Framework and overview of the Pediatric Spinal Muscular Atrophy Registry Program of Iran

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes degeneration of anterior horn alpha motor neuron cells in the spinal cord, which results in progressive hypotonia and muscular weakness [1]. SMA is the second most common autosomal recessive disorder, with an incidence rate of approximately 1 in 10,000 live births. In most cases diagnosed with SMA, a homozygous deletion mutation is reported in the survival of the motor neuron 1 (SMN1) gene [2]. The homozygous absence of detectable SMN1 in SMA patients can be used as a sensitive diagnostic test for SMA [3, 4]. Before therapies were developed, the clinical phenotypes of SMA were categorized into three main types (types I, II, and III) based on the age of symptom onset and the highest achievement of motor function [5‐7]. SMA Type I (a.k.a., Werdnig–Hoffmann disease) is a severe infantile disorder that manifests as extensive muscle weakness and hypotonia during the first 3 months of life. Patients with the type I form usually die before their second birthday due to respiratory failure [8, 9]. Type II SMA (a.k.a., Dubowitz disease) is an intermediate form; symptoms of the disease generally appear between 6 to 18 months after birth, and most patients with this type of SMA live into adulthood. Affected patients with SMA type II are able to sit but are unable to stand or walk without support [8, 10]. SMA Type III (a.k.a., Kugelberg–Welander disease) is a milder form of SMA that appears later in childhood and does not significantly shorten life expectancy. Affected patients with type III SMA are able to walk and reach major motor milestones, but as the disease progresses, they often lose the ability to walk over time [8, 9, 11]. However, it should be noted that the three aforementioned categories (types I, II, and III) are seen more as a spectrum rather than as distinct types; therefore, further modifications were also added to these categories: type IV for adult-onset cases and type 0 for patients with prenatal onset and death within weeks [5, 6].

To date, three treatment approaches for SMA have been recently approved by the U.S. Food and Drug Administration (FDA), including Nusinersen, Onasemnogene abeparvovec, and Risdiplam, and investigations on new medications are ongoing [12]. SMA is known as a devastating inherited disease that causes a range of negative effects on the well-being of patients and their family members [13, 14]. SMA may also lead to a substantial economic burden on patients and their families and put budgetary pressure on health systems [15], and Iranian SMA patients and the health system are no exception. Therefore, detecting patients through a newborn screening program is essential [16, 17]. In addition, screening of SMA carrier pregnant women is crucial because it provides an opportunity to identify high-risk pregnancies for this potentially devastating condition [18]. Nevertheless, similar to most other inherited neuromuscular disorders, scientists’ and practitioners’ knowledge and experience with SMA and its treatment are still scarce and not mature. Hence, healthcare systems, including Iran still suffer from a lack of statistical information on patients.

A patient registry was defined as “an organized system for the collection, storage, retrieval, analysis, and dissemination of information on individual persons who have either a particular disease, a condition (for instance, a risk factor) that predisposes to the occurrence of a health-related event, or prior exposure to substances (or circumstances) known or suspected to cause adverse health effects” [19]. In this context, the establishment of patient registry programs can facilitate data-driven studies and collaborative research and help scientists and practitioners enrich their knowledge and improve their understanding of the demographic characteristics, geographic distributions, and genetic and clinical characteristics of the target disease and calculate various related epidemiological measures, such as incidence and prevalence. Furthermore, registry programs can help them to track the target disease’s natural history, facilitate the conducting of clinical studies, monitor the target patients over time, and provide evidence on the effectiveness and adverse reactions of rehabilitation interventions and developed treatments for the target disease. Moreover, by providing a vivid report of the patients’ and disease’s characteristics, delivered services, and the magnitude and distribution of abnormalities in the population, registries enable healthcare systems to significantly improve efficiency and productivity through data-driven planning, budgeting and resource allocation, and decision-making for patients and the target disease [20‐22]. In this context, SMA registries have been established to record valuable long-term large-scale SMA-related real-world data at a fraction of the cost of controlled studies. Various collaborative efforts by a vast range of national, regional, and international enterprises (for instance, see the registry of the Cure SMA Care Center Network [23], CNDR SMA registry [24], SMArtCARE [22], and iSMAc registry [25]) have been conducted in recent years to form registries for SMA patients [26, 27].

