Keywords Muscular Atrophy, Spinal - Survival of Motor Neuron 1 Protein - Natural History -
Registries
Palavras-chave Atrofia Muscular Espinal - Proteína 1 de Sobrevivência do Neurônio Motor - História
Natural - Sistema de Registros
INTRODUCTION
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 ventilatory insufficiency and spinal deformity.[1 ] The most prevalent form is caused by deletions or disease-causing variants in the
survival motor neuron 1 (SMN1 ) gene, located in chromosome 5q (SMA-5q), which segregates as an autosomal recessive
trait.[2 ]
The classification of SMA-5q in at least three subtypes depends on the age of disease
onset and the achievement of motor milestones.[1 ] Type 1 SMA-5q is a severe form characterized by onset at 0 to 6 months, and children
cannot sit unaided.[3 ] In type 2 SMA-5q, the clinical manifestations start between 6 and 18 months of age,
and children cannot walk unaided. Children with type 3 SMA-5q manifest the disease
in the second year of life or later and can walk unaided.[1 ] Many patients present intermediate phenotypes between types 1 and 2.[4 ] Outliers of this classification have been recognized, including a mild adult form,
or type 4, with slow progression of weakness.[3 ]
[4 ]
The incidence of SMA-5q is around 1 every 10,000 live births.[5 ] Unfortunately, we do not have previous Brazilian data on the incidence and prevalence
of the disease. The Brazilian National Institute of Spinal Muscular Atrophy (Instituto
Nacional da Atrofia Muscular Espinhal, INAME, in Portuguese) is a nongovernmental
association of patients and families with the disease. It aims to promote public policies
to improve care for patients and health professionals' knowledge of the disease and
its clinical care. The institute has an extensive Brazilian patient database, in which
approximately 2,000 registered patients received a presumed diagnosis of SMA-5q.
The present study aimed to describe the key demographic, clinical and genetic characteristics,
and natural history data of patients with SMA-5q in Brazil through a self-reported
registry from patients who are in the INAME database.
METHODS
The INAME registry aims to obtain retrospective and longitudinal data from Brazilian
patients with SMA-5q, 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 by the ethics committee of the Instituto Dante
Pazzanese de Cardiologia (#38534320.6.0000.5462), and the patients who agreed to participate
in the study signed an informed consent form electronically.
This registry was based on the Registries Core Dataset (TREAT-NMD SMA, Newcastle,
England).[6 ] Patients or family members answered 117 questions, subdivided into seven sections,
encompassing various aspects including demographic data, socioeconomic profile, diagnosis
(time of symptoms onset, time to diagnosis, genetic characteristics), drug treatment
(start of disease-modifying drugs, switch), clinical observations (comorbidities,
hospitalization, loss of motor functions, time to ventilatory support), multidisciplinary
interventions (surgeries, respiratory and motor physiotherapy, nutritional support
and speech therapist, motor scales evaluation), and health service providers (health
insurance, public health system, home care). Additionally, the data collected in the
online questionnaire utilizing Google Forms (Google LLC., Mountain View, CA, USA)
was transferred to a digital database in an Excel (Microsoft Corp., Redmond, WA, USA)
file for further analysis.
Data were collected from January 2021 to 2022. Inclusion criteria were patients with
a confirmed molecular diagnosis of SMA-5q (regardless of age), and patients were asked
to upload the molecular test to the system. The neurologists of the scientific committee
(EZ and RHM), who specialized in neuromuscular diseases, reviewed all genetic tests;
patients without a molecular diagnosis of SMA-5q were excluded. We rely on the diagnosis
provided by the patient's doctor. Additionally, the scientific committee reviewed
the agreement between the type of SMA and maximum motor milestone provided. 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.
Statistical analysis
Quantitative variables were described by median and interquartile range (IQR), 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-
event outcomes, the Kaplan-Meier estimator was used for survival curves, and the log-rank
test was used to compare groups. All analyses were performed using the R (R Foundation
for Statistical Computing, Vienna, Austria) software, and we consistently considered
a p -value less than 0.05 indicative of statistical significance.
RESULTS
Among the 900 patients in the INAME database who were successfully contacted, 750
completed the online survey. Of these, 44 were excluded because they reported either
not having a molecular diagnosis or not uploading the test to the system. Thus, we
included 706 patients in this analysis.
