Background
Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by symmetrical progressive muscle weakness and atrophy due to degeneration of motor neurons in the anterior horn of the spinal cord, with an incidence of approximately 1 in 8000 live births [
1‐
3]. The phenotype of SMA extends from a severe presentation in childhood, with hypotonia and generalized weakness at birth, to an adult-onset disease with mild symptoms. Historically, based on the age of onset and the best motor function achieved, five types of SMA (SMA0, SMA1, SMA2, SMA3, and SMA4) have been distinguished [
4]. Type 3 SMA (SMA3) is divided into SMA3a (first symptoms appear before 3 years of age) and SMA3b (onset after 3 years of age) [
5,
6].
SMA is caused by homozygous deletion of exon 7 in the survival motor neuron 1 (
SMN1) gene [
7] or—less frequently—by
SMN1 point mutations on one allele occurring in a compound heterozygous state with deletion on the other allele [
8,
9]. An increased
SMN2 copy number alleviates the clinical course of SMA [
10]. Patients with SMA1 usually have two copies of
SMN2, those with SMA2 usually have three copies, and those with SMA3 or SMA4 have three or more copies [
10‐
13].
Registries of patients with rare disorders, such as neuromuscular diseases (NMDs), have an important role in monitoring the course of the disease, defining trial or treatment-ready population. In 2007, the Translational Research in Europe and Treatment of Neuromuscular Diseases (TREAT-NMD) project (
http://www.treat-nmd.eu) was initiated as a European Committee-funded Network of Excellence to support translational research in the field of NMDs. An important tool to achieve the aims of the TREAT-NMD project was the creation of a global database of patients in national registries. The structure of the registry and the cross-sectional results of this international collaboration have been reported previously [
14]. The Polish Registry of SMA was created in 2010 following TREAT-NMD guidelines within a research project funded by the Polish Ministry of Science and Higher Education (641/N-TREAT/09/2010/0). Since then, data have been collected, curated, and updated at a single neuromuscular referral center.
The aim of this study is to describe the patients included in the Polish Registry of SMA and to analyze the clinical course of SMA3 before disease-modifying treatment became available in Poland.
Discussion
The Polish Registry of SMA was set up under TREAT-NMD initiative in 2010. The main purpose of TREAT-NMD was to improve trial-readiness, advance patient diagnosis and care, and accelerate the search for therapies for patients with NMDs. During the last few decades, the number of SMA registries and registered patients has been growing quickly worldwide. In October 2019, the cut-off date for our analysis, the Polish Registry of SMA included 790 patients, which makes our registry one of the largest national databases of patients with SMA [
14,
15]. The most dynamic increase in the number of enrolled patients was directly related to the approval of nusinersen in 2016 in the USA and a reimbursement decision in Poland in December 2018. The first Polish patients began nusinersen treatment in the National Health Program in April 2019. Only 33 patients treated with nusinersen were included in our study (19 with SMA1, ten with SMA2, and four with SMA3) at data cut-off. The four patients with SMA3 were excluded from the analysis on ambulation, so our study was able to characterize Polish patients with SMA3 prior to the era of widely available treatment that changes the natural history of SMA.
Half of our 790 patients had SMA3. SMA1 constituted 22% and SMA2 28% of the population in the registry. The proportion of SMA types in the Polish registry reflects the real-world prevalence of SMA types, although previous data on the incidence of SMA indicate that SMA1 accounts for about 50% of all SMA patients [
2]. The predominance of SMA3 has also been observed in other registries [
14]. In the Global TREAT-NMD Registry (more than 5000 patients), the proportion of SMA1 patients was even smaller. This situation is probably caused by the severe disease course and high mortality of SMA1 before the era of pharmacotherapy.
Contrary to data in the TREAT-NMD Global Registry or Cure SMA Registry most of our patients (52%) are adults and 37% of them are in the age range 18–39 years [
14,
16]. Our observations could therefore provide new insights into the later stages of all SMA types. Additionally, this should raise awareness of the spectrum of issues associated with SMA in adult life, such as education, professional activities, parenthood, or coexisting age-related diseases.
