Perry Shieh, MD, PhD, FAAN, prepared useful practice aids pertaining to spinal muscular atrophy for this CME activity titled "Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal Muscular Atrophy." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at https://bit.ly/2AUynEw. CME credit will be available until September 9, 2021.

1. A Snapshot of Available Disease-Modifying
Therapies for SMA
PRACTICE AID
Access the activity, “Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal
Muscular Atrophy,” at PeerView.com/HNM40
AAV9: adeno-associated virus 9; ALT: alanine transaminase; aPTT: activated partial thromboplastin time; ASO: antisense oligonucleotide; AST: aspartate transaminase; INR: international normalized ratio; mRNA: messenger RNA; RTI: respiratory tract infection;
SMA: spinal muscular atrophy; SMN: survival motor neuron protein.
1. Spinraza (nusinersen) Prescribing Information. https://www.spinraza-hcp.com/content/dam/commercial/spinraza/hcp/en_us/pdf/spinraza-prescribing-information.pdf. 2. Zolgensma (onasemnogene abeparvovec-xioi) Prescribing Information.
https://www.avexis.com/content/pdf/prescribing_information.pdf. 3. Evrysdi (risdiplam) Prescribing Information. https://www.gene.com/download/pdf/evrysdi_prescribing.pdf.
Nusinersen1
SMN2-directed ASO
Onasemnogene abeparvovec-xioi2
Gene therapy
Mechanism
of Action
Indication
Dosing
Select Clinical
Studies Supporting
Approval for
Infantile-Onset SMA
Adverse Events
Monitoring
Modifies SMN2 mRNA processing to increase
production of full-length SMN
Tx of SMA in pediatric and adult pts
Recommended dosage: 12 mg (5 mL)
• Administered intrathecally
• Initiate tx with four loading doses:
first three at 14-d intervals and fourth
at 30 d after third dose
• Maintenance dose once every 4 mo
At baseline and prior to each dose, obtain
• Platelet count
• Prothombin time; aPTT
• Quantitative spot urine protein
• Symptomatic infants, likely SMA type 1
(N = 121 enrolled)
• Sham-controlled trial; first dose at
7 mo of age
• Final analysis results (56 wk)
– No death or permanent ventilation
(P = .005)
Nusinersen: 49/80 (61%)
Control: 13/41 (32%)
– Motor milestone achievement (P < .0001)
Nusinersen: 37/73 (51%)
Control: 0/37 (0%)
• Lower RTI and constipation in pts with
infantile-onset SMA
• Pyrexia, headache, vomiting, and pain in pts
with later-onset SMA
AAV9 vector designed to deliver a copy of the gene
encoding human SMN to cells
Tx of pts aged <2 y of age with SMA with biallelic
mutations in SMN1
Recommended dosage: 1.1 x 1014 vg/kg
• For single-dose IV infusion over 60 min
• Administer systemic corticosteroids for 30 d
starting 1 d before dosing
• Safety and effectiveness of repeat dosing have
not been evaluated
At baseline
• Anti-AAV9 antibodies
At baseline and regularly during the steroid taper
Liver function (AST, ALT, INR)
Platelet counts
• Symptomatic infants, likely SMA type 1
(N = 21 enrolled)
• Ongoing, single-arm, open-label trial; mean age
of 3.9 mo at treatment
• Analysis at data cutoff (March 2019; 9.4 to
18.5 mo of age)
– No death or permanent ventilation: 19/21
(90%; one withdrawal)
– Sit without support for 30 s: 10/21 (47.6%)
• Natural history comparator cohort:
25% ventilation-free survival, no ability to sit
without support
• Elevated aminotransferases and vomiting
Risdiplam3
Small-molecule splicing modifier
Modifies SMN2 mRNA processing to increase
production of full-length SMN
Tx of pts 2 mo of age with SMA
Recommended dosage: 0.2 mg/kg for 2 mo to
<2 y of age; 0.25 mg/kg for ≥2 y of age, weighing
<20 kg; 5 mg for ≥2 y of age, weighing ≥20 kg
• Administer oral solution once daily after a meal
at same time each day, using provided syringe
• Do not administer another dose if not fully
swallowed; wait until next scheduled dose
• Monitor for drug-related toxicities if
coadministration with medications eliminated via
multidrug and toxin extrusion protein transporters
(MATE1 or MATE2-K) cannot be avoided
• Symptomatic infants, likely SMA type 1 (N = 21
enrolled; N = 17 treated at recommended dosage)
• Open-label trial; median age of 6.7 mo at
enrollment
• Analysis after 12 mo of treatment
– Independent sitting 5 s: 7/17 (41%)
– Alive without permanent ventilation:
19/21 (90%)
• Natural history comparator cohort:
25% ventilation-free survival, no ability to sit
without support
• Later- and infantile-onset SMA: fever,
diarrhea, rash
• Infantile-onset SMA: upper RTI, pneumonia,
constipation, vomiting
•
•
Troponin-I•

