REVIEW ARTICLE

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
CITE AS:
CONTINUUM (MINNEAP MINN)
2020;26(5, PERIPHERAL NERVE AND
MOTOR NEURON DISORDERS):
1348–1368.
Address correspondence to
Dr Jessica Rose Nance, The Johns
S
Hopkins Hospital, David M.
Rubenstein Child Health Building,
200 N Wolfe St, Suite 2158;
Baltimore, MD 21287,
jnance6@jhmi.edu.
RELATIONSHIP DISCLOSURE:
Dr Nance receives research/
grant support from AveXis, Inc;
Biogen; Catabasis
Pharmaceuticals, Inc; Catalyst
Pharmaceuticals, Inc;
Cytokinetics, Inc; Santhera
Pharmaceuticals; and
Scholar Rock.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Nance reports no disclosure.
© 2020 American Academy
of Neurology.
1348
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Spinal Muscular Atrophy
By Jessica Rose Nance, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the pathophysiology
and clinical presentations of spinal muscular atrophy (SMA) and reviews
therapeutic developments, including US Food and Drug Administration
(FDA)–approved gene-targeted therapies and mainstays of supportive
SMA care.
RECENT FINDINGS:Over the past decades, an understanding of the role of
SMN protein in the development and maintenance of the motor unit and
the intricate genetics underlying SMA has led to striking developments in
therapeutics with three FDA-approved treatments for SMA, one targeting
SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others
enhancing SMN protein production from the SMN2 gene (nusinersen and
risdiplam). These therapies are most effective in infants treated at younger
ages, and improvement is most striking in babies treated as neonates.
Despite improvements in motor function, patients (especially those treated
at older ages) continue to experience significant weakness and require
continued close monitoring of respiratory and orthopedic symptoms.
SUMMARY: Striking therapeutic advancements have changed the clinical
course of SMA dramatically, although supportive care continues to play an
important role in patient care.
INTRODUCTION
pinal muscular atrophy (SMA) is an autosomal recessive disease of the
lower motor neurons characterized by progressive weakness and
muscle atrophy. It is caused by a homozygous deletion/mutation in
the survival motor neuron 1 (SMN1) gene on chromosome 5q13. The
disease phenotype is broad. Before the availability of SMA therapies,
the disease was classified into groups by age of symptom onset and motor
milestones achieved,1 and, although approved therapies change the
developmental trajectory, this grouping remains helpful for general
prognostication and is still used for defining cohorts in clinical trials. Patients
with type 1 (SMA1) have severe weakness, with onset at younger than 6 months
of age, and never achieve the ability to sit independently. Patients with type 2
(SMA2) have milder weakness presenting before 18 months of age and are able to
sit but never achieve the ability to walk independently. Patients with type 3
(SMA3) have weakness in childhood and are able to ambulate. Patients with type
4 (SMA4) have milder adult-onset weakness. The disease severity is influenced
by a variable copy number of a second paralogous SMN2 gene.2
With an incidence of 1 per 10,000 and a carrier frequency of 1 in 50, SMA is
one of the most common recessively inherited diseases.3 The most common form
OCTOBER 2020
of the disease, SMA1, is one of KEY POINTS
the most common genetic causes
● Spinal muscular atrophy
of death in children. In the late (SMA) is a progressive motor
1800s, Werdnig4 and Hoffmann5 neuron disease caused by
first described the histopathologic mutations/deletions in the
features in infants with severe survival motor neuron 1
(SMN1) gene. It has a broad
progressive weakness and
phenotypic spectrum and is
respiratory failure resulting in classified into categories
early death. The muscle based on age of onset,
pathology is characterized by motor milestone
achievement, and copy
groups of round atrophic fibers
number of the paralogous
and clusters of relatively FIGURE 10-1
SMN2 gene.
Hematoxylin and eosin (H&E) staining of skeletal
hypertrophic myofibers
muscle in spinal muscular atrophy showing
(FIGURE 10-16). grouped atrophy and clusters of relatively
● SMA type 1 (SMA1) is the
Over the decades since its first most common form of SMA
hypertrophic myofibers.
and is characterized by
description, the ability to provide Reprinted with permission from Pestronk A, Neuromuscular
onset of weakness in the
Disease Center.6
supportive care in the form of first few months of life.
ventilatory, nutritional, and Without disease-modifying
orthopedic interventions improved therapy, babies with SMA1
never achieve the ability to
patient longevity and comfort, yet the prognosis remained dismal. Babies with SMA1 sit independently, and the
never achieved the motor milestone of sitting and had a rapidly progressive course of average time to death or
weakness and respiratory failure resulting in death before 2 years of age without requirement for permanent
chronic pulmonary and nutritional interventions. This all changed in 2016 with the US ventilation for an infant
with untreated SMA1 is
Food and Drug Administration (FDA) approval of the first of three therapies for
13.5 months.
SMA, all of which increase SMN protein production. The first approved treatment
was nusinersen, an antisense oligonucleotide targeted at the SMN2 mRNA and
dosed intrathecally every 4 months for life.7 The second approved therapy was
onasemnogene abeparvovec-xioi, an adeno-associated virus 9 (AAV9)–mediated
SMN1 gene replacement given intravenously as a single dose.8 The third therapy,
risdiplam, a small molecule targeting SMN2 mRNA splicing, is given as a daily oral
medication and was recently approved by the FDA in August 2020. These medications
improve survival, decrease the need for respiratory intervention, improve motor
function significantly, and allow some patients with SMA to achieve motor
milestones never before observed in the disease. Improvements are most striking
when treatment is delivered to infants, especially in neonates treated with
nusinersen or onasemnogene abeparvovec-xioi before the onset of overt
symptoms of weakness. This motivates diagnosis and treatment as early as
possible, especially in babies with SMA1 or SMA2, for whom these interventions
have the largest impact. Despite the significant impact of these therapies on the
disease course, many patients experience significant weakness, necessitating
continued close monitoring and provision of respiratory, nutritional, orthopedic,
and rehabilitative interventions.

