PedsCases Podcast Scripts
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Spinal Muscular Atrophy
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
Introduction
Hello everyone! My name is Johanie Victoria Piché, and I am a fourth-year medical
student at McGill University. In today’s episode of PedsCases, we are going to discuss
spinal muscular atrophy or SMA. This episode was created in collaboration with Dr.
Maryam Oskoui, pediatric neurologist at the Montreal Children’s Hospital.
Clinical Case
Let’s start off with a clinical case.
Leo is a 6-month-old boy, born at term without any perinatal adversity, who presents to
your office because of delayed motor milestones. His parents mention that he is not able
to hold his head up when prone, that he cannot roll from side to side and that he cannot
sit in a tripod position. On further history, the parents mention that he tends to cough
with feeds. The parents deny any regression in his motor milestones. With regards to
his language, his social abilities, his cognition and his fine motor movements, there is
no evidence of delay.
On examination, you observe an alert, non-dysmorphic infant with a weak cry, tongue
fasciculations, who adopts a frog-like position when supine and who “slips through” the
examiner’s hands on vertical suspension. He shows very little spontaneous movements
of his lower limbs, no antigravity movements in his upper limbs and is areflexic
throughout.
During this podcast, we will revisit and highlight the key findings of this case.
Objectives
After listening to this podcast, the learner will be able to:
1. Define and understand the pathophysiology of SMA
2. Identify the clinical presentations of the different subtypes of SMA
3. Describe the differential diagnosis of SMA
4. Describe the screening guidelines and diagnostic evaluations of SMA
5. Describe the management of SMA
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
Part 1 - Definition and Pathophysiology
Spinal muscular atrophies encompass a group of inherited disorders causing
degeneration of the anterior horn cells of the spinal cord during fetal development and
the postnatal period. They are characterized by progressive muscle weakness and
muscle atrophy.1 This episode will focus specifically on 5q SMA, the most common of
these disorders.
About 95% of cases of 5q SMA are due to homozygous deletions of exon 7, exon 8 or
both, in the survival motor neuron 1 gene (SMN1) gene, leading to loss of function of
the SMN protein.1 5q SMA is most frequently inherited in an autosomal recessive
manner, but also occurs de novo in about 2% of cases.2 Carrier frequency is observed
across all ancestries, however it is most common in people with European and Asian
descent, with approximately 1 in 50 being carriers. In people with African ancestry the
frequency is lower at 1 in 100 and in people with Hispanic ethnicity the frequency is 1 in
763.
There are two forms of the SMN gene, which are located on chromosome 5q. First, there
is the SMN1 gene which is located on the telomeres of the chromosome, and which
produces full-length functional SMN proteins. Second, there is the SMN2 gene which is
located on the centromere of the chromosome, and which can produce both functional
and non-functional SMN proteins.1
The two genes are almost identical, but a critical difference lies in a cytosine to tyrosine
substitution in the SMN2 gene. This base substitution is significant as it creates an
exonic splicing suppressor in exon 7. This leads to the exclusion of exon 7 during
splicing of the pre-mRNA in most of the SMN2 transcripts. Therefore, the SMN2 gene
produces mostly nonfunctional, truncated SMN proteins that are quickly degraded.1
However, it is important to note that the SMN2 gene also produces a reduced amount
(about 10%) of functional SMN protein in which the exon 7 has not been spliced out. 4
This will later be relevant when we discuss further the disease severity of the different
SMA subtypes.
You may be asking yourself, “What are the functions of the SMN protein and what is its
role in the pathophysiology of SMA?” The answers to these questions remain to be fully
understood. On a molecular level, it is known that SMN proteins are expressed both in
the cytoplasm and in the nucleus of cells. SMN is also expressed in motor neuron axons.
Some of the known functions of the SMN protein include facilitating the assembly of
spliceosome complexes, which are critical for pre-mRNA splicing, and transporting
axonal mRNAs in motor neurons. It is therefore hypothesized that spinal motor neurons,
which are known to have long axons and which are most likely very dependent on axonal
mRNA transport, may be especially vulnerable to decreased SMN protein expression 5.
Moreover, the SMN protein is known to be critical in the embryological development of
the anterior horn cells of the spinal cord. Indeed, when its function is altered, it can result
in continued apoptosis of the anterior horn cells 6. In short, more research is needed to
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
determine whether a splicing defect due to SMN protein deficiency, a disruption of the
embryological development of the anterior horn cells, an unknown function of the SMN
protein or a combination of all is responsible for the pathogenesis of SMA.
Part 2 - Clinical Presentations and Classification of SMA
There is a wide spectrum of severity in patients with SMA, as the more severe subtypes
have their onset in utero and the less severe phenotypes may present only in
adulthood1.
