A self-reported Brazilian registry of spinal muscular atrophy: data from natural history, genetic characteristics, and multidisciplinary care

doi:10.21203/rs.3.rs-2882037/v1

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A self-reported Brazilian registry of spinal muscular atrophy: data from natural history, genetic characteristics, and multidisciplinary care

https://doi.org/10.21203/rs.3.rs-2882037/v1

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Background. Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. This study is intended to describe the key demographic, clinical and genetic characteristics, and natural history data of patients with SMA registered through a self-reported survey by patients or their parents.

Results. By January 2022, 706 patients with 5q SMA had completed the questionnaire and had confirmatory molecular testing. Most patients reported having type 1 SMA (42%); 33% had type 2 SMA, and 23% had type 3 SMA. Six hundred sixty-seven patients (94.4%) had a homozygous SMN1-exon 7 deletion. One hundred thirty-one (18.6%) patients had a previous family history, and the familial recurrence rate was higher in patients with type 3 SMA, at 25.6%. The consanguinity rate was 5.2% in the studied population. Type 1 patients had a mean age of 3 months at the onset of symptoms and a delay of more than 3 months until genetic diagnosis. The median survival of patients with type 1 SMA without invasive ventilation was 27 months. Before 2018, the median age at the endpoint was 16 months, and after 2018, most patients (71%) were not submitted to invasive ventilation. About 50% of patients with type 3 SMA lost their walking ability by 37 years of age. Three hundred eighty-four (54.4%) patients claimed to have had access to some disease-modifying therapy, and 62.3% of type 1 patients were in treatment, while only 47.2% of type 2 SMA patients and 31.9% of type 3 SMA patients were in treatment.

Conclusions. This is the first Brazilian registry of SMA and evidenced the accuracy and reliability of patient-reported data compared to previous studies. There is still a substantial diagnostic delay, especially in those patients with types 2 and 3 SMA. However, the study demonstrated prolonged survival, especially in type 1 patients.

Spinal muscular atrophy

patient registry

online registry

SMN1

diagnosis delay

natural history data

Spinal muscular atrophy (SMA) is a neurodegenerative disorder of lower motor neurons from the spinal cord and motor nuclei of the brainstem, leading to severe proximal and symmetrical weakness associated with progressive motor function disability, ventilatory insufficiency, and spinal deformity [1]. The most prevalent form of SMA is caused by deletions or disease-causing variants in the survival motor neuron 1 (SMN1) gene, which segregates as an autosomal recessive trait [2].

The classification of SMA in at least three subtypes depends on the age of disease onset and the achievement of motor milestones [1]. Type 1 SMA is a severe form characterized by an onset at 0–6 months, and children cannot sit unaided [3]. In type 2 SMA (intermediate form), the clinical manifestations start between 6 and 18 months of age, and children cannot stand or walk unaided. Children with type 3 SMA (mild form) manifest the disease in the second year of life or later and can walk unaided [1]. Type 3 SMA can be classified as 3a or 3b, with onset before 3 years of life, with earlier gait loss in 3a and symptoms starting later (from the third year until adolescence) in type 3b [4]. Outliers of this classification have been recognized, including a mild adult form or type 4 disease with slow progression of weakness [3, 4].

SMA incidence is around 1 in every 10,000 live births [5]. Unfortunately, we do not have Brazilian data on the incidence and prevalence of the disease. The National Institute of SMA (INAME) is a Brazilian non-governmental association of patients and families with SMA. It aims to promote public policies to improve care for patients with the disease and health professionals’ knowledge of the disease and its clinical care. In the informal INAME register, about 2,000 registered patients received a medical diagnosis of SMA, but a scientific committee has not validated these data.

Starting from the INAME database, the association’s scientific committee prepared an online survey to be completed by the patients or their families to collect epidemiological data, establish the genetic characteristics and genotype–phenotype correlation, and understand the data on the natural history of the disease in our country as well as the provided multidisciplinary care. In this work, we intend to present the data collected from the first year of this registry.

The INAME’s registry aims to obtain retrospective and longitudinal data from Brazilian patients with SMA, and here, we report on the initial retrospective phase. Patients or families from the INAME database were invited to participate in the self-reported registration. The project was approved the ethics committee, and the patients who agreed to participate in the study signed an informed consent form electronically.

This registry was based on the TREAT-NMD SMA Registries Core Dataset [6]. Patients or family members answered 117 questions, which encompassed demographic aspects, diagnosis, natural history, and treatments, among others. Table 1 shows subdivisions of the survey into seven sections encompassing various aspects. The complete questionnaire is available in the supplementary material. In addition, the data collected in the online questionnaire was transferred to a digital database for further analysis.