GENETICS AND PATHOPHYSIOLOGY

Our understanding of the molecular genetics underlying SMA has improved
significantly over the past few decades. A basic familiarity with these advances is
necessary to understand the variability in disease phenotype and the targets of
current therapeutic approaches (FIGURE 10-2). The SMN1 gene on chromosome
5q13 encodes the SMN protein.9 Humans and higher primates also have a variable
copy number of a paralogous SMN2 gene, which significantly differs from SMN1

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SPINAL MUSCULAR ATROPHY

FIGURE 10-2
Genetic mechanism for spinal muscular atrophy (SMA). A, Region of interest in the SMN
gene on chromosome 5q13 showing the deleted SMN1 gene and variable copy number of
SMN2 gene. In the absence of the SMN1 gene, motor neuron survival depends upon a
diminished amount of SMN protein that can be produced from the mutated SMN2 gene.
The majority of SMN2 mRNA lacks exon 7 (Δ7-SMN) and produces a protein product that
is degraded. Exon 7 is included in a minority of transcripts (FL-SMN) that produce functional
SMN protein. B, The severity of the SMA phenotype can generally be predicted by the
SMN2 copy number and is inversely related to the patient’s number of copies.
DNA = deoxyribonucleic acid; FL-SMN = full-length SMN mRNA. mRNA = messenger ribonucleic acid.
Data from Feldkötter M, et al, Am J Hum Genet.2

because of a C to T change in the splicing region of exon 7 that reduces splicing

efficiency.10 This results in exclusion of exon 7 in the majority of mRNA
transcripts produced from the SMN2 gene and subsequent degradation of the
abnormal protein.11 Thus, only a minority of SMN2 mRNA transcripts include
exon 7 and are able to produce normal protein. Normally, the level of SMN protein
that is required to maintain lower motor neurons can be achieved in individuals with
at least one copy of the SMN1 gene. In SMA, however, both SMN1 copies are absent,
usually because of deletion, although in about 5% of cases because of a point
mutation. Thus, motor neuron survival becomes dependent on an insufficient
amount of SMN protein that can only be produced by an individual’s SMN2 copies.
Individuals with more copies of SMN2 produce more SMN protein and thus have a
milder phenotype.2,12 With this understanding, SMN1 gene replacement and
augmentation of protein production from the SMN2 gene were seen as important
targets in the development of SMA therapeutics.
The absence of sufficient levels of SMN protein leads to lower motor neuron
death, resulting in progressive weakness and skeletal muscle atrophy in individuals
with SMA. However, the exact role of SMN protein in the motor neuron remains
unknown. On a molecular level, SMN protein is expressed in all cells, but motor
neurons are the most severely affected by reduced levels.13 The primary role of
SMN protein is thought to involve assembly of small nuclear ribonuclear protein
(SnRNP) complexes required for pre-mRNA splicing.14 At least some SMN protein
is required for life, as demonstrated by multiple animal models (which lack SMN2

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genes) in which SMN knockout is lethal, either embryonically or very early in KEY POINT
life (Caenorhabditis elegans,15 Drosophila,16 zebrafish,17 mouse18). That a complete
● In SMA, both copies of
lack of SMN protein in humans is embryonically lethal is supported by the absence the SMN1 gene are absent.
of reported cases of patients lacking both SMN1 and SMN2 genes. Introduction of a Thus, motor neuron survival
human SMN2 transgene into the homozygous mutant Smn-/- mouse avoids is dependent on the number
embryonic lethality, and, similar to in human disease, an increase in the number of SMN2 copies. Patients
with SMA with more SMN2
of SMN2 copies produces increasingly milder phenotypes with later onset of
copies have a milder
symptoms in a dose-dependent fashion.19 phenotype.
Development of a mouse model recapitulating human disease has been vital to
investigating the role of SMN protein in maintenance of motor neurons and the
motor circuit. Selective motor neuron loss in the mouse model has the same pattern
seen in humans, in which motor neurons innervating axial and proximal limb
muscles are affected more severely and earlier compared to those innervating distal
muscles.20 In the presence of reduced levels of SMN protein, motor neuron death
and dysfunction in motor neuron synapses in the anterior horn of the spinal cord are
seen.20 At the same time, inadequate SMN levels disrupt neuromuscular junctions
and are associated with impaired development, atrophy, and denervation of
myofibers (FIGURE 10-321).22,23 Similar findings are noted on autopsy of human
patients with SMA.24 Increasing SMN expression in the early postnatal period in
severely affected mice ameliorates the phenotype, but later restoration of SMN
expression is ineffective, suggesting that high levels of SMN protein are especially
important during embryonic and early postnatal development.25 Autopsy studies of
SMN protein levels in human control and SMA tissues also suggest the importance
of SMN protein during gestational and neonatal stages of motor neuron

FIGURE 10-3
Inadequate SMN protein levels disrupt several interactions within the motor unit.
MN = motor neuron; NMJ = neuromuscular junction.
Reprinted from Tisdale S, Pellizzoni L, J Neurosci.21 © 2015 The Authors.

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SPINAL MUSCULAR ATROPHY

development.26 Thus, in both mouse models and human patients, SMN protein
appears to play a role in both embryonic development of the motor unit and in the
maintenance of motor neurons postnatally and throughout life.

CLINICAL PRESENTATION
Over time, the classification of SMA has evolved based on a clinical understanding
of SMA, including the age of onset of weakness and the degree of motor milestone
achievement (TABLE 10-1). Along this continuum of disease, weakness is more
rapidly progressive in patients with earlier-onset disease, whereas weakness can
be relatively stable in patients with adult-onset disease. Available therapies have
had a striking impact on the clinical course of the disease, but the classification
continues to be useful in allowing clinicians to provide prognostic information to
patients and their families and to anticipate the individual patient’s needs. This
classification also plays an important role in stratifying patients in clinical trials.

Spinal Muscular Atrophy Type 1

The majority of individuals affected with SMA present in infancy with muscle
weakness and delay or absence of early motor milestones. An infant with SMA1
shows symptoms in the first few months of life and, before the approval of
gene-targeted therapies, was never able to achieve a sitting position
(FIGURE 10-4A27). The majority never gained head control or rolled over.
Neurologic examination of an untreated symptomatic infant reveals a
nonencephalopathic infant with diffuse proximally predominant muscle
weakness and diffusely decreased muscle tone and bulk. Deep tendon reflexes

TABLE 10-1 Classification of Spinal Muscular Atrophy by Typea

Spinal SMN2 Lifespan

Muscular Age of Maximum Motor Copy Without
Atrophy Type Onset Milestone Number Intervention Other Clinical Features

0 <1 week No milestones 1 <1 month Congenital weakness, severe joint

achieved contractures, neonatal respiratory failure

1 2–6 months Never sits 2, 3 <2 years Early proximal weakness, areflexia, tongue
fasciculations, respiratory failure and swallowing
dysfunction, scoliosis, joint contractures

2 6–18 months Sits independently 3, 4 >2 years Proximal weakness, tongue fasciculations,
tremor, respiratory muscle weakness, scoliosis,
joint contractures

3A <3 years Walks 3, 4 Adult Often loses ability to walk in later childhood or
independently early adulthood, tremor, scoliosis

3B 3–21 years Walks 3, 4 Adult Often maintains walking into adulthood, tremor,
independently scoliosis

4 >21 years Walks 4 or Adult Mild proximal weakness

independently more

a
Type is based on age of onset and motor milestone achievement.