2. Monitoring and Treatment
Recommendations for SMA1,2
PRACTICE AID
Access the activity, “Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal
Muscular Atrophy,” at PeerView.com/HNM40
Respiratory Recommendations
Goals Assessments Interventions
Proactive approach
• Earlier introduction of treatments to support
airway clearance and ventilation
• Physical examination
• Hypoventilation (end tidal CO2
)
• Sleep study or pneumograms (symptomatic
patients, to assess need for NIV)
• Gastroesophageal reflux
• Airway clearance
– Oral suctioning
– Physiotherapy/respiratory therapy (manual chest
therapy, cough insufflator/exsufflator)
• Ventilation: bilevel NIV in all symptomatic patients
• Medication: nebulized bronchodilators if asthma
suspected
• Cough function
• Physical examination
• Sleep study or pneumograms (symptomatic
patients, to assess need for NIV)
• Gastroesophageal reflux
• Spirometry
• Airway clearance
– Physiotherapy/respiratory therapy (manual chest
therapy, cough insufflator/exsufflator)
• Ventilation: bilevel NIV in all symptomatic patients
• Medication: nebulized bronchodilators if asthma
suspected
• Spirometry
• Airway clearance
– Physiotherapy/respiratory therapy (manual chest
therapy, cough insufflator/exsufflator)
• Ventilation: bilevel NIV in all symptomatic patients
• Medication: nebulized bronchodilators if asthma
suspected
NonsittersSittersAmbulatory

3. Monitoring and Treatment
Recommendations for SMA1,2
PRACTICE AID
Access the activity, “Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal
Muscular Atrophy,” at PeerView.com/HNM40
Rehabilitation Recommendations
Goals Assessments Interventions
• Optimize function and positional tolerance
• Minimize impairment
• Posture, scoliosis, hip dislocation, sitting tolerance,
chest deformities
• Contractures
• Muscle weakness, functional and motor
development scales
• Positioning/bracing (postural, thoracic, cervical)
• Stretching (orthoses)
• Promote function/mobility (mobility systems,
adapted equipment/toys)
• Spine deformity management: changing scenario
• Prevent contractures, scoliosis
• Promote function/mobility
• Posture, foot and chest deformities, scoliosis,
hip dislocation
• Contractures
• Muscle weakness, functional scales
• Positioning/bracing (thoracic, cervical)
• Stretching (orthoses)
• Promote function/mobility (mobility systems or
devices based on individual ability, exercise)
• Spine deformity management: orthoses in
growing children; “growth friendly” rods; rods
(skeletally mature)
• Promote function, mobility, joint range,
balance, endurance
• Mobility, timed tests, endurance, functional scales,
muscle weakness, falls
• Contractures
• Posture, scoliosis, hip dislocation
• Promote function/mobility (aerobic and general
conditioning exercise monitored by therapist)
• Stretching (assisted, orthoses as needed)
• Positioning/bracing (lower limb, thoracic)
• Scoliosis surgery
NonsittersSittersAmbulatory