With the expansion of SMA organizations and registries around the world and the emergence of novel therapies, the Translational Research in Europe for the Assessment and Treatment for Neuromuscular Disorders (TREAT-NMD) global network [28] was initiated in 2007 to bring together independent neuromuscular diseases (NMDs) patient registries from across the globe to improve trial readiness, accelerate the research and development of effective treatments, and establish the best in diagnosis and care of target patients [29]. Over the years, more than a hundred research centers and other NMD-related stakeholders across the world joined this global network. In this context, currently, a federated network of 67 individual, independent, national, and regional registries from 61 countries has collected longitudinal standard and systematic data on NMD patients (including SMA patients). In this context, the TREAT-NMD global registry network captures patients’ characteristics and natural history, measures the effectiveness of interventions, and informs standards of care [30].

This study aims to report the framework and design of the Pediatric Spinal Muscular Atrophy Registry Program of Iran (PSMAIR) (official registered name: Iranian Registry of patients with Spinal Muscular Atrophy (SMA)), an approved member of the TREAT-NMD global network, and to provide an overview of the findings obtained thus far in this registry program. Furthermore, under the umbrella of this study, we aim to provide some of the experiences gained during the running of this longitudinal data-gathering program for Iranian pediatric SMA patients and highlight and discuss some of the challenges, as well as insights and lessons learned from our program that was established in the setting of a developing country.

The PSMAIR registry program (https://iraniansma.ir) was publicly introduced in February 2021 with the aim of enrolling and recording the various characteristics of Iranian SMA patients under 18 years of age. This registry is prospective and nonrandomized. The registry program was designed and conducted at the Pediatric Neurology Research Center of Mofid Children’s Hospital [Shahid Beheshti University of Medical Sciences (SBMU)], Tehran, Iran. The Tabriz University of Medical Sciences, Tabriz, Iran, and Iran University of Medical Sciences, Tehran, Iran, also collaborated with the program. The PSMAIR registry is a member of the TREAT-NMD global registry network. The date of approval of this registry project by the scientific committee was April 2019. The research ethics committee of the Research Institute of Children’s Health of SBMU approved the proposal for the registry project in January 2020 (Approval ID: IR.SBMU.RICH.REC.1398.032). The basic inclusion criterion for patient enrollment in the registry was that SMA disease was genetically confirmed in the children. The SMA patient can be enrolled in the registry if informed consent has been obtained from the legal guardian. The special SMA clinic was organized every month by the registry program. The academic committee of this clinic is composed of a physiatrist, a pediatric neurologist, a pediatric pulmonologist, and a geneticist. The members of this clinical academic board have assessed and supervised the physical examination of patients, as well as all the processes of data gathering for patients with SMA. Several training workshops have been conducted in this program to increase the coordination among the staff involved in the registry and improve the knowledge and skills of the team members.

An electronic data capture (EDC) and management system is used in this program to gather the data of the registered patients and organize, conduct basic manipulation, visualize, and store the data in a database. To this end, a web-based data entry and management portal with a 3-tier architecture was developed and launched on the SBMU IT infrastructure based on the RABIT health information management system (https://disreg.sbmu.ac.ir/q/sma.html). Under our program, the registry of patients was started in October 2021. The data about patients are currently registered in this system through the completion of standardized e-forms by the authorized staff in the program. All the submitted records are screened manually once again by a staff member in charge to assure the quality of the data.