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FIGURE 10-4
Clinical features differentiating spinal muscular atrophy (SMA) types. A, Baby with SMA type 1
showing diffuse weakness, prominent frog-leg posturing, and bell-shaped chest. B, Siblings
with SMA type 2 are able to sit. Note diffusely decreased muscle bulk and prominent joint
contractures. C, Patient with SMA type 3 is able to stand and walk. Note decreased muscle
bulk, joint contractures, and scoliosis.
Panel A reprinted with permission from Oskoui M, et al.27 © 2018 Academic Press.
Panel B reprinted with permission from Angelini C.30 © 2018 Springer International Publishing Switzerland.
Panel C reprinted with permission from reprinted from Crawford TO.31 © 2018 Academic Press.

are absent. Early on, muscles of facial expression are strong, but bulbar weakness
and tongue fasciculations are a common finding. Over time, scoliosis and joint
contractures develop. Weakness is often accompanied early on by respiratory
muscle weakness, and patients have a characteristic bell-shaped chest. Because
of respiratory failure and bulbar weakness with swallowing dysfunction,
untreated infants require respiratory and nutritional interventions in the first
year or two to prolong life. Without disease-modifying therapy, babies with
SMA1 are expected to die or require permanent ventilation by the average age
of 13.5 months.28 The majority of patients with SMA1 possess two copies of the
SMN2 gene (FIGURE 10-2B).2,29

Spinal Muscular Atrophy Type 2

A smaller proportion of patients with SMA are classified as having SMA2. These
individuals typically present between 6 and 18 months of age with diffuse
weakness, decreased muscle bulk, and absent reflexes (FIGURE 10-4B30). Tongue
fasciculations and a fine motor tremor are common. Without therapy, patients
with SMA2 achieve the ability to sit but never ambulate independently, and they
may lose the ability to sit independently as they age. Swallowing and respiratory
function decline over time, and, although individual patients with SMA2 may
have a normal life span, they are vulnerable to respiratory infections and may
require ventilatory support at some point. Respiratory function worsens as
scoliosis develops and progresses, and spinal fusion surgery is helpful in some
patients. Joint contractures can also limit the function and comfort of these
patients. Therapies ameliorate these features, especially when delivered earlier in
the course of the disease. The majority of patients with SMA2 possess three copies
of the SMN2 gene (FIGURE 10-2B).2,29

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SPINAL MUSCULAR ATROPHY

Spinal Muscular Atrophy Type 3

Patients with SMA3 present in later childhood (between the ages of 18 months
and 21 years) and all will achieve the ability to walk independently, although gait
stability is often impaired and many may lose the ability to walk later in life
(FIGURE 10-4C31). Weakness is primarily proximal. The phenotypic spectrum is
broader for this type, as patients will sit and walk with varying degrees of
weakness throughout childhood and adulthood. SMA3 has been further
subdivided into type 3a (with symptom onset before 3 years of age) and type 3b
(with symptom onset after 3 years of age). Those with SMA3b are more likely to
continue to walk independently after 20 years of age.1 Therapy, especially when
delivered early, ameliorates features of the disease. Patients with SMA3 have a
normal life expectancy. The majority of patients with SMA3 have three or four
copies of the SMN2 gene (FIGURE 10-2B)2,29

Other Types of Spinal Muscular Atrophy

Rarely, patients with SMA may present at the opposite ends of the disease
spectrum. Infants with SMA type 0 (SMA0) develop weakness prenatally and
are born with arthrogryposis multiplex congenita and severe respiratory failure.
They cannot breathe on their own and do not typically survive past 6 months of
age. They commonly have one copy of SMN2. Patients with SMA4 present in
adulthood, usually with varying degrees of leg weakness. They have a normal life
span. The SMN2 copy number is greater than four in the majority of these
patients (FIGURE 10-2B).2,29

TABLE 10-2 Evaluations to Measure Motor Function Status in Patients With Spinal
Muscular Atrophy

Test
Scale Name Scoring Duration Examples of Functions Evaluated Target Population

Hammersmith Infant 8 items 20 min Head control, sitting, grasping, Infants 2–24 months, spinal
Neurological Examination kicking, rolling, crawling, standing, muscular atrophy (SMA) types
Section 233 walking 1 and 2

Hammersmith Functional 33 items 20 min Rolling, sitting, lying to sitting, SMA types 2 and 3
Motor Scale Expanded34 kneeling, kneeling to standing, (24 months to adult)
squatting, jumping, stair climb/
descent

Children’s Hospital of 16 items 20 min Head control, rolling, gross motor Neonates and infants with
Philadelphia Infant Test of functions of upper and lower SMA type 1
Neuromuscular Disorders35 limbs, axial strength/tone

Revised Upper Limb 19 items 10 min Upper limb gross and fine motor SMA types 2 and 3 (3 years to
Module36 functions adulthood)

Motor Function Measure37,38 Adult: 32 20 min Upper and lower limb gross and General neuromuscular
items fine motor functions, rolling, lying disorders (3–64 years)
to sitting, sitting to standing,
Child: 20
running, hopping
items

6-Minute Walk Test39 Distance in 6 min Walk as fast as possible along a SMA type 3
meters 25-m loop for 6 minutes