4. Monitoring and Treatment
Recommendations for SMA1,2
PRACTICE AID
Access the activity, “Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal
Muscular Atrophy,” at PeerView.com/HNM40
NIV: noninvasive ventilation; SMA: spinal muscular atrophy.
1. Mercuri E et al. Neuromuscul Disord. 2018;28:103-115. 2. Finkel RS et al. Neuromuscul Disord. 2018;28:197-207.
Nutritional Recommendations
Caregiver Resources
Swallowing and feeding
difficulties/safe swallowing
Appropriate calorie
intake/weight control
Monitor and treat
gastrointestinal dysfunction
• Monitor (eg, swallow tests, choking or coughing)
• Feeding tube may be necessary for total or
supplemental nutrition
• Avoid undernutrition
• Monitor fasting times during acute care episodes
• Examples: reflux, constipation, use of
bowel-regulating agents, delayed gastric
emptying, vomiting
• Monitor (eg, swallow tests, choking or coughing)
• Feeding tube may be necessary for total or
supplemental nutrition
• Avoid undernutrition
• Avoid overweight/obesity
• Monitor fasting times during acute care episodes
• Examples: reflux, constipation, use of
bowel-regulating agents, delayed gastric
emptying, vomiting
• Not usually a problem in walkers
• Avoid overweight/obesity
• Monitor fasting times during acute care episodes
• Examples: reflux, constipation, use of
bowel-regulating agents, delayed gastric
emptying, vomiting
NonsittersSittersAmbulatory
CureSMA:
https://www.curesma.org/
SMA Foundation:
https://smafoundation.org/
Muscular Dystrophy Association:
https://www.mda.org/
TREAT-NMD:
https://treat-nmd.org/
National Organization for Rare Disorders:
https://rarediseases.org/
Rare Diseases Clinical Research Network:
https://www.rarediseasesnetwork.org/

5. Access the activity, “Ensuring Optimal Management Throughout the Clinical
Spectrum of Spinal Muscular Atrophy,” at PeerView.com/HNM40
Motor Function Assessment
Scales for SMA1-4
PRACTICE AID
Hammersmith Infant Neurological Examination (HINE)
HINE Section 2: Motor Milestonesa
Simple and scorable method for evaluating infants from 2 mo to 2 y of age
Section 1:
Neurologic exam assessing
cranial nerve function,
posture, movements, tone,
reflexes, reactions
Section 2:
Motor milestones (head
control, sitting, voluntary grasp,
ability to kick, rolling, crawling,
standing, walking)
Section 3:
Behavioral assessment (state
of consciousness, emotional
state, social orientation)
Score 0 1 2 3 4
Head control
Unable to keep
head upright
Wobbles
(4 mo)
Keeps upright
all the time
(5 mo)
Sitting Cannot sit
Sits with support at
hips (4 mo)
Props self up
(6 mo)
Stable sitting
(7-8 mo)
Pivots
(9 mo)
Voluntary grasp No grasp Uses whole hand
Index finger and
thumb but
immature grasp
Pincer grasp
Ability to kick No kicking
Kicks horizontally
but legs do not lift
Upward
(vertical; 3 mo)
Touches leg
(4-5 mo)
Touches toes
(5-6 mo)
Rolling No rolling
Rolls to side
(4 mo)
Prone to supine
(6 mo)
Supine to prone
(6 mo)
Crawling or
bottom shuffling
Does not lift head
On elbow
(3 mo)
On outstretched
hand (4 mo)
Crawls flat on
abdomen
(8 mo)
Crawls on
hands/knees
(10 mo)
Standing
Does not support
weight
Supports weight
(4 mo)
Stands with support
(7 mo)
Stands unaided
(12 mo)
Walking
Bouncing
(4 mo)
Cruising
(12 mo)
Walking
independently
(15 mo)
a
Normal achievement age is in parentheses.