The PSMAIR registry form generally contains 16 major items (following the TREAT-NMD registry protocol), including enrollment details, demographic (and geographic) information, living (vital) status, genetic diagnosis results, clinical characteristics, scoliosis condition, motor function, wheelchair or other assisted mobility devices usage, nutrition status, pulmonary function, therapies and medications, hospitalization and comorbidity history, history of participation in clinical research, motor measures, patient-reported outcomes, and electrophysiologic and biomarkers information [31, 32]. The Iranian Identity Card Number of the registered patient was also recorded as a unique nationwide identifier (a key) in the database of the registry. In addition to these main items, some other paraclinical characteristics of patients with SMA are also registered in this program. This information includes the results of the bone mineral density (BMD) test, venous blood gas (VBG) test, chest X-ray, spinal X-ray, polysomnography test, complete blood count (CBC) test, vitamin D test, ferritin level test, and compound muscle action potential (CMAP) amplitude. The data were collected during routine patient visits. After the baseline data were collected, the patients normally visited the specialized clinic that was designed for the SMA patients follow-up twice a year (every 6 months).

Based on recent recommendations, all patients diagnosed with SMA should undergo neurologic examination, such as motor function assessment [33]. In this regard, an appropriate functional scale should be selected based on the patient’s age, SMA type, and current neurological status [34]. In this study, the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) was selected as a measure of motor function in children aged less than 2 years and who are not able to sit independently [35, 36]. The Chop-INTEND scale, which provides a total score between 0 and 64, comprises 16 items (which are rated from zero to four) addressing spontaneous movements, hand grip, head stabilization, flexion, and extension of the limbs [33, 35]. For children aged 2 years and over, the Hammersmith Functional Motor Scale Expanded (HFMSE), which consists of 33 items (scored on a scale of 0–2), was adopted as a motor function scale [37‐39]. These 33 items, which assess a child's ability to perform various activities, form an ultimate single score for HFMSE ranging from 0 to 66 [40]. The CMAP records the electrical activity of the muscle in response to transcutaneous stimulation of the motor nerve [41]. The CMAP amplitude was recorded for the patients who performed nerve conduction study (NCS). The ACTIVLIM is a 22-item questionnaire that measures the perceived limitations (by NMD patients) in their daily activities [42, 43]. As it exhibited good power to quantify small but significant changes in activity for a variety of NMDs [44], the ACTIVLIM score was recorded in the registry for patients older than 6 years old according to the existing recommendation.

In this section, an overview of some of the main collected information in the PSMAIR at the first stage of running the program is presented briefly, and some key points are highlighted. Table 1 describes the various features of our registered patients (“Number of patients”, “Sex”, “Age”, “Age of symptoms onset”, number of “Positive family history”, “SMN2 copy number”, number of patients using a wheelchair or other assisted mobility devices (“Assistive device”), number of “Acute hospitalization” days, number of “Death” among registered patients, number of patients with “Scoliosis”, number of patients using “PEG/NGT”, number of patients using “Ventilation assist”, number of patients in each “Ambulation” status, “Motor outcome” score of patients, number of patients received “Rehabilitation intervention”, “CMAP Amplitude” of patients, “ACTIVLIM” score of patients, and number of patients received disease-modifying therapies (“Previous DMT”) per SMA type.

Since the program’s electronic registration platform started to collect the patients’ data (October 2021) until September 2022, a total of 59 patients were registered in the PSMAIR, of which 31 (52.5%) of them were female and 28 (47.5%) of them were male. The average age of the patients was 4.98 ± 4.08 years. Figure 1 illustrates the age–sex structure of the registered population.

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Twenty-nine of the registered SMA patients (49%) were under 2 years old, 9 patients (15%) were 2 to less than 5 years old, and 21 of them (36%) were 5 to under 18 years old (Table 1).