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FOLLOWING DISEASE ACTIVITY IN SPINAL MUSCULAR ATROPHY KEY POINT
In addition to recognition of the importance of the SMN2 copy number in
● The majority of patients
predicting SMA type, the development and validation of additional measures with SMA type 1 possess two
of motor neuron function have facilitated disease monitoring and have been SMN2 gene copies. Those
instrumental as end points in SMA clinical trials. Electrophysiologic with SMA type 2 usually
modalities are used to evaluate the extent of muscle denervation and can have three copies, those
with SMA type 3 have three
quantify changes in motor unit numbers over time in SMA. Compound muscle
or four copies, and patients
action potential (CMAP) amplitude provides a measure of the number of with SMA type 4 typically
intact motor neurons supplying a given muscle. CMAP amplitudes decrease as have more than four copies.
weakness progresses in infants, and the maximum CMAP amplitude is lower Those with SMA type 0,
which presents with
in patients with an SMN2 copy number less than three and in those with more
arthrogryposis multiplex
decreased motor function.32 Standard EMG measuring voluntary motor unit congenita and severe
action potential amplitudes and durations as well as the pattern of recruitment respiratory failure, typically
can also help to evaluate and follow the degree of muscle denervation in have one copy.
patients with SMA.
Several different motor function scales are used to measure SMA disease
activity across multiple ages and SMA types (TABLE 10-233–39). A basic familiarity
with these scores is useful in evaluating clinical trial data and in assessing
therapeutic response to molecular therapies (a practice that may be required for
prior authorization for insurance). Some of these functional outcome measures are
specifically validated for SMA, and others are validated for patients with
neuromuscular disorders in general. The Hammersmith Functional Motor Scale
Expanded (HFMSE) is an SMA-specific scale validated to assess disease
progression in patients with SMA2 or SMA3.34,40 It has 33 items scored on a scale of
0 to 2, with a score range of 0 to 66; a higher number indicates more advanced
motor function. The Hammersmith Infant Neurological Examination Section 2
(HINE-2) is used to evaluate infants with SMA1.33 It is an eight-item scale, with a
score of 0 to 5 for each activity. The Children’s Hospital of Philadelphia Infant Test
of Neuromuscular Disorders (CHOP-INTEND) is validated for infants and young
children with SMA1.35 It includes 16 motor activities graded on a scale of 0 to 4,
with a maximum score of 64.
Respiratory failure is a significant cause of morbidity and mortality in young
patients with SMA, but pulmonary function testing is difficult and unreliable in
this age group. Therefore, the amount of time until chronic respiratory support
is required (defined as either invasive or noninvasive respiratory intervention
for 16 or more hours per day for more than 14 days or tracheostomy) is a useful
outcome measure for respiratory failure in SMA clinical trials.7,8
Neurofilament proteins represent an emerging area of biomarker
development in patients with SMA. Neurofilament proteins are intermediate
filaments expressed specifically in neurons and are the dominant component
of the motor axon cytoskeleton.41 They are heteropolymers composed of
neurofilament light, medium, and heavy chains. Neurofilament proteins are
released into the extracellular space following axonal damage, and
neurofilament light chains and phosphorylated neurofilament heavy chains
are measurable in the blood and CSF.42 Neurofilament proteins have been
studied as biomarkers of disease activity in several other neurodegenerative
diseases, including amyotrophic lateral sclerosis, Alzheimer disease, and
multiple sclerosis, with mixed results.43 Evaluation of neurofilament protein
levels in patients with SMA receiving SMN-dependent genetic therapies
demonstrate a striking decrease following treatment, thus representing a

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SPINAL MUSCULAR ATROPHY

potentially powerful biomarker for following SMA disease activity and

response to therapy.44

SMN–DEPENDENT THERAPIES
An understanding of the genetic mechanisms of SMA, together with
development of validated outcome measures assessing degrees of weakness and
developmental delay, was instrumental in the success of the three FDA-approved
therapies targeting gene expression in SMA.

Nusinersen
In December 2016, the FDA approved nusinersen, an antisense oligonucleotide that
promotes the inclusion of exon 7 during splicing of SMN2 RNA. The medication
is given intrathecally, initially with four loading doses (the first three loading doses
every 14 days and the fourth loading dose given 30 days after the third dose)
followed by maintenance dosing every 4 months. The pivotal ENDEAR (A Study to
Assess the Efficacy and Safety of Nusinersen [ISIS 396443] in Infants With Spinal
Muscular Atrophy) trial enrolled infants with SMA1 who were younger than
6 months of age.45 At final analysis, 50% of treated infants demonstrated
improvement in motor milestones (as measured by the HINE-2), compared to 0%
in the control group. Additional studies in neonates (NURTURE [A Study of
Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically
Diagnosed and Presymptomatic Spinal Muscular Atrophy] trial)46 and in older
patients with SMA2 or SMA3 (EMBRACE [A Study to Assess the Safety and
Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular
Atrophy] trial)47 were also encouraging. The most striking finding in the nusinersen
trials was that the improvement in function was most impressive in babies treated at
younger ages. This was further supported in the ongoing open-label NURTURE
trial, in which asymptomatic neonates with two or three copies of SMN2 began
treatment at the age of 6 weeks or younger. Thus far, all are alive and breathing
independently after 2.9 years of follow-up (average age 34.8 months).46
Importantly, at an age at which we expect to see decreased motor milestone
development, these subjects demonstrated a striking improvement in motor
function, with 100% able to sit, 92% walking with support, and 88% walking
independently. The rationale behind this improvement is that asymptomatic babies
have a population of motor neurons that can be rescued and thus have greater
capacity to experience a more normal developmental trajectory. This is in contrast to
symptomatic infants and older patients who already manifest significant weakness
because they have lost a critical population of motor neurons and are in a slower
phase of decline. This is consistent with mouse and human data suggesting that
higher levels of SMN are most important during gestational and neonatal stages of
motor development.
No side effects have been identified related to nusinersen itself, but
complications associated with intrathecal administration have been reported,
including low-pressure headaches and pain at the injection site. Intrathecal
administration is a straightforward procedure in many patients with SMA, and in
younger and weaker children, it can be done without anesthesia. The clinician
may opt for sedation or general anesthesia in older and stronger children to
improve comfort and ease of administration. In older children and adults with
significant scoliosis or spinal fusion, involvement of interventional radiology
with fluoroscopy or CT guidance may be helpful. In some of these patients with