Demographic data
The most prevalent subtype was SMA-5q type 1 (44%). Among the others, 33% had type
2, and 23% had type 3. There were seven patients with type 0 SMA-5q, and eight had
type 4 ([Figure 1A ]). Most patients were from the Southeastern region (51%) of Brazil, while others
were from the Northeastern (19.5%), Southern (16.9%), Midwestern (7.6%) and Northern
(5%) regions. Distribution according to sex was similar in the total study population
and in those with types 1 and 2. Among patients with the milder form, there was a
slight predominance of females (61.2%, [Figure 1B ]).
Figure 1 (A ) The distribution of SMA-5q types in the registry. (B ) Gender distribution in the general group, and according to types and median age
in each subtype. (C ) The age distribution in type 1. (D ) The age distribution in type 2.
The median age of patients with type 1 SMA-5q was 3.0 (1.0–6.0) years ([Figure 1C ]). At the time of data cut-off, 37.5% of patients with type 1 were older than 4 years.
The median age of patients with type 2 was 11.0 (6.0–21.5) years, and 45% were adolescents
or adults ([Figure 1D ]). The median age of patients with type 3 was 26.0 years (12.0–36.2).
Diagnosis and genetic data
Regarding mutations in the SMN1 gene, 667 patients (94.4%) had a homozygous SMN1 -exon 7 deletion. There were 38 patients (5.5%) with 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 multiplex ligantion-dependent
probe amplification (MLPA). The polymerase chain reaction (PCR) for detecting homozygous
SMN1 -exon 7 deletion was used in another 191 (27%).
Regarding the SMN2 copy number, two copies of SMN2 occurred in 78.1% of SMA-5q type 1 patients. Most patients with type 2 (72.4%) presented
three copies of SMN2 , and 31.4% of type 3 presented four or more copies ([Figure 2A ]). From the total, 131 (18.6%) patients had a family history of the disease, and
the familial recurrence rate was higher in those with type 3 (25.6%), as shown in
[Figure 2B ]. The consanguinity rate was low, and only 37 (5.2%) patients noted some degree of
relation between the parents.
Figure 2 (A ) The distribution of SMN2 copy number according to SMA-5q types in those with MLPA confirmation (n = 505, types 0 and 4 not included). (B ) The proportion of previous family history of SMA-5q according to patients' type.
Note a more significant proportion of recurrence cases in type 3.
Regarding the time until diagnosis, patients with type 1 had a mean age of 3 months
at the onset of symptoms and an additional 3 months elapsed until genetic diagnosis
([Table 1 ]). In 2018, the pharmaceutical industry began offering free molecular testing (MLPA
and gene sequencing). Thus, 55% of the diagnostic tests registered in this study were
performed in 2018. From that year on, the average time for genetic diagnosis of all
types of SMA-5q 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 3 from 11 to 9 months and from 24 to 22 months, respectively ([Table 1 ]).
Table 1
Time elapsed in the natural history of the disease from symptom onset to diagnosis
and initiation of treatment, and the difference in diagnostic times before and after
2018
Clinical characteristics
Total
N = 706
SMA1
N = 296
SMA2
N = 235
SMA3
N = 160
p -value[a ]
Time between birth and symptom onset (mo) (median, IQR)
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
Time between symptom onset and clinical diagnosis (mo) (median, IQR)
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
Time between symptom onset and genetic diagnosis (mo) (median, IQR)
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
Time between clinical diagnosis and initiation of DMT (mo) (median, IQR)
14.0 (3.0–95.5)
6.0 (2.0–29.0)
37.5 (12.0–116)
*
< 0.001
Time between symptom onset and clinical diagnosis (mo) (median, IQR)
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
Time between symptom onset and genetic diagnosis (mo) (,median, IQR)
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
Abbreviations: DMT, disease-modifying therapy; IQR, interquartile range; mo, months.
Notes: a Kruskal-Wallis test, *data unreliable because most SMA type 3 patients did not have
access to therapies.
Natural history data
In type 1 SMA-5q 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), as shown in [Figure 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 and,
as such, did not receive treatment with disease-modifying drugs, the median time until
the use of invasive ventilation was 16 (IQR: 10–27) months, and for those born after
2018, the median could not be estimated because only 29% of patients underwent invasive
ventilation (p = 0.002, [Figure 3B ]).
Figure 3 (A ) The Kaplan-Meier curve for invasive ventilation-free survival in patients with type
1 according to SMN2 copy number. For patients with two copies of SMN2 , the median time was 24 months and did not differ significantly from those with three
copies (p = 0.5). (B ) The survival curve relative to the time until invasive ventilation of type 1 patients,
according to birth year. In those born before 2018, the median time until invasive
ventilation use was 16 months (IQR: 10–27), and for those born after 2018, it was
not possible to estimate because less than 25% of patients achieved this outcome (p = 0.002).