The mean of the patients’ weight was 12.43 ± 8.76 kg. Regarding the frequency of SMA types, 28 patients (47%) were categorized as type I, 17 patients (29%) as type II, and 14 patients (24%) as type III (Table 1 and Fig. 2). Ten (17%) of the patients had at least one known family member with SMA (Table 1) (7 patients from the mother’s side and 3 patients from the father's side had a positive SMA history). In total, 26 patients (44%) had a history of hospitalization; among them, 23 patients (37%) were hospitalized acutely. Among these 23 people, 19 people (32%) were hospitalized due to respiratory disorder (the most common cause), and the other children were hospitalized acutely due to fever, febrile convulsion, diabetic ketoacidosis (DKA), and gastroenteritis. The proportions of a wheelchair or other mobility assistive device use, scoliosis, tube feeding use, and mechanical ventilation (noninvasive and invasive) use in the patients’ population were 15%, 15%, 19%, and 20%, respectively (Table 1). According to Table 1, the statistics on the age of symptom onset, CMAP amplitude, and the ACTIVLIM score of patients increased from the more severe form of SMA (type I) to the milder type (type III). Furthermore, the total number of deaths (11 patients) were attributed to patients with SMA type I (in other words, approximately 39% of Type I enrolled patients or 19% of the registered patients died). A history of feeding tube use and ventilation assistance was observed only in type I patients. The use of assistive devices for ambulation was more common among type II patients: 41% of type II patients used a wheelchair or other mobility assistive devices, while this percentage was 4% and 7%, respectively, among patients with SMA types I and III. Scoliosis was more frequently observed in type II (observed in 29% of type II patients) and type III (observed in 28% of type III patients) patients, while it was not observed among type I patients (Table 1). The values for the outcome measures of motor function are reported in Table 1. According to these statistics, the average score of the CHOP-INTEND questionnaire was considerably greater for children with SMA type II than for those with type I, and the average score of the HFMSE questionnaire was considerably better in type III than in type II patients.

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Figure 3 shows the geographical distribution of the registered patients according to their place of birth. Of the 59 SMA patients, 18 (30%) were born in the city of Tehran, and the rest were born in other cities in Iran. A total of 28 (47%) patients were born in the Province of Tehran, and 31 (53%) SMA patients were born in other provinces of Iran. The place of birth of registered patients is distributed in 15 provinces (out of 31 provinces) of Iran.

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Figure 4 shows the geographical distribution of the registered patients according to their place of residence. A total of 21 (35%) patients were living in the city of Tehran, and the rest were living in other cities in the country. Of the 59 registered patients, 25 patients (42%) were living in the province of Tehran, and the others were traveling from other provinces of Iran to visit our center at Mofid Children’s Hospital. The place of residence of the enrolled patients was distributed in 18 provinces of Iran.

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Figure 5 shows the frequency distribution of the distances from the patients’ place of residence (center of city or village of residence) to the Mofid Children’s Hospital (center of Tehran city).

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The distance matrix analysis in Geographic Information System (GIS) revealed that for patients who were living outside of Tehran city, the distance from the patient’s place of residence to Mofid Children’s Hospital ranged from approximately 21 km (for a patient who was living in Eslamshahr city in Tehran province) to 1388 km (for a patient was living in one of the villages located near to the Saravan city in Sistan and Baluchestan province of Iran). The mean distance between the residence place of patients living outside of Tehran city and the Mofid Children’s Hospital is approximately 463 km.

Table 2 reports the features of the registered patients (“Number of patients”, “Sex”, “Age”, “Age of symptoms onset”, number of “Positive family history”, “SMA type”, number of patients using a wheelchair or other assisted mobility devices (“Assistive device”), number of “Acute hospitalization” days, number of “Death” among registered patients, number of patients with “Scoliosis”, number of patients using “PEG/NGT”, number of patients using “Ventilation assist”, number of patients in each “Ambulation” status, “Motor outcome” score of patients, “ACTIVLIM” score of patients, “CMAP Amplitude” of patients, number of patients received disease-modifying therapies (“Previous DMT”), and number of patients received “Rehabilitation intervention”) per the frequency of SMN2 gene copy number.