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spinal fusion, a lumbar laminectomy may help to further optimize access to KEY POINTS
the spinal canal. Although it is too early to know the long-term outcomes in
● In December 2016, the
patients treated presymptomatically and the drug is not a cure for those treated US Food and Drug
after symptom onset, nusinersen certainly offers significant hope for those Administration approved
with a disease without any previous interventions to slow the progression of nusinersen as the first
weakness. The observation that treatment is most helpful when given early in therapy for SMA. An
antisense oligonucleotide,
presymptomatic infants emphasizes the need to identify these babies early to
nusinersen targets increased
expedite treatment. In many states, SMN genotyping is now included in efficiency of inclusion of
newborn screening programs, as discussed in greater detail below. exon 7 during splicing of
SMN2 RNA.
Onasemnogene Abeparvovec-xioi
● Neonates with SMA with
In May 2019, the FDA approved onasemnogene abeparvovec-xioi for patients two or three SMN2 copies
younger than 2 years of age with all types of SMA. Onasemnogene treated with nusinersen
abeparvovec-xioi is an AAV9-delivered SMN1 gene replacement therapy that is before the onset of
administered as a single weight-based IV dose. symptoms demonstrate
striking improvement in
The pivotal trial for onasemnogene abeparvovec-xioi enrolled 12 babies with motor function, with the
predicted SMA1 phenotype (two copies of SMN2), who each received open-label large majority able to walk
therapy administered before 6 months of age.48 Response to therapy was independently.
compared to a natural history cohort and unaffected cohort. Compared to
● Onasemnogene
untreated natural history cohort patients with SMA1 who never achieve the
abeparvovec-xioi is an
ability to sit, at 24 months posttreatment, 92% sat unassisted for 5 seconds or adeno-associated virus
more and 75% achieved sitting for 30 seconds or more. Survival free of 9–mediated SMN1 gene
respiratory intervention was also significantly improved in the treated infants. replacement therapy given
as a single IV dose. It is
Similar to nusinersen, the impact of therapy was greater in patients treated at
indicated for patients of all
younger ages and with fewer symptoms. SMA types who are 2 years
In clinical trials, elevated liver enzymes and elevated platelets were observed. of age or younger at the
Liver function, however, was not affected. Additionally, some patients exhibited time of dosing. Similar to
elevated troponin I levels without changes in heart function, and the clinical nusinersen, the impact of
therapy is greatest in
significance of this finding is not understood. Because of concerns for liver patients treated at a younger
toxicity, patients should be treated with systemic corticosteroids equivalent to age and greater in those with
oral prednisolone 1 mg/kg/d for 30 days. The dose may be tapered over the next three SMN2 copies than in
28 days if liver function testing (specifically aspartate transaminase [AST], alanine those with two copies.
transaminase [ALT], bilirubin, and prothrombin time) remains unremarkable.
The prevalence of exposure to and development of antibodies against AAV9,
and thus the AAV9 vector, is relatively low compared to other adeno-associated
virus types.49 Special consideration of this is required in newborns before
onasemnogene abeparvovec-xioi treatment. Given concern for reduced vector
transduction at the time of treatment, consideration of neutralizing antibodies
passively transferred to the affected neonate across the placenta or in breast milk
is important. A baseline anti-AAV9 antibody titer should be measured before
infusion. If titers are greater than 1:50, the titer should be rechecked again no
more than 2 weeks later. Because 2 weeks could represent a period in neonatal
development during which a delay in treatment could make a significant
difference in the outcome, this interval should be determined with consideration
of SMA type and the rate of progression of weakness, favoring checking sooner in
patients with SMA1 with more rapid progression. It should be noted that no
specific data are available regarding the level of IgG antibodies that could inhibit
onasemnogene abeparvovec-xioi vector transduction, and the titer of less than
1:50 was a conservative choice during the clinical trials.50 Although breast-
feeding was prohibited in the onasemnogene abeparvovec-xioi trials based on

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SPINAL MUSCULAR ATROPHY

the theoretical risk of anti-AAV9 antibody transfer, no clear evidence indicates

that IgA antibodies transferred in this way could inhibit vector transduction.50
Thus, the decision of whether or not to hold off on breast-feeding during the
pretreatment and immediate posttreatment periods should be considered in
the context of its potential impact on the therapy compared to the impact of
short-term use of infant formula. A discussion between the provider and the
family is recommended.
To monitor for toxicity, a series of laboratory tests are recommended over the
weeks after dosing. ALT, AST, bilirubin, and prothrombin time should be
checked before infusion, weekly for the first month, then every other week for
the second and third months, until the results are normal. Platelets and troponin I
should be measured before infusion and weekly for the first month. Platelets
should then be followed every other week and troponin I monthly for the second
and third months.
The nonreplicating AAV9 viral capsid taken up by motor neurons exists as an
episome and is not diluted because motor neurons do not divide. Little theoretical
risk exists for the therapy to impact caregivers or those who interact closely with
patients in the short or long term. Based on viral shedding testing during the
clinical trial, caregivers should use protective gloves when coming into direct
contact with patient feces and use good hand hygiene for approximately 60 days
after the injection.50 This is especially true for caregivers or mothers with potential
or known pregnancies as the effect of onasemnogene abeparvovec-xioi on the
developing fetus is unknown. Additionally, it is not known if this exposure to the
vector is sufficient to induce an antibody response in a seronegative mother who
is at risk of future pregnancies with a fetus affected with SMA.

Risdiplam
In August 2020, the FDA granted approval for risdiplam, a small molecule
therapy that increases splicing efficiency at exon 7 in the SMN2 mRNA, thus
increasing the amount of functional protein that can be produced in the absence
of SMN1.51 Risdiplam is approved as a daily oral medication for patients with
SMA of all types ages 2 months and older. In an open-label clinical trial involving
patients with SMA1 aged 1 to 7 months, 41% were able to sit unsupported for at
least 5 seconds following 12 months of treatment and 90% were alive without
permanent ventilation by at least 15 months of age.52 Patients with type 2 or type 3
SMA between the ages of 2 and 25 years treated with risdiplam for 12 months
demonstrated a significant improvement in gross motor performance, including
upper limb functions, compared to those treated with placebo.52
The medication so far has been well tolerated in trials, with the most common
side effects in patients with SMA1 being upper respiratory tract infection,
pneumonia, cough, and vomiting. Patients with SMA2 or SMA3 more commonly
experienced fever, diarrhea, and rash. None of the side effects reported in the
trials necessitated discontinuation of therapy.52 At the time of this writing,
no additional information regarding safety monitoring recommendations is
available.

SMN-INDEPENDENT THERAPIES
The absence of SMN protein affects multiple components of the motor unit, and
these components are also targets for therapeutic development. Two therapies
targeting muscle growth and function in SMA are currently in clinical trials.