Data were collected from January 2021 to January 2022. Inclusion criteria were patients with a confirmed molecular diagnosis of SMA (regardless of age), and patients were asked to upload the molecular test to the system. The neurologists of the scientific committee (EZ and RHM), specialized in neuromuscular diseases, reviewed all genetic tests; patients without a molecular diagnosis of 5q-SMA were excluded. On several occasions, the study’s auxiliary team contacted patients or family members directly (by telephone) to help complete the questionnaire or collect missing data.

The second phase of the study, to be started in 2023, will collect missing data in the initial period and include data on survival and complications presented in the follow-up. In addition, the further phases will be essential to update the data regarding the pharmacological therapies in use, given our country’s constant evolution to access these therapies.

Table 1

Study design and form sections.
Online survey answered by patients
Retrospective data collected from January 2021 to January 2022
A) IDENTIFICATION (demographic data) B) SOCIOECONOMIC PROFILE C) DIAGNOSIS (time of symptoms onset, time to diagnosis, genetic characteristics) D) DRUG TREATMENT (time to start disease-modifying drugs, switch) E) CLINICAL OBSERVATIONS, comorbidities, HOSPITALIZATION (data from natural history, loss of motor functions, time to ventilatory support) F) MULTIDISCIPLINARY INTERVENTIONS (surgeries, respiratory and motor physiotherapy, nutritional support and speech therapist, motor scales evaluation) G) HEALTH SERVICE PROVIDERS (Health insurance, public health system, home care)
Follow-up: from 2023 to 2026

Statistical analysis

Quantitative variables were described by median and interquartile range, while absolute and relative frequencies described qualitative variables. The Kruskal-Wallis test was used to compare quantitative variables between types of SMA. For time-to-an-event outcomes, the Kaplan-Meier estimator was used to estimate survival curves, and the log-rank test was used to compare groups. All analyses were performed using the R software, always considering a 5% significance level.

Seven hundred fifty participants completed the online questionnaire. Of these, 44 were excluded from this initial analysis because they reported either not having a molecular diagnosis or did not upload the test to the system. Thus, we included 706 patients in this initial analysis.

Demographic data

Most of the 706 patients had type 1 SMA (42%). Among the others, 33% had type 2 SMA, and 23% had type 3 SMA. Seven patients had type 0 SMA, and eight had type 4 SMA (Fig. 1A). Distribution according to sex was similar in the total study population and in those with types 1 and 2 SMA. Among patients with the milder form, there was a slight predominance of females (61.2%, Fig. 1B).

The median age of patients with type 1 SMA was 3.0 (1.0, 6.0) years (Fig. 1C shows the distribution of patients with type 1 SMA according to age). At the time of data cut-off, 37.5% of patients with type 1 SMA were older than 4. The median age of patients with type 2 SMA was 11.0 (6.0, 21.5) years, and 45% were adolescents or adults (Fig. 1D).

Diagnosis and genetic data

Regarding mutations in the SMN1 gene, 667 patients (94.4%) had a homozygous SMN1-exon 7 deletion. Thirty-eight patients (5.5%) had a heterozygous deletion in SMN1 and a point mutation in the other allele. Only one patient had a point mutation in both SMN1 alleles (p.Gly261.Leufs*8); in this situation, the parents were consanguineous. The molecular test used for diagnosis in 515 (73%) patients was MLPA (Multiplex Ligantion-dependent Probe Amplification). PCR reaction for detecting homozygous SMN1-exon 7 deletion was used in another 191 (27%).

Regarding the SMN2 copy number, two copies of SMN2 correlated with a more severe condition (type 1 SMA) and occurred in 78.1% of these patients. A higher number of SMN2 copies correlated with milder phenotypes (Fig. 2A), with most patients with type 2 SMA (72.4%) presenting three copies of SMN2 and 31.4% of type 3 SMA patients presenting four or more copies. One hundred thirty-one (18.6%) patients in the entire group had a family history of the disease, and the familial recurrence rate was higher in those patients with type 3 SMA, at 25.6% (Fig. 2B). The consanguinity rate was low in the studied population, and only 37 (5.2%) patients answered that there was some degree of relation between the parents.

Regarding the time until diagnosis, patients with type 1 SMA had a mean age of 3 months at the onset of symptoms and a mean time elapsed of an additional 3 months until genetic diagnosis (Table 2). The year 2018 was noteworthy, as the pharmaceutical industry began offering the molecular testing (MLPA and gene sequencing). Thus, 55% of the diagnostic tests registered in this study were carried out in 2018. From that year on, the average time for genetic diagnosis of all types of SMA shortened from 14 to 9 months. Awareness about the signs and symptoms of the disease also increased, which shortened the time for clinical diagnosis of type 2 and type 3 SMA from 11 to 9 months and from 24 to 22 months, respectively (Table 2).