All the patients (59 individuals) had a deletion of the SMN1 gene; out of them, 53 patients were tested by multiplex ligation-dependent probe amplification (MLPA) genetic analysis. Among the 53 patients who underwent MLPA genetic testing, 2 patients (3.4%) had only 1 copy, 27 patients (45.8%) had 2 copies, 17 patients (28.8%) had 3 copies, and 7 patients (11.9%) had 4 copies or more of the SMN2 gene. Among the 24 type I patients (with MLPA test), most (63%) had 2 copies of the SMN2 gene, a single patient (4%) had 1 SMN2 copy, 16.5% had 3 SMN2 copies, and 16.5% had ≥ 4 SMN2 gene copies (Table 2). Figure 6 shows the distribution of SMN2 copy number by SMA type among the 59 patients registered in PSMAIR. In the population of the patients who underwent MLPA genetic testing (a total of 53 patients), the majority (63%) of the 16 type II patients had 2 SMN2 copies, 31% had 3 SMN2 copies, 6% had ≥ 4 SMN2 copies, and no patients had single SMN2 copies in this type. From 13 SMA type III patients (who performed with MLPA test), most of them (62%) had 3 copies of the SMN2 gene, 15% carried 2 SMN2 copies, 15% carried ≥ 4 copies, and 8% carried 1 copy of the SMN2 gene. Therefore, it can be concluded that 67% of type I patients (with the MLPA test) carried 2 ≤ copies of the SMN2 gene, and 77% of type III patients (with the MLPA test) carried ≥ 3 copies of the SMN2 gene. Furthermore, among the population of patients (who underwent the MLPA test) with 2 copies of the SMN2 gene, the number of cases decreased from SMA type I to type III. Moreover, the frequency of patients from SMA type I to SMA type III increased in the population of patients (with MLPA test) with 3 copies of the SMN2 gene (Table 2).

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Table 3 describes the features of the registered patients (“Age”, number of “Acute hospitalization” days, “SMN2 copy number”, number of patients using “PEG/NGT”, “Motor outcome” score of patients, and number of patients who received “Rehabilitation intervention”) according to their living status.

The follow-up of the registered patients at the end of September 2022 revealed that a total of 11 patients (18.6%) died; which all of them were diagnosed with SMA type I. The cause of death in all aforementioned patients was pneumonia or respiratory failure. Compared to surviving (alive) patients (age: mean ± SD = 4.85 ± 4.03 years/CHOP-INTEND score: mean ± SD = 17.05 ± 14.27), the non-surviving (dead) patients were considerably younger (mean ± SD = 0.75 ± 0.54 years) and had lower CHOP-INTEND score (mean ± SD = 8.57 ± 4.58) (Table 3). Among the patients who died, the use of PEG/NGT during the patient’s lifetime was more common (45% of patients who died) than in the surviving patients (12.5% of patients who survived) (Table 3).

By running this registry program, our main goal is to enable all children with SMA to improve their quality of life and to allow them to be involved in society. On top of enjoying the general benefits of creating a registry that were discussed before, within the framework of a pediatric SMA registry, we particularly aim to promote our limited insights into the demographic, geographic, genetic, and clinical characteristics of Iranian pediatric patients with SMA. Furthermore, we aim to monitor disease complications, assess the genotype–phenotype correlation, gather accurate clinical data for future trial studies, track the evolving natural history of SMA disease according to different conventional interventions and disease-modifying therapies, and provide evidence on the long-term effects and safety of new treatment options. Moreover, as a part of this program, we aim to accumulate knowledge and experience (on the management and treatment of SMA patients) in our healthcare system in a systematic manner (while tracking the impacts of clinical care and rehabilitation interventions), enhance national and international cooperation [between specialized centers and academic networks and the related non-governmental organization (NGOs)], raise awareness about the disease, as well as the necessity for pre-implantation and pre-natal screening, and care and treatment methods, provide reliable scientific theoretical and practical resources and informational materials in Persian (for patients, parents, and healthcare providers), and establish a reliable database to assist decision-makers and managers in performing knowledge-based planning and management to provide more efficient and effective care and treatments, produce operational excellence, and stimulate innovations and positive cultural changes.