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Promotion of Muscle Growth KEY POINTS
Because muscle atrophy is such a prominent feature in neuromuscular disorders,
● Risdiplam was approved
targeting enhancement of muscle cell growth is an attractive therapeutic in August 2020 and is a daily
approach. Myostatin is an endogenous protein that limits muscle cell growth. oral small molecule therapy
Several trials of antibodies targeted against activation of myostatin’s active form that increases production of
have been unsuccessful.53 SRK-015 is an antimyostatin antibody that differs from full-length SMN protein
from the SMN2 mRNA. After
previous forms in that it targets the latent form of the protein and prevents its
12 months, nearly half of
activation in muscle.54 Preclinical animal studies of the compound demonstrated infants with SMA type 1
target engagement and showed increased function and weight. The compound is treated first between 1 and
currently in phase 2 studies in patients with SMA2 and SMA3. 7 months of age were able to
sit supported for at least
5 seconds. Older individuals
Enhancement of Muscle Function with SMA type 2 or SMA
Improvement in the efficiency of muscle force generation is also a target for type 3 treated with risdiplam
therapeutic development. Reldesemtiv (formerly CK-2127107) is an activator of also showed improvement in
fast skeletal muscle troponin, which has demonstrated increased force of motor function compared to
a placebo-controlled group.
contraction in healthy subjects.55 Phase 2 testing in patients with SMA1, SMA2,
and SMA3 demonstrated increased distance in the 6-Minute Walk Test and ● Response to nusinersen,
improvement in respiratory function compared to controls.56 onasemnogene
abeparvovec-xioi, and
risdiplam therapies is more
DIAGNOSIS AND MANAGEMENT striking when they are
Before the approval of SMN-dependent therapies, confirmation of a genetic delivered during the first
diagnosis of SMA occurred after onset of weakness, when babies or children with months of life. Early
motor delays were identified and tested by clinicians who suspected the disease treatment of SMA type 1
enables patients to achieve
based on the classic clinical features described above. Because these treatments
motor milestones never
work best in children before the onset of symptoms, the challenge is now to identify before possible. Some
and diagnose patients much earlier in the disease course. Despite these therapeutic patients with SMA type 1
advances, the response often remains incomplete, and the types of supportive treated within the first weeks
of life are able to walk.
care that have been a mainstay of SMA treatment in the past remain important.
● Although striking
Early Diagnosis Through Newborn Screening and Maternal Carrier Screening improvement in motor
With commercial availability of nusinersen, onasemnogene abeparvovec-xioi, and milestone achievement is
risdiplam and clear evidence of improved outcomes with treatment in the neonatal seen in patients with
SMA after treatment
period, the challenge of identifying babies as early as possible arises (CASE 10-1). with nusinersen,
The Recommended Uniform Screening Panel recently added SMA as a standard onasemnogene
disease, which means that states are legally required to test for SMA as part of their abeparvovec-xioi, or
standard newborn screening. Thus, states are currently ramping up their programs risdiplam, they still
experience significant
(FIGURE 10-5).57 It is important to note that newborn screening for SMA includes weakness.
only testing of the SMN1 gene. SMN2 copy number must be ordered by the clinician
evaluating the baby. Additional efforts to identify prenatal cases are also under way, ● Clinical trials are
with the American College of Obstetrics and Gynecology officially recommending currently evaluating agents
that promote muscle growth
that SMA screening be offered to all women who are pregnant or considering
(antimyostatin antibody) and
pregnancy.58 enhance muscle function (an
Although patients are able to be identified within the first week of life through activator of fast skeletal
newborn screening, a time gap remains before they can receive medication muscle troponin).
because insurance authorization is required for these very expensive
medications. Before the approval of risdiplam, to justify insurance coverage and
timely approval in this critical population, key opinion leaders presented an
algorithm regarding treatment recommendations for gene-targeted therapies in
individuals with SMA identified through newborn screening.59 The consensus is
that all newborns with two, three, or four copies of SMN2 (especially those in

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SPINAL MUSCULAR ATROPHY

whom an SMA type 1 or type 2 phenotype is expected) should receive immediate

therapy with either onasemnogene abeparvovec-xioi or nusinersen. In patients
with five or more copies (who are expected to develop an SMA type 4
phenotype), treatment can be deferred with close monitoring for symptom
development.59 A summary of tests recommended for monitoring symptom
onset in patients with five or more copies of SMN2 is presented in TABLE 10-3.
Given that SMA carrier screening and SMA newborn screening are not yet
widespread in the United States or around the world, a significant number of
patients are not identified at birth. In these patients, the physician’s suspicion
should be roused in patients with a clinical history and examination features as
described in TABLE 10-1. Genetic testing for the SMN1 mutation and SMN2 copy
number is available from several commercial laboratories. In older patients with
SMA who were not diagnosed by newborn screening, the decision to treat is
based upon the presence of symptoms as defined in TABLE 10-3. In states and

CASE 10-1 A pediatric neurologist received a phone call from the state health
department reporting the newborn screening identification of a 5-day-
old baby girl with spinal muscular atrophy (SMA). The provider scheduled
an appointment with the baby and her parents the next day.
On initial examination in the clinic on day of life 6, the baby was
bright-eyed and well appearing, with normal muscle bulk. She was
feeding well and breathing comfortably with antigravity strength in all
four extremities. She had head lag on pull to sit and slight slip-though on
vertical suspension, but both findings were within the broad range of
normal limits for the baby’s age. Tendon reflexes were absent. Although
the baby’s examination was nearly normal, because of the highest
prevalence, the phenotype was most likely SMA type 1. After a
discussion, the family wished to pursue onasemnogene abeparvovec-xioi
therapy, so the SMN2 copy number and absence of anti–adeno-
associated virus 9 (AAV9) antibody titer had to first be confirmed before
proceeding. While waiting for these results, the provider began the prior
authorization for onasemnogene abeparvovec-xioi therapy. The SMN2
copy number returned 4 days later with two copies of SMN2, and the
family returned for results disclosure.
At follow-up examination 4 days later, the provider noted some very
mild paradoxical breathing and increased head lag. Although still having
antigravity strength, the baby moved less in proximal muscle groups and
felt “less sturdy” in the provider’s arms. The examination was now more
consistent with an SMA type 1 phenotype.
Onasemnogene abeparvovec-xioi is expensive and prior authorization
is complicated, but with progression of weakness, the provider pushed
urgently for approval. Additional time was required to establish the
institution’s protocol regarding the administration of gene therapy. Final
insurance authorization and institutional approval for treatment was
achieved 3 weeks after the last visit. At that point, the baby had
progressed mildly in weakness and hypotonia.