Table 2

Time elapsed in the natural history of the disease from the onset of symptoms to diagnosis and initiation of treatment (disease-modifying therapy). The difference in diagnostic times before and after 2018.
Clinical characteristics	Total, N = 706¹	Type 1, N = 296¹	Type 2, N = 235¹	Type 3, N = 160¹	Value p²
The time between birth and onset of symptoms (months)	7.0 (2.0, 18.0)	3.0 (1.0, 5.0)	10.0 (6.0, 15.0)	27.0 (15.0, 50.5)	< 0.001
The time between the onset of symptoms and clinical diagnosis (months)	6.0 (1.0, 18.0)	2.0 (1.0, 4.0)	10.0 (4.0, 20.0)	24.0 (9.0, 89.0)	< 0.001
The time between the onset of symptoms and genetic diagnosis (months)	14.0 (3.0, 95.5)	3.0 (2.0, 6.0)	29.0 (11.5, 181.5)	169.5 (25.2, 296.2)	< 0.001
The time between clinical diagnosis and initiation of pharmacological treatment (months)	14.0 (3.0, 95.5)	6.0 (2.0, 29.0)	37.5 (12.0, 116)	*	< 0.001
The time between the onset of symptoms and clinical diagnosis (months)
Before 2018	8.0 (2.0, 23.0)	2.0 (0.0, 4.0)	11.0 (5.8, 24.0)	24.0 (6.2, 89.0)	< 0.001
After 2018	3.5 (1.0, 14.0)	2.0 (0.0, 4.0)	9.0 (3.0, 18.0)	22.0 (11.2, 53.0)	< 0.001
The time between the onset of symptoms and genetic diagnosis (months)
Before 2018	18.0 (5.0, 84.0)	4.0 (2.0, 9.8)	53.5 (14.2, 227.8)	164.0 (24.5, 311.0)	< 0.001
After 2018	10.0 (2.0, 100.5)	3.0 (1.0, 5.0)	18.0 (7.0, 43.5)	106.5 (25.2, 255.5)	< 0.001
¹Median (IQR); ²Kruskal-Wallis test ; * Data not reliable because most SMA type 3 patients did not have access to therapies.

Natural history data

In type 1 SMA patients, 50% underwent invasive ventilation up to 27 months of age. For patients with two copies of SMN2, the median time was 24 months. It was impossible to estimate the median in those patients with three copies, although no difference was observed between the survival curves (p = 0.5) (Fig. 3A).. The survival curve relative to the time until invasive ventilation in type 1 patients according to birth year shifted starting in 2018. For those born before 2018, the median time until the use of invasive ventilation was 16 months (IQR: 10–27), and for those born after 2018, the median was not possible to estimate because only 29% of patients underwent invasive ventilation (p = 0.002, Fig. 3B).

Other natural history data obtained included the loss of gait in type 3 SMA patients. Patients answered the date on which they lost the ability to walk for at least 10 meters without support. About 50% of patients with type 3 SMA lost walking ability by 453 months of age, or 37 years (first quartile of 22.3 years, Fig. 4A). Gait loss appeared earlier in patients with three copies of SMN2 than in those with four copies. The Kaplan-Meier curve of gait loss according to SMN2 copy number showed a p-value close to statistical significance (p = 0.077, Fig. 4B). The median age of patients who lost independent walking ability was 12 years (IQR: 8–21).

Multidisciplinary care and previous surgery

Most patients with type 1 SMA (60.5%) were on invasive ventilation, as mentioned before. Among type 2 SMA patients, 49.3% did not use any ventilatory support, and 42.5% used noninvasive ventilation for some period (Fig. 5A). Regarding respiratory assistance, 411 (58.2%) patients received respiratory physiotherapy at least once weekly. Two hundred patients (28.3%) said they knew or performed the air stacking technique with bag valve mask. Although many patients reported undergoing respiratory physiotherapy, only 276 (39.1%) stated that they had already performed a vital capacity test or spirometry. Only 33% said they knew about or used cough-assist machines.

Regarding motor rehabilitation care, 534 patients (75.6%) said they received motor physical therapy at least once weekly. Of these, 359 (50.8%) received it more than twice a week. Although many patients had received motor physical therapy at least once, only 379 (53.7%) responded that they had already been evaluated through some motor function scale. The proportion of patients evaluated by motor scales according to the SMA types did not differ between groups, with 175 (59.1%) in type 1 and 118 in types 2 (50.2%) and 3 (52.5%).