In all 790 patients, the diagnosis of SMA5q was confirmed by genetic testing, which has been widely available in Poland since 2000. In the past decade the SMN2 copy number has also been assessed routinely at diagnosis. Additionally, many patients who were diagnosed with SMA earlier were referred to genetic laboratories for evaluation of their SMN2 copy number.
Data on
SMN2 copy number were available in 672 patients in the registry.
SMN2 copy number is known to be an important modifier of the disease, but it is not sufficient to predict phenotype [
12,
13]. Nevertheless, three copies of
SMN2 are usually attributed to the SMA2 phenotype [
10,
12,
17]. This fact was also confirmed in our study as 82% of patients with SMA2 had three copies of
SMN2. Interestingly, the percentage of patients with three copies of
SMN2 in our cohort is also high among patients with SMA1 (57%) and SMA3 (54%). In a study of the Spanish population, 86% of patients with SMA1 had two copies of
SMN2 and only 6% had three copies [
10]. By contrast, in a Dutch study 21 of 23 patients with a milder course of SMA1 had three copies of
SMN2 [
18]. Additionally, in a previous study in the Polish population, 41% of 204 patients with SMA1 had three copies of
SMN2 [
13].
Our results are probably related to the structure of the analyzed group, which included a high percentage of patients with SMA1 with a long survival time. This overrepresentation of a milder form of SMA1 in our registry could be explained by the burden on the parents of children with a severe SMA1 phenotype precluding enrollment of acute cases in the registry.
We observed 21 (6%) patients with SMA3 and two copies of
SMN2. A similar proportion was reported in several studies. Calucho et al. [
10] reported that about 5% of patients with SMA3 had two copies of
SMN2 in a combined large cohort of patients. Similarly, in a recently published multicenter study on clinical variability in SMA3, 5% of 182 patients had two copies of
SMN2. Interestingly, in a group of ambulant patients with SMA3b, this percentage reached 13% [
19]. Among German patients with SMA3a, nearly 12% had two copies of
SMN2 [
11].
The milder course of the disease in patients with two copies of
SMN2 could be explained by the presence of additional modifying factors, such as the polymorphism c.859G > C in exon 7 or A-44G transition in intron 6 of the
SMN2 gene [
20,
21]. We did not test this hypothesis in our cohort. It is recognized that other factors modify the phenotype. In some cases of SMA3 with two copies of
SMN2 or SMA3b with three copies of
SMN2 the polymorphism c.859G > C in exon 7 of the
SMN2 gene was excluded [
10,
22].
In our cohort, we observed five patients with SMA1 and four copies of
SMN2. Single patients with such a discrepancy between genotype and expected phenotype have been reported previously [
10,
18]. We are aware that, if in doubt, the
SMN2 copy number should be validated by an expert laboratory with good quality control. This is of utmost importance in pre-symptomatic patients, as it may determine the treatment strategy [
23].
44% of patients with SMA3 in our registry were still able to walk. The mean age of immobilization of patients with SMA3 was 14.0 years. In the TREAT-NMD Global Registry, some country-specific differences in the age of immobilization were observed. For example, the mean age of loss of ambulation in Ukraine was 9 years, compared with 19 years in the UK [
14]. In a prospective, multicenter study of 28 patients with SMA3 from France, Belgium, and Germany as well as in a study based on the International SMA Registry, the mean age of loss of ambulation was 12 years [
17,
19]. Besides being based on a smaller number of patients, both studies included only young adults, compared to the wide age range in our registry.
The Kaplan–Meier survival curves showed that the prognosis for being ambulant was significantly worse for patients with SMA3a than for those with SMA3b. 58% of patients with SMA3a were still able to walk after a disease duration of 10 years, 37% after 20 years, and 33% after 30 years, whereas the prognosis was much better in patients with SMA3b and the corresponding numbers were 89%, 78%, and 69%. A similar analysis was presented in a collaborative study on German and Polish patient data collected from the 1960s to the 1990s. In that study, the probability of being ambulatory was 70% after 10 years, 33% after 20 years, and 22% after 30 years for patients with SMA3a, and the corresponding numbers for SMA3b were 96%, 84%, and 70% [
5]. Our data confirm the observation that earlier symptom onset leads to a more severe phenotype [
5,
22]. This further supports the need for early diagnosis and pharmacotherapy [
23].