When evaluating a child in whom we suspect SMA, red flags on history and on physical
examination should raise our clinical suspicion for SMA. First, delayed motor milestones
can be reported by the parents. Let’s recall Leo from our introductory case presentation.
His parents reported that he has poor head control when prone, that he cannot sit in the
tripod position and that he is unable to roll over. All of these motor milestones are
typically attained by his age. Second, appendicular hypotonia, meaning hypotonia in the
limbs, may be observed on examination. In our case, Leo was adopting a “frog-like”
posture when lying, which is suggestive of appendicular hypotonia. Third, Leo was also
“slipping through” on vertical suspension, which is characteristic of axial hypotonia.
Fourth, the finding of fasciculations of Leo’s tongue is a sign of denervation, which is
typical of motor neuron disorders. Finally, Leo was found to be areflexic on examination,
which is also characteristic of a disorder of the peripheral nervous system. In short, an
important learning point is that the combination of gross motor delay, axial and
appendicular hypotonia, proximal weakness, tongue fasciculation and areflexia should
all raise our suspicion for SMA.
The clinical classification of SMA ranges from type 0, the most severe form of disease,
to type 4, the least severe form of disease. One of the factors influencing the severity of
the phenotypes is the number of copies of the SMN2 gene. Indeed, the SMN2 gene can
produce a small amount of functional SMN protein. Therefore, a lower copy number of
SMN2 gene is associated with a lower amount of functional SMN protein and therefore
with more severe phenotypes and earlier presentation of the disease. Studies have
shown that patients with SMA type 1, one of the most severe forms of SMA, have the
lowest copy number of the SMN2 gene. Absent SMN protein level is incompatible with
life and embryonically lethal 1.
I will now go over each type of SMA. This classification is based on the anticipated
progression of motor development in the natural history of the disease, as understood
prior to the availability of newer disease-modifying therapies. It helps determine the
expected motor developmental regression and life expectancy without supportive care1
Therefore, as you listen to this section, please keep in mind that outcomes for patients
receiving these treatments may differ from the descriptions I am about to provide. We
will discuss the newly observed phenotypes following the administration of disease-
modifying therapies in the management section of this podcast.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
SMA Type 0
SMA type 0 represents the most severe form of the disease, as the onset of muscle
weakness begins in utero. Infants are symptomatic at birth. They present with hypotonia,
areflexia, contractures from limited mobility in utero and respiratory failure. In terms of
developmental milestones without disease modifying therapies, they don’t acquire the
ability to roll nor sit. In these infants, respiratory failure is inevitable without supportive
care 1.
SMA Type 1
Infants with SMA type 1 present before 6 months of age with axial hypotonia and
proximal weakness. Without disease modifying therapies, these infants don’t achieve
the ability to stay seated without support, but some may learn to roll over. They develop
respiratory failure at a median of 1 year of age 1. In addition, upon examination, the
examiner may note tongue fasciculations, a weak cry and areflexia. On history, feeding
difficulties may be reported by the parents.
SMA Type 2
Children with SMA type 2 are able to sit independently, though some may lose this ability
over time. Some children with SMA type 2 may also be able to stand with or without
support and crawl, although they do not achieve the ability to walk independently without
disease modifying therapies. The onset of SMA type 2 usually starts between the ages
of 6 and 18 months, and parents describe concerns about their inability to bear weight
on their legs. On examination, fine tremor of the fingers, hyporeflexia or areflexia,
proximal weakness, and a nasal voice may be noted. After two years of age, risks of
aspiration and the need for ventilatory support become greater 1.
SMA Type 3
Whereas children with SMA type 2 could not walk independently, children with SMA type
3 can achieve the ability to walk independently without support. However, they may lose
this ability over time without disease modifying therapy. These children usually present
by 3 years of age as parents are concerned for lower limb weakness. On examination,
some children may have preserved deep tendon reflexes, but they may lose them over
time1. They may also display a positive Gower sign. Remember, a positive Gower sign,
indicating proximal leg weakness, means that when the patient rises from a sitting
position on the floor, the patient presses their hands along their thighs for support.
SMA Type 4
Finally, SMA type 4 refers to individuals in whom symptom onset begins only after the
age of 21 years with slowly progressive proximal limb weakness 1.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
I know that this is a lot of information to digest, but let’s summarize the most important
points to remember. The SMA types range from the most severe form, SMA type 0, to
the milder phenotype, SMA type 4. An important factor influencing disease severity is
the number of copies of the SMN2 gene, as the amount of SMN protein is inversely
correlated to disease severity.
Part 3 – An Approach to the Differential Diagnosis of SMA
As the differential diagnosis of pediatric neuromuscular disorder is quite wide, it is
important to use a systematic approach. You can listen to the PedsCases podcast on
Neonatal Hypotonia for more details to this approach in infants.