In addition to PSMAIR, another independent nationwide registry named the Iranian Registry of SMA (IRSMA) [45] (established by the Tehran University of Medical Sciences) is also active in Iran and has been recording the demographic, clinical, and genetic characteristics of SMA patients since 2018. Compared with our registry, the IRSMA focuses on a wider group of patients, including children and adults. By October 1, 2022, the IRSMA registered 781 patients with SMA (including patients with types I, II, III, and IV). The mean age of their registered patients was 13.5 ± 13.9 years, whereas the mean ages of their surviving and deceased patients were 16.6 ± 14.0 years and 1.8 ± 2.8 years, respectively (for more information, see [45]).

According to previous studies, SMA type I has the highest incidence among the SMA types (accounting for approximately 50% to 60% of all cases diagnosed with SMA) but has the lowest prevalence due to its higher mortality rate [6, 46, 47]. SMA type II and type III patients represent approximately 20% to 30% and 10% to 20% of SMA patients, respectively [6, 48]. Our findings based on our registered population are generally consistent with these studies. The majority of our registered SMA patients were diagnosed with type I SMA (approximately 47% of registered patients), followed by type II SMA (approximately 29% of registered patients) and type III SMA (approximately 24% of registered patients). Moreover, 100% of the reported deaths among our registered patients were attributed to patients with SMA type I (the mortality rates in the populations of patients with SMA type I, type II, and type III were 39%, 0%, and 0%, respectively). On the day of follow-up (at the end of September 2022), the number of existing alive cases of SMA type I, II, and III patients in our registry, was 17, 17, and 14, respectively. In IRSMA, it was reported that from a total of 781 enrolled patients, 287, 165, 286, and 43 patients were diagnosed with SMA type I, II, III, and IV, respectively. Out of the 738 patients who were diagnosed with SMA type I, II, or III in the IRSMA, approximately 39% had SMA type I, 39% had SMA type III, and 22% had SMA type II. Furthermore, from 164 dead cases in IRSMA, 162 and 2 had SMA type I and type II, respectively, and no death was reported from other SMA types. In this context, in the population of patients with SMA types I, II, and III, the majority (approximately 98.8%) of the reported deceased patients in this population were patients with SMA type I, followed by those with SMA type II (approximately 1.2%). Previous studies [49, 50] have shown that the shorter life expectancy of patients with SMA type I may reduce their chance of being alive on the prevalence day and decrease the likelihood of being registered by parents in the patient registry. Therefore, the number of patients with SMA type I is usually underrepresented in SMA registries. For example, a study [49] indicated that most patients registered in the TREAT-NMD Global SMA Patient Registry and the Care and Trial Sites Registry (CTSR) are reported to have SMA type II, and less than 20% of patients in these registries were classified as type I. In contrast, another study [50] named a number of national registries where SMA type III was reported as the type of the majority of the registered patients [50]. Despite the differences in the specifications of PSMAIR and IRSMA, at first glance, some similar general trends in the comparable aspects of the enrolled patients in the two registries can be observed. Among others, the predominance and relatively high proportion of patients diagnosed with SMA type I (in the population of SMA type I, II, and III patients) in both registries are notable and show the considerable success of the PSMAIR and IRSMA programs in case finding and providing relatively more realistic estimates from the distribution of SMA type I in this population.

Generally, an inverse association between SMA clinical severity and SMN2 copy number was observed in many previous studies [51, 52]. These studies observed that patients suffering from milder forms of SMA disease usually carry more copies of the SMN2 gene compared with patients diagnosed with more severe SMA [53, 54]. In this context, it has been widely reported that the SMN2 copy number is a key positive modifier of the disease and can generally serve as a prognostic factor in SMA disease [8, 55]. A significant correlation between the SMN2 copy number and the SMA phenotype was also observed in this study (p-value < 0.05).

