2.5%) patient could stand alone. Ventilatory support was provided to 14 out of 36 (39%) SMA2 patients, with 12 out of 14 (85.7%) on noninvasive support and two out of 14 (14.3%) on invasive ventilatory support. Only two out of 37 (5.4%) patients received nutritional support. Physical therapy was received by 29 out of 38 (76.3%) patients, and 13 out of 46 (28%) patients needed orthopaedic equipment or assistive devices such as orthoses and orthopaedic shoes. Only one patient needed orthopaedic surgery for scoliosis. Hospitalisation occurred in 14 out of 34 (41%) SMA2 patients, primarily due to respiratory complications.
Among the 19 SMA3 patients, symptoms appeared at a median age of 24 (IQR 21–36) months. The median duration from symptom onset to a confirmed diagnosis was 35.9 (IQR 17.4–68.4) months. By the conclusion of the study, 10 SMA3 patients (52.6%) could walk unassisted, seven (36.8%) needed assistance to walk, one (5.3%) could sit without support for at least 10 s and another one (5.3%) stood with assistance. None of these patients required ventilatory or nutritional support. Physical therapy was received by 10 out of 16 (63%) patients, and two out of 16 (12.5%) patients needed orthopaedic equipment or assistive devices. Only one out of 16 (6.3%) patients was hospitalised due to respiratory complications.
SMN2 copy number analysis
SMN1 gene deletion was confirmed in all patients. However, SMN2 copy number analysis was performed in only 38 out of 110 (34.6%) patients (table 2). Among the 38 patients, the SMN2 copy distribution varied according to SMA type.
Survival analysis
By the end of the study, 34 SMA patients (one with SMA0 and 33 with SMA1: type 1B (n=12) and type 1C (n=21)) had died, with a median follow-up of 64.5 (24.0–112.1) months. The mortality and combined endpoint data for SMA1 patients are presented in figure 1. Among SMA1 patients, 33 (12 with type 1B and 21 with type 1C) died during the follow-up period. The probability of combined endpoint-free survival in SMA1 patients was 50% at 24 months. This distribution did not significantly differ by SMA1 subtype (figure 2). The probability of combined endpoint-free survival in SMA1 patients with 2 SMN2 copies is presented in figure 3. Specifically, the median age at the combined endpoint was 21.1 (5.5–24.0) months for SMA type 1B and 24 (19.2–24.0)months for SMA type 1C.
Comparison of time-to-event outcomes for SMA1: current studya Kaplan–Meier survival curves for SMA1 age-related survival probability by SMA1 subtype in this study (type 1B, n = 12; type 1C, n = 21). Abbreviation: SMA1, spinal muscular atrophy type 1. aThe data of six patients without ventilator support and aged 24 months were imputed and assumed deceased in line with the natural history of SMA1.
Kaplan–Meier survival curves for SMA1 age-progression likelihood of not reaching the combined endpointa in this study. Abbreviation: SMA1, spinal muscular atrophy type 1. aThe events in the present study covered death or tracheostomy support. However, the Paediatric Neuromuscular Clinical Research Network study defined it as death or a need for a minimum of 16 hours/day of noninvasive ventilation support for 14 continuous days, excluding acute reversible illnesses or perioperative cases.
Kaplan–Meier survival curves for SMA1 probability, by age, of not reaching the combined endpointa based on SMN2 copy number (2 copies, n = 14) in this studyb. Abbreviations: SMA1, spinal muscular atrophy type 1; SMN2, survival of motor neuron. aThe events in the present study covered death or tracheostomy support. However, the Paediatric Neuromuscular Clinical Research Network study defined it as death or a need for a minimum of 16 hours/day of noninvasive ventilation support for 14 continuous days, excluding acute reversible illnesses or perioperative cases. bThe data illustrate 14 patients with two copies of SMN2 since only one patient had three SMN2 copies.
Among 37 SMA1 patients who had hospital record, 27 (73%) passed away by the end of the study. No deaths were reported during the study period for SMA2 and SMA3. Their median monitoring periods were 90 (IQR 22.0–239.9) months and 164 (IQR 55.2–271.5) months, respectively.
Discussion
This multi-centre research offers an analysis of 110 SMA patients from all regions in Thailand. Notably, the study highlights a significant diagnostic delay that might affect the outcomes associated with DMTs. Additionally, SoC was provided in all SMA types including ventilator support (52%), nutritional support (34%) and physical therapy (62%). Delayed diagnosis resulting in delayed access to SoC and DMTs for SMA was notable. Improved care plans for SMA patients in Thailand are urgently needed.
The clinical course, age at onset and delay in diagnosis observed for all SMA types in the Thai population aligned with findings from previous studies.13 17 18 Relevant factors were discussed. They include a low suspicion index among primary care providers, limited access to genetic testing and a lack of coverage of genetic testing and DMT costs by Thailand’s Universal Coverage Scheme. Notably, there is an optimal window for the most effective SMA treatments.19 Achieving optimal outcomes hinges on early detection, timely intervention and the administration of DMTs. NBS offers an opportunity for early diagnosis, which can expedite and streamline the diagnostic process. However, while early screening is feasible, the substantial disease treatment costs raise essential considerations.