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countries in which these therapies are approved and newborn screening is
widespread, the population of symptomatic untreated patients is expected to decline.

Nusinersen Versus Onasemnogene Abeparvovec-xioi Versus Risdiplam

The decision of which drug to offer patients depends on several factors. All three
drugs are commercially approved for all types of SMA, and, so far, they appear to
have similar efficacy. The age of the patient is an important consideration.
Whereas nusinersen is approved for all ages, onasemnogene abeparvovec-xioi is
approved for treatment of individuals before their third birthday. Because
risdiplam is not approved for babies younger than 2 months of age, very early
symptomatic newborns and those diagnosed presymptomatically through
newborn screening will be eligible only for nusinersen or onasemnogene
abeparvovec-xioi. For these very young individuals, it is important to discuss the
mode of therapy with parents/guardians. For many, the single IV dose of

Oral prednisolone 1 mg/kg was started on day of life 29, and

onasemnogene abeparvovec-xioi treatment was delivered on day 30. The
baby did well, with mild elevation in liver transaminases during the first
2 weeks after dosing that subsequently resolved. Prednisolone was weaned
without problems. She was followed closely over the next months and had
no significant progression of weakness. At her 8-month follow-up, she had
gained head control. She could not raise arms above her head but could
reach for toys in front of her and sit with support at both hips.

This case highlights that although newborn screening allows earlier COMMENT
diagnosis of SMA, barriers to early treatment still exist. Even if the SMA
type is suspected based on examination, the SMN2 copy number must be
determined to confirm the expected phenotypic trajectory. Additionally,
the process of insurance authorization and establishing an institutional
protocol for treatment can, in some cases, take weeks. This is valuable time
during which degenerating motor neurons could potentially be rescued by
therapy. Many institutions have already treated children with some of
these therapies and have an institutional policy for treatment. For those
that do not but anticipate treating patients, proactively getting a treatment
policy in place will save time. Because of the expense, each new insurance
authorization is challenging and requires persistent attention, especially in
cases in which the patient is declining.
The case also highlights that even with early therapy and gain of
measurable milestones that would otherwise not be attained, treated
children can still have considerable weakness. In the case of this patient,
onasemnogene abeparvovec-xioi effectively changed the early course
from an SMA type 1 to an SMA type 2 or type 3 phenotype. This patient will
need close monitoring for respiratory dysfunction, contractures, and
scoliosis, and she may need a wheelchair at some point. It is thus important
that even patients who are treated early receive continued follow-up with
an experienced provider in a clinic equipped to care for patients with SMA.

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SPINAL MUSCULAR ATROPHY

KEY POINTS

● Increased need exists for

early diagnosis of SMA,
which drives the inclusion of
SMA testing in newborn
screening programs and the
promotion of female carrier
testing in pregnant women.

● All newborns with two,

three, or four copies of
SMN2 (especially those in
whom an SMA type 1 or type
2 phenotype is expected)
should receive immediate
therapy with either
onasemnogene
abeparvovec-xioi or
nusinersen. In patients with
five or more copies (who are
expected to develop an
SMA type 4 phenotype), FIGURE 10-5
treatment can be deferred Status of spinal muscular atrophy newborn screening programs in the United States as of
with close monitoring for August 2020.
symptom development. Reprinted with permission from curesma.org.57 © 2020 Cure SMA.

onasemnogene abeparvovec-xioi may be preferable to repeated dosing of

nusinersen by lumbar puncture every 4 months over a lifetime. Parents and
guardians, however, should be aware that elevation of liver enzymes in the weeks
after onasemnogene abeparvovec-xioi dosing could represent liver inflammation
that may become severe in rare cases, and close monitoring by the treating
physician is important. In rare patients in whom baseline liver enzymes or
anti-AAV9 antibody titers are elevated, nusinersen may be preferable. An open-
label trial evaluating risdiplam in patients with SMA treated first between birth
and 6 weeks is currently ongoing.52 For infants 2 months and older, daily oral
risdiplam may be presented as an additional option.
For individuals 3 years of age and older, nusinersen and risdiplam are the
approved options. Although no side effects to nusinersen itself have been
identified, the repeated lumbar punctures required for nusinersen treatment can
have procedure-related side effects. In addition, many children require general
anesthesia for comfort during the procedure, and individuals with severe
scoliosis may require repeated radiation exposure to be dosed by interventional
radiology under fluoroscopy or CT guidance.
Clinical trials of risdiplam have identified no significant treatment-limiting
side effects; however, this drug lacks the longer-term postmarketing safety
analysis that is available for nusinersen. For patients in whom repeat lumbar
punctures with or without anesthesia and radiation exposures are undesirable,
daily oral risdiplam is the appropriate alternative. In conversations involving
older patients with childbearing potential who are considering either risdiplam or
nusinersen, it should be mentioned that the effects of both drugs on fertility and
fetal development are unknown.
Also unknown are the effects of using these medications in combination.
While the idea of increasing total SMN protein production from both SMN1 and

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SMN2 simultaneously using onasemnogene-abeparvovec-xioi with either
nusinersen or risdiplam is appealing, organized trials have not yet been
conducted to establish safety or efficacy. Similarly, no data are yet available to
suggest that risdiplam and nusinersen used together are more efficacious in
increasing SMN protein production from the SMN2 gene than either drug alone.
Although early efficacy and safety data appear to be comparable between
risdiplam and nusinersen, decisions about switching from one drug to another
should be made cautiously at this early juncture. Additional trials to evaluate
these kinds of treatment scenarios are anticipated or under way.
Because of the extraordinary cost of these medications, challenges associated
with prior authorization for insurance coverage may also play an important role
in treatment decisions. In the United States, nusinersen is priced at $125,000
dollars per dose, costing $750,000 in the first year and then $375,000 per year for
the duration of the patient’s life. This does not include additional costs required
for intrathecal medication administration, for example, in the operating room

Summary of Tests Used to Monitor Patients With ≥5 SMN2 Copies for TABLE 10-3
Whom Treatment Is Not Initiated Immediatelya

Level of Change/Results Which Would Prompt Appropriate Age of

Test or Outcome Measure Initiation of Treatment Patient for Test

EMG/nerve conduction studies Any active or chronic neurogenic change All

Compound muscle action potential Below normative values for an age-matched child All
(CMAP)