Let’s recall the four components of the motor unit 7:
1. The motor neuron within the anterior horn of the spinal cord
2. The peripheral nerve
3. The neuromuscular junction
4. The muscle
The most important goal of the detailed history and physical examination is to localize the
primary site of dysfunction within the motor unit, thereby narrowing the differential
diagnosis. I now will describe some key findings, which can orient us in the process of
localization of the lesion within the motor unit.
First, the findings of proximal weakness, areflexia, muscle atrophy, fasciculations without
sensory deficits make an anterior horn cell disorder more likely. Other than SMA,
diseases affecting the anterior horn cells include SMARD1 (or spinal muscular atrophy
with respiratory distress type 1) or Hiramaya disease.
Second, the combination of distal weakness, hyporeflexia or areflexia with sensory
deficits makes a disorder of peripheral nerves more likely. For instance, Charcot Marie
Tooth disease is a peripheral nerve disorder where different gene variants cause impaired
growth or function of the axons or the Schwann cells.
Third, fatiguability and fluctuating weakness without sensory deficits, without muscle
atrophy and with preserved deep tendon reflexes are more suggestive of a
neuromuscular junction disorder. Examples of neuromuscular junction disorders include
botulism and Lambert-Eaton myasthenic syndrome.
Finally, proximal weakness accompanied by muscle atrophy without fasciculations,
without sensory involvement and with preserved or reduced deep tendon reflexes is more
suggestive of a muscle disorder. Examples of congenital myopathies include X-linked
myotubular myopathy or Nemaline myopathies.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
Part 4 – Screening Guidelines and Diagnostic Evaluations
Screening Guidelines
Affected babies with SMA are diagnosed through two different clinical pathways: first, as
part of routine newborn screening programs and second, after a symptomatic
presentation.
Newborn screening programs in Canada play a significant role in the early diagnosis of
SMA and help identify presymptomatic newborns. In the recent years, almost all
Canadian provinces and territories have added SMA to their newborn screening program
8
. Indeed, knowing that disease-modifying therapies are available and most effective if
initiated before significant loss of motor neurons occurs, early diagnosis allows for earlier
access to treatment and a better overall prognosis.
Newborn screening programs use single gene testing as a screening method. In 95% of
cases, we will find a homozygous deletion of the SMN1 gene, which is essentially 100%
specific for the diagnosis of SMA 9.
Diagnostic Evaluations
When a child presents with signs of peripheral hypotonia and weakness and when SMA
is suspected clinically, the first line of investigations is targeted genetic testing looking for
SMN1 deletion. The absence of the two SMN1 copies confirms the diagnosis of 5q SMA.
If one full copy of SMN1 is detected and the clinical presentation is suggestive of 5q SMA,
this remaining SMN1 copy should be sequenced to evaluate for point mutations. If two
full copies of SMN1 are detected, a diagnosis of 5q SMA is unlikely and other motor
neuron disorders should be considered. Therefore, neuromuscular gene panels should
be sent, and, depending on the clinical picture, electromyography (EMG) and nerve
conduction studies could be considered. Although the number of SMN2 copies may not
be essential to reach a diagnosis of SMA, it should be routinely assessed as it is an
important prognostic factor in terms of severity of the SMA phenotype 10.
Part 5 – Management
Disease-Modifying Treatments
Disease-modifying therapies have revolutionized the management of SMA. These
treatments target the underlying cause of SMA, aiming to improve motor function, in some
cases maintain acquired abilities and, in other cases, to extend survival. In this section,
we’ll discuss the most prominent therapies, their mechanisms and their impact on the
natural history of disease.
Understanding the pathophysiology of SMA is central to understand the principles behind
the available disease-modifying treatments. Indeed, these medications aim to increase
SMN protein production in one of two ways: either by acting as a splicing modifier in the
SMN2 gene to promote inclusion of exon 7 or either by introducing functional copies of
the SMN1 gene that will get translated into full-length SMN proteins.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
Let’s go over 3 disease-modifying treatments currently available in Canada, which are
Onasemnogene abeparvovec, Risdiplam and Nusinersen.