The rate of ventilatory support in SMA1 patients in our study (63%) is aligned with Taiwan (67.6).20 However, the rates were different among studies such as the Paediatric Neuromuscular Clinical Research study (47%) and 83% in the Argentinian study.13 21 Several reasons might account for this discrepancy. Most patients in our study were not diagnosed with SMA before intubation due to the inaccessibility of genetic testing. When a SMA diagnosis was suspected, a lack of genetic counselling for parents was an additional barrier. Furthermore, parental choices may be influenced by cultural and ethical nuances.
Nutritional support was less common in SMA2 patients compared with SMA1 and rarely needed in SMA3, consistent with previous studies.22–24 Additionally, only half of the SMA 22 in our study received physical therapy, contrasting with other research.25 According to the International SMA Consensus guidelines, enhancing the SoC involves consistent, personalised physical therapy encompassing stretching, mobility exercises and customised chest physiotherapy.5 Early initiation of these interventions maximises their benefits.25
SMA1 patients in our study received DMTs at a median age later than those in the FIREFISH and STR1VE-EU trials. Specifically, the administration of risdiplam was at 7.8 months in our study compared with 5.3 months in FIREFISH, while OA was given at 16.5 months in our study compared with 4.1 months in STR1VE-EU.26 27 All patients who received OA had severe neurological status and required respiratory support at the time of treatment in our study. Other studies have reported that the effectiveness of DMTs was influenced by the age at which treatment was initiated, with better outcomes observed with earlier treatment.27–29 These findings highlight the importance of early detection in symptomatic patients and the need for NBS. In addition, early administration of DMTs is crucial for achieving better outcomes, as demonstrated in presymptomatic SMA1 patients less than 6 weeks old in the RAINBOWFISH and SPR1NT trials for risdiplam and OA, respectively.30–32 In these trials, all patients not only survived but also maintained good motor function without requiring respiratory and nutritional support.
Although SMN1 gene deletion was confirmed in all participants, only one-third underwent SMN2 copy number testing. However, quantitative PCR and PCR-RFLP have limitations in analysing SMN2 copy numbers. Using MLPA testing for SMN1/SMN2 would provide a more accurate quantification of SMN2 copy number.
This retrospective study has limitations including recall bias, incomplete data and missing SMN2 copy number data, due to unavailable SMN2 copy testing in Thailand before 2017 and the lack of a disease registry. It is important to consider these limitations when interpreting the results. No statistical testing was performed. Furthermore, the study did not compare outcomes between patients who received DMTs and those who did not—and that was not our intention—our aim was to describe the clinical characteristics and natural progression of SMA and to document the real-world implementation of the SoC for SMA patients in a setting with relatively limited resources. Future ongoing prospective national registry research in this area could provide valuable insights, thereby advocating for necessary funding and support from healthcare authorities and policymakers. However, a strength of this study is its multi-centre data source, making the findings more applicable to a large portion of the Thai population and the broader middle-income Southeast Asian community.
Early diagnosis, physical therapy, disease registry and a multidisciplinary approach are vital for enhancing SMA care. This study underscores the importance of supporting NBS, genetic testing and making early DMT more affordable. Implementing the SoC can help prevent disease progression while awaiting targeted therapies.5 33 This study will contribute to a greater understanding of SMA and serve as a foundation for future clinical and translational studies assessing therapeutic impacts. Furthermore, this study could provide information for driving SMA comprehensive access to diagnosis, care and specific interventions.
Data availability statement
Data are available upon reasonable request. Data supporting the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Siriraj Institutional Review Board Faculty of Medicine Siriraj Hospital, Mahidol University COA no. Si 268/2022.
Acknowledgments
We acknowledge the Center of Excellence for Biomedical and Public Health Informatics, Faculty of Tropical Medicine for managing and analysing the collected data, Cheewasan Apirukpanakhet, Jinjutha Nithiuthai, Boonchai Boonyawat, Tim Phetthong, Rattanaporn Boonyobol, Titaporn Thamcharoenvipas, Kittichote Duangnum and Pavinee Kungwanpongpun.
References
Footnotes
Contributors The study was conceived and conceptualised by KS, KK, UI, TP, PS, CK and OS, who were all involved in the initial planning and data collection process. KS and OS played key roles in the research design, data curation and guarantor. They were also instrumental in conducting the formal analysis and preparing the data visualisations, which were essential to the presentation of the study’s findings. In addition to these contributions, KS and OS took the lead in drafting the original manuscript, ensuring that the study’s methodology and results were clearly communicated. OS further contributed by supervising the overall investigation, providing guidance and oversight throughout the study. The final manuscript benefited from the collaborative efforts of all contributors. KS, KK, UI, TP, PS, CK and OS reviewed and edited the document, making critical revisions to enhance its intellectual content. Each author gave their approval for the final version of the manuscript, ensuring that it met the highest standards before submission.
Competing interests No, there are no competing interests.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.