Other natural history data obtained included the loss of gait in type 3 SMA-5q patients.
Patients answered the date on which they lost the ability to walk for at least 10 m
without support. The median of walking loss was 37 years, with a first quartile of
22.3 years ([Figure 4A ]). Gait loss appeared earlier in patients with three copies of SMN2 than in those with four. The Kaplan-Meier curve of gait loss according to SMN2 copy number showed a p -value close to statistical significance (p = 0.077, [Figure 4B ]). The average age of lost independent walking ability was 12 (IQR: 8–21) years.
Figure 4 (A ) The estimated curve of walking loss in SMA-5q type 3. About 50% of type 3 patients
lost walking ability by 453 months (37 years) of age. (B ) The Kaplan-Meier curve of gait loss in type 3 according to SMN2 copies. The outcome appeared to be earlier in those patients with three copies of
SMN2 , a median of 36 years (first quartile of 15 years) compared with those with four
copies, with a p -value close to statistical significance (p = 0.077).
Multidisciplinary care and previous surgery
As mentioned before, most patients with type 1 SMA-5q (60.5%) were on invasive ventilation.
Among type 2 patients, 49.3% did not use any ventilatory support, and 42.5% used noninvasive
ventilation for some period ([Figure 5A ]). Regarding respiratory assistance, 411 (58.2%) patients received respiratory physiotherapy
at least once weekly. There were 200 patients (28.3%) who said they knew or performed
the air stacking technique with a bag valve mask. Although many reported undergoing
respiratory physiotherapy, only 276 (39.1%) had already performed a vital capacity
test or spirometry. Only 33% said they knew about or used cough-assist machines.
Figure 5 (A ) The distribution of ventilatory support according to SMA-5q types. (B ) The level of nutritional support/feeding route according to types.
Regarding motor rehabilitation, 534 patients (75.6%) said they underwent motor physical
therapy at least once a week. Of these, 359 (50.8%) underwent it more than twice a
week. Despite this, 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-5q types did not differ between groups, with 175 (59.1%) in type
1 and 118 in types 2 (50.2%) and 3 (52.5%).
Gastrostomy was used by 32% of patients ([Figure 5B ]). The use of gastrostomy was higher in type 1 (78.7%) patients, with an inversion
of this proportion occurring in type 2, with 21.3% needing a gastrostomy tube. Additionally,
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 patients (70.6%), followed by those with type 3 (57.5%), and type 1 (42.2%). A total
of 21% patients underwent scoliosis surgery, more than half of whom had type 2.
At least 101 patients (14.3%) reported one unplanned hospitalization last year. Patients
with type 1 SMA-5q reported having had one or two unplanned hospitalizations in the
previous year (24%), compared with the other types of SMA-5q (type 2: 6.3%, type 3:
4.3%, p < 0.001).
Disease-modifying therapies (DMTs)
By the cut-off date in January 2022, 384 (54.4%) patients had access to some DMTs.
Most patients (359; 93.5%) were using nusinersen, as it was the only drug available
through the Brazilian public health system. Another 18 (4.7%) patients reported using
gene therapy, and 7 (1.8%) used risdiplam. The median treatment duration was 15 (IQR:
6–26) months.
When stratifying access to nusinersen use according to SMA-5q types, 62.3% of patients
with type 1, 47.2% of type 2, and 31.9% of type 3 patients were using this drug in
treatment. This difference is justified because, at the time of the data analysis,
nusinersen was only distributed in the public health system for patients with type