Onasemnogene abeparvovec, or OA, is a form of gene replacement therapy that
introduces a functional copy of the SMN1 gene. It is administered as a one-time
intravenous injection, leading to the expression of the SMN protein. Its efficacy was
studied in two important phase 3 trials: the SPR1NT and STR1VE studies. The SPR1NT
study, which evaluated the efficacy of OA in presymptomatic children with biallelic SMN1
mutations, showed significant improvements in motor function, with all participants able
to stand independently prior to 14 months of age and most able to walk independently. It
also demonstrated survival benefits without the need for ventilatory or feeding support.11
In the STR1VE study, OA was shown to be effective in symptomatic patients with SMA
type 1, as most patients achieved the ability to sit independently at 18 months of age and
survived without requiring permanent ventilation.12
Risdiplam is a molecule that modifies the splicing of SMN2 pre-mRNA. It is administered
orally as a liquid solution on a daily basis. Three pivotal studies have assessed the
efficacy of Risdiplam in different stages of the disease. First, the ongoing RAINBOWFISH
study demonstrated Risdiplam's efficacy in presymptomatic children, with results showing
that the infants were alive without permanent ventilation and maintained their swallowing
and feeding abilities.13 Second, the FIREFISH study evaluated symptomatic infants with
SMA type 1 and found that Risdiplam improved developmental motor milestone
achievement, with many infants able to sit without support.14 Finally, the SUNFISH study
demonstrated that Risdiplam improved motor function in patients aged 2 to 25 years with
type 2 or non-ambulant type 3 SMA15.
Finally, Nusinersen, which is administered by intrathecal injections, is a molecule that
modifies the splicing of SMN2 pre-mRNA. It has been shown to be efficacious in
improving motor milestones in infants with SMA Type 1 in the ENDEAR trial16, and in
children with SMA Type 2, aged 2 to 12 years, in the CHERISH trial17.
Although these new medications show great promise in improving motor function, they
also represent an important financial cost for our healthcare system. For instance, the
annual cost of Nusinersen averages $700,000 per patient in the first year and $350,000
in subsequent years. A one-time injection of Onasemnogene abeparvovec costs nearly
$3 million per patient.18 Moreover, caregivers of patients with SMA often face significant
additional expenses related to accessing these therapies. Even when caregivers are able
to secure coverage through private or public reimbursement plans, travel expenses to
treatment facilities are often not covered, creating an additional barrier to care for some
families19.
Multidisciplinary Care
While disease modifying treatments have played a significant role in improving prognosis
and life expectancy in patients with SMA, a multidisciplinary approach to the management
of SMA patients remains crucial given the multiple comorbidities associated with SMA.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
Rehabilitation
Rehabilitation aims at optimizing function and minimizing impairment. It includes
stretching with orthoses, splints and passive techniques to improve range of motion.
Thoracic and cervical bracing is also recommended for postural. Chest physiotherapy
during illness may be considered to promote airway clearance. Aquatic therapy and
general conditioning exercises with and without resistance can be used to improve
mobility in people who can sit and people who can walk.10
Orthopedic Management
Scoliosis is very common in children with SMA, hence the importance of spine inspection
during routine clinical examination. When scoliosis is suspected, a spinal X-ray should be
performed to determine if thoracic bracing or surgery is necessary. Hip subluxation or
dislocation is also common in children with SMA, especially those who are non-ambulant.
When it causes significant pain, surgical management should be considered.10
Nutritional Management
During routine visit of children with SMA, it is important to inquire about gastrointestinal
symptoms such as gastroesophageal reflux, constipation, and vomiting. Moreover, it is
important to assess for safe swallowing mechanism, as bulbar dysfunction can result in
aspiration and pulmonary infections. If a swallowing study is failed or if there is growth
failure, short-term nasogastric tube is recommended until a long-term gastrostomy tube
can be placed.10
In brief, a multidisciplinary team approach is central to the management of SMA patients,
including neurology, respirology, nutrition, physical and occupational therapy as well as
orthopedics.
Conclusion
That’s all for today! Let’s review the main learning points from this episode:
1. Spinal muscular atrophy is defined as a group of inherited disorders causing
degeneration of the anterior horn cells of the spinal cord during fetal development
and the postnatal period. It is characterized by progressive muscle weakness and
muscle atrophy1.
2. About 95% of cases of 5q SMA are due to homozygous deletions of exon 7, exon
8 or both, in the SMN1 gene, leading to loss of function of the SMN protein 1.
3. There are 5 types of SMA that range from type 0, the most severe form, to type 4,
the milder phenotype.
4. The combination of gross motor delay, hypotonia, weakness, fasciculations and
areflexia should raise our suspicion for SMA and should prompt genetic testing.
5. While disease modifying treatments have played a significant role in improving
prognosis and life expectancy in patients with SMA, a multidisciplinary approach
to the management of SMA patients remain crucial given the multiple comorbidities
associated with SMA.
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
You should now be able to:
1. Define and understand the pathophysiology of SMA
2. Identify the clinical presentations of the different subtypes of SMA
3. Describe the differential diagnosis of SMA
4. Describe the screening guidelines and diagnostic evaluations of SMA
5. Describe the management of SMA.
Thanks for listening!
Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
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Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
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Developed by Johanie Victoria Piché and Dr. Maryam Oskoui for PedsCases.com.
April 1, 2025.