6. Access the activity, “Ensuring Optimal Management Throughout the Clinical
Spectrum of Spinal Muscular Atrophy,” at PeerView.com/HNM40
Motor Function Assessment
Scales for SMA1-4
PRACTICE AID
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders
(CHOP INTEND)
Hammersmith Functional Motor Scale—Expanded (HFMSE)
Valid for motor assessment of children ranging in age from 3.8 mo to over 4 y
• Developed in the context of SMA assessment
• Each item graded on a scale of 0-4, with 0 as “no response” and 4 as “complete response”
• Total score ranges from 0 to 64
Spontaneous
movement
(upper extremity)
Hip adductors
Shoulder flexion and
elbow flexion
Elbow flexion
Sitting
Items 1-4
Rolling
Items 5-9
Transitions/
crawling
Items 10-17
Standing/
stepping
Items 18-20
Transitions/
kneeling
Items 21-27
Squat/
jump
Items 28-29
Stairs
Items 30-33
Hand grip
Rolling:
elicited from arms
Hip flexion and
foot dorsiflexion
Head/neck extension
Spontaneous
movement
(lower extremity)
Rolling:
elicited from legs
Knee extension
Neck flexion
Head in midline with
visual stimulation
Shoulder and
elbow flexion and
horizontal abduction
Head control
Spinal incurvation
Evaluates motor function in individuals with later-onset SMA
• Each item scored on a scale of 0-2, with patient fatigue an important consideration
• Total score ranges from 0 to 66, with lower scores indicating poorer motor function

7. Access the activity, “Ensuring Optimal Management Throughout the Clinical
Spectrum of Spinal Muscular Atrophy,” at PeerView.com/HNM40
Motor Function Assessment
Scales for SMA1-4
PRACTICE AID
SMA: spinal muscular atrophy.
1. https://smauk.org.uk/physiotherapy-based-measures-hine-chop-intend-hmfse-for-people-with-sma-and-how-they-are-used-to-monitor-treatment-outcomes. 2. Mazzone E et al. Neuromuscul Disord.
2011;21:406-412. 3. Montes J et al. Neurology. 2010;74:833-838. 4. https://www.who.int/childgrowth/standards/motor_milestones/en/.
World Health Organization (WHO) Motor Development Milestones
Explores the windows of achievement of six gross motor milestones
for children aged 4 to 24 mo
Sitting without
support
Standing with
assistance
Crawling on
hands and knees
Walking with
assistance
Standing alone
Walking alone
6-Minute Walk Test (6MWT)
Evaluates exercise capacity in ambulatory individuals with later-onset SMA
• Test course has start line, with horizontal lines placed every 1 m; running/jogging
not permitted
• Participants walk as fast as possible along 25-m course on flat linoleum surface,
turn around marker cone, return in opposite direction, repeating loop as often
as possible for 6 min
25 m
Upper Limb Module (ULM)
Assesses functions related to everyday life in nonambulatory individuals
with SMA aged 30 mo to 27 y
Pencil Coins Push light
Container
lid
Paper Plastic cups Weights

8. Diagnostic Testing for SMA1-3
PRACTICE AID
Access the activity, “Ensuring Optimal Management Throughout the Clinical Spectrum of Spinal
Muscular Atrophy,” at PeerView.com/HNM40
NM: neuromuscular; SMA: spinal muscular atrophy; SMN: survival motor neuron.
1. Mercuri E et al. Neuromuscul Disord. 2018;28:103-115. 2. Glascock J et al. J Neuromuscul Dis. 2018;5:145-158. 3. Glascock J et al. J Neuromuscul Dis. 2020;7:97-100.
• Additional tests (eg, electromyography, nerve conduction tests) are not usually required for diagnosis
Clinical
suspicion
of SMA
0 copies
Other SMA or
NM disorders
SMN1
Confirmatory
testing
(SMN1 deletion
testing)
1 copy
≥2 copies
Confirmed 5q SMA
Mutation
No mutation
Predictive value of
SMA severity
Allows immediate
inclusion in therapies
SMN2 copy #1 (probable type 0): treatment based on symptoms
SMN2 copy #2 (probable type 1): treat
SMN2 copy #3 (probable type 2/3): treat
SMN2 copy #4 (probable type 3/4): treat
SMN1 sequencing
Positive
newborn
screening
SMN2