1 SMA-5q without permanent invasive ventilation use.
DISCUSSION
The present study is the first SMA-5q patient registry in Latin America.[7 ] Although subject to systematic errors and lack of information, self-reported registries
by patients with neuromuscular diseases have proven to be useful and provide realistic
results.[8 ]
[9 ]
[10 ]
[11 ] The self-reported data here are comparable to other registries, and the proportion
between the SMA-5q types is similar to previous studies.[12 ] Although the data presented here is about prevalence and not incidence, 42% of the
patients in our study reported having type 1, which may reflect an ascertainment bias
of our database. Interestingly, a recently published Italian survey showed a prevalence
of type 1 in only 22.6% of patients in the era of DMTs, the same context as our study.[13 ]
Also corroborating the quality and reproducibility of our results is 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 SMA-5q patients with homozygous exon 7-SMN1 deletion, perhaps because
they presented a higher proportion of patients with milder disease phenotypes.[15 ]
The diagnostic journey of SMA-5q in our population still involves challenges. The
mean age at onset of symptoms for type 1 was similar to other studies, ranging from
2 to 3 months old.[16 ]
[17 ] Considering the time from symptom onset to genetic diagnosis, a delay is seen in
all types of SMA-5q. The diagnostic delay exhibited an inverse relationship with disease
severity, with a median duration of 3 months for type 1, 29 months for type 2, and
169 months for type 3, reflecting longer diagnostic delays than those previously reported
in systematic reviews,[16 ] especially in types 2 and 3. Although the time between symptom onset and clinical
and genetic diagnosis has improved since 2018, there is still a gap, considering that
the final diagnosis time for type 1 has only improved by 1 month since 2018.[17 ] Another gap in our study is the difficulty in accessing therapies within the country,
which prevents us from determining treatment times correctly, starting from the symptom
onset, especially in type 3 SMA-5q.
Regarding the genetic data of our population, the presence of consanguinity was low
in this study's population (less than 5%), which shows considerable regional variability.
A recent Iranian registry showed a rate of 52.4% of consanguinity.[18 ] The low rates 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 people, as reported by another
study in the Brazilian population.[19 ] The high recurrence rate of type 3 SMA-5q (around 25%) was similar to the report
by a recent Iranian registry.[18 ] Given the milder phenotype, it may reflect a longer diagnostic delay, preventing
adequate genetic counseling.
It was possible to evaluate survival beyond the expected span for patients with SMA-5q
type 1 because it was the most prevalent form in our registry (42%). Of those, 37.5%
were older than 4 years, unlike the data reported by current SMA-5q registries.[13 ]
[18 ] This finding may be associated with an improvement in multidisciplinary care and
the introduction of DMTs.[20 ]
[21 ] Additional information from this work is the large number of adolescent and adult
patients in the sample, with 45% of type 2 patients being over 12-years-old and type
3 patients having a median age of 26. These data reflect the need to develop scales
and surveys for this group concerning disease progression and quality of life.[22 ]
[23 ]
Natural history data in the Brazilian population are unpublished, however, the mean
age at the start of invasive ventilation in type 1 SMA-5q patients is already much
better than that reported by other natural history studies. The patients in this registry
had a median survival of 27 months until invasive, permanent ventilation, compared
with 8 months in the Neuronext study,[24 ] and 13.5 months in the PNCR study.[3 ] However, evaluating ventilation-free survival before and after 2018, when DMTs started
to be used (mainly nusinersen), we found a drastic change from a median of 16 months
data like that of the PNCR study,[3 ] to an estimate that cannot be measured after 2018. This suggests the effectiveness
of current therapies in modifying the natural history of type 1 SMA-5q together with
an earlier diagnosis and introduction of multidisciplinary care.
Loss of walking ability in type 3 SMA-5q patients is also important natural history
data. A recent observational study showed 14-years-old was the time of motor skills
loss, compared with a median age of 12-years in our registry.[25 ] Currently, this is the only SMA-5q population in our country that does not have
access to DMTs through the public and universal healthcare system, and progressively
loses functionality and independence, which is characteristic of a disease that occurs
at all ages.[26 ]
This study has some limitations. First, it consisted of a survey answered by patients
and their families, in which there may be interviewer and social desirability bias,
mainly regarding the more technical data. Second, many answers about natural history
depend on the memories of the interviewees regarding the dates or periods in which
losses of motor functions occurred, which may lead to recall bias. Additionally, we
lack the exact data regarding the age of permanent ventilation. Instead, we only have
data on the age at which invasive ventilatory support was initiated. Finally, another
limitation is the possibility that our registry does not faithfully represent the
Brazilian population, since we do not know the actual adherence of patients in the
INAME database.
As a future direction concerning access to DMTs, the data need to be updated, given
the constant changes in local protocols making new therapies available, and including
patients with type 3 SMA-5q as eligible for treatment in the public health system
of Brazil.[27 ]
[28 ]
[29 ] 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.
In conclusion, the results of the present study are unprecedented in the Brazilian
population, as this is the country's first SMA-5q registry. There is a substantial
diagnostic delay in the Brazilian population, especially in those with types 2 and
3 SMA-5q, 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 the advent of DMTs. Patients with
type 3 SMA-5q suffer from progressive loss of gait and functionality and lack broad
access to new therapies.
Bibliographical Record