The existence of two distinct registries for SMA in Iran, where little information about SMA disease condition is still available, can be considered as an opportunity. However, this also underscores the need for a centralized information facility to facilitate data exchange and integration at the ministerial level. This recommendation is pivotal to ensure efficient collaboration and synergy between the existing SMA registries (as well as other registries in the country) that were developed under the different aims and scopes, thereby enhancing the accessibility, completeness, and coverage of the data. The establishment of such an integrated platform would harmonize practices in this area across the country, enable seamless sharing of patient information, and ultimately optimize resource allocation and empower healthcare stakeholders to make informed decisions regarding SMA management.

To create a more efficient and precise disease registry program, we held several training sessions to keep our affiliated physicians and healthcare providers up-to-date with the latest scientific information about SMA disease and its rehabilitative care and novel treatments as well as protocols related to the registry.

Despite the emergence of novel SMA drugs (for instance, Nusinersen) in recent years, individualized interdisciplinary management of SMA is still the cornerstone of treatment. In this context, it is recommended that multiple actors, including a wide-ranging medical expert team, be involved in caring for an SMA patient, together with the family [56]. However, we observed that some families, particularly those from low socioeconomic levels or outside of Tehran city, did not participate regularly in the follow-up care sessions organized for managing their children’s disease, mainly due to the segregated nature of the provided check-up services (that were offered in the different timeframes) as well as the various associated indirect and direct incurred costs for the visits. Hence, to overcome these problems to some extent in our program, we held a monthly integrated SMA clinic based on international recommendations at Mofid Children’s Hospital. In this context, a more holistic and concentrated check-up package for our monthly SMA clinic was designed. In this plan, for each type of SMA complication, easy access to a relevant specialist was provided. In this sense, respiratory issues were addressed by a pediatric pulmonologist, skeletal complications, and rehabilitation needs by a physiatrist, and medication protocols were overseen by a pediatric neurologist. Furthermore, most of these provided therapeutic and rehabilitative services were covered by government insurance. To enhance disease management outcomes, it is crucial to empower patients, their families, and other stakeholders by providing sophisticated theoretical and practical information and rich materials related to disease and treatment. In this context, to inform the target group about the nature of the SMA and its best care options, the Persian language version of the booklet entitled “A Guide to the 2017 International Standard of Care for SMA” [57] was translated and provided for use by the patients, parents, and caregivers under the umbrella of our program.

Another challenging issue in our project is currently the lack of comprehensive promotion and advertising programs for raising public and target group awareness to recruit more patients from different regions in our country. A considerable portion of the registered patients came by themselves and (their legal guardians) requested to be registered in our registry program to be evaluated for eligibility to receive Nusinersen and Risdiplam drugs. This wave of registration occurred just after they were informed (mostly through their associations and circles) that only the registered patients (in one of the existing SMA registries in the country) could receive these drugs provided by the Ministry of Health and Medical Education (MOHME) of Iran. In this sense, more robust promotion and advertising measures should be adopted, and closer and more effective communications with the target group and related associations and their circles should be formed in the future to increase the initial participation and long-term engagement of patients in our program.

Our registry systematically captures spatial information about the patients, encompassing details such as birthplace and their current residential address. The inclusion of locational data about patients within our registry can potentially offer several benefits. Geographical information on the birthplace of patients can be used in epidemiologic studies for investigating the patterns of disease incidence, prevalence, and symptoms and providing valuable insights into spatially correlated factors influencing disease incidence and progression. Additionally, the spatiotemporal information recorded in our geodatabase may also help to explore temporal trends and variations in disease prevalence and outcomes within the geographic context. By increasing the number of registered patients over time in our database, it is expected that more accurate and meaningful spatial analyses can be conducted in these interesting research lines in the future. The incorporation of data on patients’ places of residence supports appropriate resource allocation strategies for optimizing healthcare delivery and management efforts. The majority of our patients, accounting for approximately 58%, reside outside Tehran province, with a significant portion traveling considerable distances, often hundreds of kilometers from their respective cities or villages, to access our center in Tehran. The geo-data collected on patients’ places of residence hold significant potential for addressing a multitude of location-based problems. For instance, these data can be effectively leveraged to identify optimal locations for establishing future affiliated referral centers, distributing medications, and delivering essential services nationwide, particularly in light of our resource constraints. By enhancing accessibility to these centers and mitigating existing geographical disparities, such initiatives ultimately promise to promote patient care standards and improve health outcomes.