We also analyzed the influence of
SMN2 copy number on the age of onset and walking functions in patients with SMA3. The age of first symptoms in patients with three copies of
SMN2 was more than two times earlier than in those with four copies (3.01 years vs. 6.71 years). Additionally, patients with SMA3a more frequently had three than four copies of
SMN2 (64% vs. 28%), in contrast to SMA3b (40% vs. 52%). The empirical subdivision of patients with SMA3 into SMA3a and SMA3b was first supported by genetic testing by Wirth in 2006 [
10,
11,
13,
18,
22].
Although, by definition, SMA3 should be diagnosed in children with symptom onset after 18 months of age [
4‐
6], 59 patients with SMA3 in our cohort had their first symptoms earlier. Our observations show that the age of onset in SMA3 overlaps with that of SMA2, illustrating the continuum of clinical severity. Classification based on age of onset with a cut-off of 18 months to separate SMA2 and SMA3 can result in about 15% of patients not fitting any traditionally defined type of SMA. An age of onset below 18 months was also reported in patients with SMA3 in previous studies [
22,
24].
We also confirmed that
SMN2 copy number plays a substantial role in the prognosis for ambulation in SMA3. Patients with four copies of
SMN2 had a significantly higher chance of walking independently after a certain disease duration than patients with three copies of
SMN2. Additionally, patients with SMA3b with three or four copies of
SMN2 had a substantially better prognosis for ambulation. The largest differences in the probability of preserving the ability to walk were noted between patients with SMA3b with four copies of
SMN2 and patients with SMA3a with three copies of
SMN2. Multifactorial analysis showed that patients with three or fewer copies of
SMN2 have a two times higher risk of immobilization than those with four copies. Although the number of copies of
SMN2 plays an important role in the disease course, there are certainly other SMA-modifying factors [
25]. Better prognosis for ambulation in patients with SMA3 with four copies of
SMN2, regardless of the age of onset, was also reported in other studies [
18,
22,
26].
Interestingly, a recent multicenter study on the natural history of SMA3 in a large cohort reported that age, SMA type, and ambulatory status were significantly associated with changes in mean Hammersmith Functional Motor Scale Expanded (HFMSE) score, but that sex and
SMN2 copy number were not [
19].
Our study revealed the influence of sex on some aspects of SMA. There was a significant male predominance among patients with SMA3b (female:male = 0.58, p < 0.001) as well as in patients with SMA3 with four copies of SMN2 (female:male = 0.43). In SMA4, all six patients were male. In SMA1 and SMA3, the age of onset was significantly earlier in female patients.
The influence of sex was observed in some previous studies, which reported a low proportion of female patients with symptom onset after 8 years of age [
27,
28]. Male predominance in the chronic form of SMA was also described previously in a Spanish cohort and in the International SMA Registry (female:male = 0.7) [
19,
29]. In another study on patients with Spanish origin, a significant predominance of male patients was found among those with SMA2 and SMA3 [
22].
The small number of female patients with SMA3 and four copies of
SMN2 in our cohort corresponds with the small number of female patients with SMA3b. In our registry, a significantly smaller number of female patients with four copies of
SMN2 may support the view that a higher proportion of female individuals are asymptomatic carriers of biallelic
SMN1 deletions [
28,
30,
31].
In our study, Kaplan–Meier statistics did not show statistically significant differences in the prognosis for ambulation between female and male patients with SMA3 or in subgroups with SMA3a or SMA3b. However, in a multifactorial analysis that took into account sex,
SMN2 copy number, and disease duration, the risk of loss of ambulation for a female patient was two times lower than for a male patient. All these observations indicate a possible relationship between sex and the course of SMA, as reported in other studies [
13,
19,
22,
27‐
31].