Myometry Decrease in extent of muscle contraction ≥4 years

Physical examination/reflexes Any of the following: loss of reflexes, failure to meet or All
regression in ability to perform motor milestones,
proximal weakness, and weakness in trunk righting/
derotation

Children’s Hospital of Philadelphia A failure to gain motor functions with age in keeping with Infants
Infant Test of Neuromuscular normal development OR a drop in total score from
Disorders previous assessment

Hammersmith Infant Neurological A failure to gain motor functions with age in keeping with Infants
Examination normal development OR a drop in total score from
previous assessment

Hammersmith Functional Motor Scale A failure to gain motor functions with age in keeping with ≥2 years
Expanded normal development OR a drop in total score from
previous assessment

6-Minute Walk Test A failure to gain motor functions with age in keeping with ≥5 years
normal development OR a drop in total score from
previous assessment

Bayley Scales of Infant and Toddler A failure to gain motor functions with age in keeping with Infants/toddlers
Development normal development OR a drop in total score from (recommended 1 to
previous assessment 42 months)

EMG=electromyography.
a
Modified with permission from Glascock J, et al, J Neuromuscul Dis.59 © 2020 IOS Press and the Authors.

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SPINAL MUSCULAR ATROPHY

with anesthesia. The single weight-based IV dose of onasemnogene abeparvovec-

xioi costs $2.1 million. Daily oral risdiplam pricing is also weight-based, with a
maximum cost of $340,000 per year for the duration of the patient’s life. Paying
for these kinds of medications individually or in combination may place a
significant burden on the country’s health care systems.

Continued Importance of Supportive Therapy

Despite the remarkable advances in treatment, many patients continue to
experience significant weakness,45,48 and the complications of SMA, although
ameliorated by these therapies, continue to cause morbidity and mortality.
The mainstays of supportive therapy, which have been employed and refined
over decades of SMA care, continue to play a vital role in treatment of the
respiratory, nutritional, and orthopedic vulnerabilities experienced by
patients with SMA.

PULMONARY MANAGEMENT. The risk of pulmonary dysfunction in SMA is

related to hypoventilation and decreased ability to maintain a clear airway in
the setting of primarily intercostal respiratory muscle weakness (it is not known
why the diaphragm remains relatively spared until late in the disease). Because
worsening respiratory status correlates with worsening weakness, assessment
and management of pulmonary dysfunction in SMA can be considered
differently based not on SMA type but on the patient’s ability to sit or walk.60
Assessments should be performed at least every 6 months, with a low threshold
for obtaining a sleep study if any concern for nocturnal hypoventilation exists.
Airway clearance methods, such as oral suctioning, pulmonary physical therapy,
and cough assist, should be instituted early in nonsitting patients who are
particularly weak. Noninvasive ventilatory methods or tracheostomy should be
considered early in symptomatic patients depending on the preference of the
patient or parents (depending on age). This is also true of patients with the ability
to sit and walk, although less need exists for intermittent or continuous ventilatory
support in these stronger patients. Respiratory muscle weakness and impaired
airway clearance make both nonsitting and sitting patients with SMA especially
vulnerable to pulmonary infections, including aspiration pneumonia.
Standard immunizations are indicated, with annual influenza and
pneumococcal vaccinations. Annual respiratory syncytial virus vaccination is
indicated for infants with SMA. Of note, for infants treated with glucocorticoids
after treatment with onasemnogene abeparvovec-xioi, the provider may
consider delaying some immunizations during the immunosuppressed period.50

NUTRITIONAL MANAGEMENT. Bulbar muscle weakness can be a significant

problem for individuals with SMA, especially those who are unable to sit. In
nonsitting and sitting patients, a baseline barium swallow study is recommended
shortly after the time of diagnosis; aspiration risk should be followed closely,
especially if concerns exist for choking with feeds or progressive cough
weakness.60 Enteral feeding may safely provide nutrition to help protect against
aspiration pneumonia in these patients. Enteral feeding may also be necessary in
weaker patients with SMA1 or SMA2, in whom limitation of mouth opening
caused by contracture of the masseter muscle may limit oral feeding.

REHABILITATIVE AND ORTHOPEDIC MANAGEMENT. Rehabilitative management of

patients with SMA should focus on accommodating weakness and promoting

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mobility to improve patients’ engagement and minimize the orthopedic KEY POINTS
complications of progressive weakness.61 Positioning and bracing are especially
● The efficacy of
important for both sitting and nonsitting patients to avoid worsening nusinersen, onasemnogene
contractures and scoliosis. Slowing of progressive joint contractures is helpful in abeparvovec-xioi, and
motor function and independence. Spinal fusion can play an important role in risdiplam appears to be
patient comfort and preservation of respiratory function. equivalent. Decisions
between the medications
should be based on the
patient’s age and discussion
CONCLUSION of mode of delivery and side
Striking advances in understanding of the pathophysiology and genetics of SMA, effects with the patient or
the patient’s parents or
along with improved understanding of the disease’s natural history and
guardians.
validation of meaningful outcome measures, have created a clinical and research
environment for the development of successful gene-targeted therapies. With ● Clinical trials evaluating
the approval of nusinersen, onasemnogene abeparvovec-xioi, and risdiplam, the the potential benefits of
prognosis of SMA is now more hopeful, especially in very young babies with combination treatments
with SMN1- and SMN2-
SMA1, who, with early treatment, are able to attain even the earliest motor enhancing therapies are
milestones never before possible. Despite these advances, children and adults anticipated or currently
with SMA continue to have varying degrees of weakness that require under way.
accommodation. Many are still vulnerable to pulmonary failure and orthopedic
● The extraordinary cost of
complications. Additional improvement upon current gene-targeted therapies
SMN-targeted therapies
requires early identification and treatment and may require refinement of the may complicate the process
dose or dosing interval. The combination of SMN1 replacement and SMN2- of obtaining prior insurance
enhancing therapy may provide additional benefit, but currently there is no authorization.
definite evidence for this. Furthermore, although not yet approved, the potential
● Supportive therapy,
exists that the addition of non-SMA–specific therapies targeting muscle growth including pulmonary,
and function may improve outcomes. Despite the progress in disease-modifying nutritional, and
therapies, continued symptomatic management with close respiratory, rehabilitative management,
nutritional, and orthopedic care is vital to the success of these treatments. plays a vital role in the
treatment of SMA since
many patients continue to
experience significant
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