Thirty-two percent of patients answered that they used gastrostomy (Fig. 5B). The use of gastrostomy was higher in type 1 (78.7%) patients, with an inversion of this proportion occurring in type 2, with 78.7% of patients on an exclusively oral diet. In addition, 299 (42.3%) patients said they had access to a speech therapy professional at least once a week. Scoliosis was reported in 54.4% of all patients and was higher in type 2 SMA patients (70.6%), followed by those with type 3 (57.5%) and type 1 (42.2%). Twenty-one percent of patients had undergone scoliosis surgery, more than half of whom had type 2 SMA.

At least 101 patients (14.3%) reported one unplanned hospitalization last year. Patients with type 1 SMA reported having had one or two unplanned hospitalizations in the previous year (24%), compared to the other types of SMA (6.3% for type 2 and 4.3% for type 3, p < 0.001)

Disease-modifying therapies

By the cut-off date in January 2022, 384 (54.4%) patients claimed to have had access to some disease-modifying therapy. The majority, 359 (93.5%) patients, were using nusinersen, as it was the only drug available through the public health system in Brazil. Another 18 (4.7%) patients reported using gene therapy, and 7 (1.8%) used risdiplam. The median treatment time was 15 months (6, 26).

When stratifying access to nusinersen treatment according to SMA types, 62.3% of patients with type 1 were in treatment, while only 47.2% of type 2 patients and 31.9% of type 3 patients were in treatment. This difference is justified because, at the time of the data analysis, nusinersen was fully distributed in the public health system only for patients with type 1 SMA.

The importance of patient registries concerning hereditary neuromuscular diseases such as SMA has increased. In North America and Europe, national registries have identified more than 5,000 patients with SMA, making it possible to know and measure the regional characteristics of the disease and its care [7]. These records are scarce in Latin America [8], and this report concerns the first SMA patient registry.

Although subject to systematic errors and lack of information, self-reported registries by patients with neuromuscular diseases have proven useful and provide realistic results [9, 10]. High-quality data and convergence of patient- and physician-reported outcomes in similar registries of other neuromuscular diseases have been reported [11]. The self-reported data here seem to be reliable, and the proportion between the SMA types is similar to that previously reported, in which the most frequent presentation of the disease is its most severe form [12]. Although the data presented here are about prevalence and not incidence, 42% of the patients reported in our study reported having type 1 SMA. Interestingly, a recently published Italian survey showed a prevalence of type 1 SMA in only 22.6% of patients in the era of disease-modifying therapies, the same context as our study [13].

Also corroborating the quality and reproducibility of our results is the fact that the number of patients with a homozygous deletion in the SMN1 gene was closer to that reported in previous studies [14], at around 94.4% of patients. In a previous Brazilian study, authors reported less than 90% of patients with SMA having a homozygous exon 7-SMN1 deletion, perhaps because the latter presented a higher proportion of patients with milder disease phenotypes [15].

The diagnostic journey of SMA in our population still involves challenges. The mean age at onset of symptoms for type 1 SMA was similar to other studies, ranging from 2 to 3 months old [16, 17]. Considering the time from symptom onset to genetic diagnosis, a diagnostic delay is seen in all types of SMA. The greater the delay, the milder the phenotype of SMA, of the order of 3 months in type 1, 29 months in type 2, and 169 months in type 3—longer diagnostic delay times than previously reported in systematic reviews [16], especially in types 2 and 3. Although the time between the onset of symptoms and clinical and genetic diagnosis has improved dramatically since 2018, there is still a gap to be improved, considering that the final diagnosis time for type 1 SMA has only improved by 1 month since 2018 and compared to recent studies [17]. Another gap in our country is the difficulty in accessing therapies, which makes it difficult to determine the treatment time correctly starting from the onset of symptoms, especially in type 3.

Still, regarding the genetic data of our population, the presence of consanguinity was low in the study population (less than 5%), which shows considerable regional variability. A recent Iranian registry showed a rate of 52.4% of consanguinity [18]. This low consanguinity rate in our population alerts us to a possible high prevalence of asymptomatic carriers for SMN1 deletion, which should be in the order of 1 to 37 persons, as reported by other studies in the Brazilian population [19]. The high recurrence rate of type 3 SMA (around 25%) was similar to that reported by a recent Iranian registry [18]. It may reflect a longer diagnostic delay, preventing adequate genetic counseling given the milder phenotype.