The PSMAIR is currently designed and performed with a very top-down conventional approach. However, it is believed that the inclusion of the bottom-up and citizen-engaged perspectives under the concept of citizen science in the current framework of this registry in the future stages of its development may bring some unique benefits and create significant opportunities for this program. Citizen science, which is defined as public participation in conducting scientific research, has garnered increasing interest in various areas of the health sciences in recent years [58, 59]. The participation of volunteer patients and their relatives (hereinafter referred to as citizen scientists) in citizen science health-related projects often allows scientists to accomplish research tasks at a fraction of the cost and time of traditional approaches. The citizen science approach can also help to integrate the personal, local, and traditional knowledge, experiences, and ideas of citizen scientists into health-related research. It provides learning opportunities for citizen scientists, raises their awareness about disease and treatment, increases advocacy among them, promotes behavior change, fosters social interactions, strengthens connections between citizen scientists and health sciences researchers and professionals, and improves the living situation of volunteer patients [58, 60]. To date, relatively few health-related projects have examined leveraging citizen scientists’ power in the different stages of rare diseases research (for instance, see [61‐67]). Overall, previous studies showed that the integration of the citizen science approach in rare diseases research frameworks is an effective strategy and can open up new opportunities and perspectives. Furthermore, given the various benefits, the value of patient-centric registries formed under the citizen science paradigm is increasingly being recognized in health-related research [68‐70], including in the area of rare disease studies [71, 72]. Citizen scientists can potentially fully or partially be involved in the conceptual and operational aspects of a registry, such as defining research questions, measures, and priorities, identifying new candidates to be recruited in the registry, collecting data for the registry, communicating the outcomes in patient-friendly language, disseminating outcomes, and co-authoring papers on the findings of registers [68‐70, 73]. In this context, to address some of the current limitations of our study (for instance, limited geographical and temporal coverage of the registry, as well as limited budget and professional human resources), and enhance the robustness of the registry (for instance, by incorporating the voices and priorities of the patients and their relatives in the improvement of registry design and increasing the collaboration between patients, as well as patient community and other stakeholders of the registry), one of the future directions of this research is to investigate the feasibility of adopting citizen science and explore the various dimensions and levels of integration of the citizen science approach (in other words, studying the possible levels of citizen scientists engagement [74]—particularly beyond the self-reporting of basic information) into our program.

It is widely believed that early diagnosis of SMA in children is critical to modifying disease progression, increasing the chance of survival, improving intervention outcomes, and reducing patient and caregiver stress [9, 75]. Including SMA in the routine of national screening program will not only promote patients’ quality of life and life expectancy but is also essential for reducing some of the direct and indirect costs of the disease that are imposed on society [76, 77]. In the absence of a national screening program for SMA disease in our country, we hope that the current activities and outcomes of the existing SMA registries in the country can provide enough evidence for policy-makers in the future to assess the cost and benefits of establishing a nationwide SMA screening program more precisely. Furthermore, we hope that the conducting of this registry program will gradually increase awareness within society regarding the disease’s symptoms and existing treatments, particularly among those with a positive family history of SMA. This heightened awareness is anticipated to facilitate early intervention and treatment initiation for affected children, which consequently leads to better outcomes.

This study presented the framework and initial findings of the pediatric SMA registry in Iran. This initiative marks a step forward in understanding the demographic characteristics, geographic distributions, genetic and clinical characteristics, and treatment outcomes of the Iranian pediatric SMA population. The insights gained from this registry are instrumental in shaping SMA care standards, informing policy, optimizing healthcare services, and ultimately improving outcomes for pediatric SMA patients in Iran and beyond.