It was possible to evaluate survival beyond the expected span for patients with type 1, since the most prevalent form of SMA in our registry was type 1 (42% of patients), and 37.5% of them were older than 4 years, unlike the data reported by current SMA registries [13, 18]. This finding reflects an improvement in multidisciplinary care and the institution of disease-modifying therapies [20, 21]. In addition, the large number of adolescent and adult patients in this sample is noteworthy, with 45% of type 2 patients being over 12 years of age and type 3 patients having a median age of 26. These data reflect the need to develop scales and surveys for this kind of patient concerning disease progression and quality of life [22, 23].

Natural history data in the Brazilian population are unpublished, and the mean age at the start of invasive ventilation in type 1 SMA is already much better than that reported by natural history studies. The patients in this registry had a median survival of 27 months until invasive ventilation, compared to 8 months in the Neuronext study [24] and 13.5 months in the PNCR study [25]. Unlike the study by Finkel et al., it was not possible to verify differences in ventilation-free survival between patients according to two or three copies of SMN2. However, evaluating ventilation-free survival before and after 2018, when disease-modifying therapies started to be used (mainly nusinersen), we found a drastic change from a median of 16 months (before 2018) data similar to that of the PNCR study [25], for an estimate that cannot be measured after 2018. This reinforces the high effectiveness of current therapies in modifying the natural history of type 1 SMA.

Loss of walking ability in type 3 SMA patients is also important natural history data. For example, our study showed that half of the patients with type 3 SMA would lose their ability to walk by age 37. In addition, those patients who had already lost the ability had a median age of 12 years. A recent observational study of type 3 SMA showed an age of 14 years at the loss of these motor skills [26]. Currently, this is the only SMA population in our country that does not have access to disease-modifying therapies through the public and universal health system and progressively loses functionality and independence, which is characteristic of a disease that occurs at all ages [27].

The study has some limitations. First, it consisted of a survey answered by patients and their families, in which there may be biases in the reliability of some more technical data. Second, many answers about natural history depend on the memories of those answering the questions regarding the dates or periods in which losses of motor functions occurred. Finally, the data were collected until the end of 2021. Concerning access to disease-modifying therapies, the data need to be updated, given the constant changes in local protocols making new therapies available and including patients with type 2 SMA as eligible for treatment in Brazil [28]. The prospective phase is intended to correct this limitation, updating the data regarding access to therapies. In addition, the prospective phase is intended to better assess the incidence of intercurrences and hospitalizations and to evaluate improvements implemented in multidisciplinary care, in addition to better assessing the survival of the most severe forms with the institution of therapies.

Our results are unprecedented in the Brazilian population, as this is our country’s first SMA registry. We evidenced the accuracy and reliability of patient-reported data compared to previous studies. There is a substantial diagnostic delay, especially in those patients with types 2 and 3 SMA, but there has been an improvement since 2018. Natural history data already demonstrate prolonged survival, especially for type 1 patients, and the outcome of invasive ventilation has changed dramatically since 2018 with the advent of disease-modifying therapies. Patients with type 3 SMA suffer from progressive loss of gait and functionality and lack broad access to new therapies. In the prospective phase of the study, we will assess improvements in access to therapies and changes in clinical outcomes.

Ethics approval and consent to participate

The project was approved by the ethics committee of Instituto Dante Pazzanese de Cardiologia (project number 38534320.6.0000.5462, final approval of ethics committee number 5.621.165).

Consent for publication

The patients who agreed to participate in the study signed an informed consent form electronically.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available due to containing personal data but are available from the corresponding author upon reasonable request.

Competing interests

RHM received fee from Novartis for speaking at symposia and participating in clinical trials. EZ received fee from Novartis for speaking at symposia and participating in clinical trials. Other authors declare no conflicts of interest in relation to this publication.

Funding

The study received financial support from Novartis Biociencias and Roche Pharmaceuticals.

Authors' contributions

RHM acquired data, conceived and designed the work, revised and approved the final version of the manuscript. JSAG acquired data and conceived the work. EZ designed the work, revised and approved the final version of the manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgements

We thank all SMA patients and their relatives who agreed to participate and respond to the online survey. We also thank the entire INAME team, who carried out a task force to gather all the data.

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A self-reported Brazilian registry of spinal muscular atrophy: data from natural history, genetic characteristics, and multidisciplinary care

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Abstract

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Background

Methods

Statistical analysis

Results

Demographic data

Diagnosis and genetic data

Natural history data

Multidisciplinary care and previous surgery

Disease-modifying therapies

Discussion

Conclusions

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References

Supplementary Files

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