AN OVERVIEW OF INFANTILE SPINAL MUSCULAR ATROPHY (SMA)

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(1)

AN OVERVIEW

OF INFANTILE

SPINAL MUSCULAR

ATROPHY (SMA)

(2)

SPINAL MUSCULAR ATROPHY

OR

SMA

IS A

RARE NEURODEGENERATIVE GENETIC DISEASE

SMA is a progressive neuromuscular disease

that causes motor neurons in the spinal cord

to deteriorate.

1

It leads to muscle weakness and muscular atrophy,

which can affect patients’ respiratory function and

life expectancy.

1

SMA IN THE UK AND IRELAND: RARE

THE PREVALENCE RATE IS 1.87/100,000

2

THE INCIDENCE RATE IS APPROXIMATELY 1-2 PER 100,000

3

Brain

Spinal cord

Motor neuron

Muscle

in the UK and Ireland

~

100

4

new cases per year

1,200-2,500

cases

SMA patient population estimated at

(3)

SMA IS AN

AUTOSOMAL RECESSIVE

GENETIC DISEASE

5

SMA IS CAUSED BY A DEFICIENCY

OF SMN PROTEIN

7

Just 10% of SMN proteins produced

by the SMN2 gene are functional.7, 8 100% of SMN proteins produced

by the SMN1 gene are functional.8

CHROMOSOME 5

SMN2gene SMN1 gene

PARENTS

CHILDREN

RISK OF SMA

HEALTHY CARRIER

OF SMA HEALTHY CARRIER OF SMA

HEALTHY

CARRIER OF SMA SMA NOT

AFFECTED

25

%

50

%

25

%

HOW SMA IS TRANSMITTED

5, 6

SMN protein is essential to the survival of motor neurons.

It is coded by two genes located on the long arm of

chromosome 5 : SMN1 and SMN2.

7, 8

100% of SMN proteins produced by the SMN1 gene

are

functional.

8

Just 10% of SMN proteins produced by the SMN2 gene

are

functional.

7, 8

– Unlike the SMN1 gene, SMN2 produces mRNA that

often excludes exon 7 during splicing.

7

– SMNΔ7 mRNA produces truncated, unstable and

non-functional SMN protein.

7

(4)

The number of copies of the SMN2 gene is hugely variable in patients with SMA.

A larger number of copies of SMN2 has typically been associated with less severe forms of the

disease, but is not directly predictive and should not be used as the basis for treatment decisions.

Given its potential role in modulating the severity of the disease, SMN2 is a

target for treatments.

SMN1 AND SMN2 IN A PATIENT WITH SMA

7, 9, 10

NORMAL PRODUCTION OF SMN PROTEIN BY SMN1 ABNORMAL PRODUCTION OF SMN PROTEIN BY SMN2 IN SMA SMN1 pre-mRNA SMN1 mRNA

Complete, normal length SMN protein SMN1 6 6 7 7 8 8

Quickly broken down

SMN2 pre-mRNA

SMNΔ7 mRNA SMN2 mRNA

Unstable, non-oligomeric

truncated SMN protein Complete, normal length SMN protein SMN2 6 7 8 6 7 8 6 8 80–90% 10–20%

C

T

(5)

There is more than one form of SMA. SMA is categorised into the following phenotypes, based on age at symptom onset and maximum acquired motor function:1, 9, 11

Little to no foetal movement prior to birth Very low muscle tone from the first weeks of life Very short life expectancy (several weeks) Severely low muscle tone

(unable to control head, difficulty rolling over etc.)

Unable to sit unsupported

Short life expectancy (often less than 2 years) Axial and proximal muscle weakness

(scoliosis, limb contractures)

Unable to walk unaided

Decreased life expectancy (but longer than 2 years) Learns to walk unaided, but this may be lost over time Muscle weakness, predominantly proximal lower limb Normal life expectancy

Able to walk unaided, retains this ability over time Mild proximal muscle weakness

Normal life expectancy

Age

TYPE 0

TYPE I

TYPE II

TYPE III

TYPE IV

INF ANTILE ONSET INF ANTILE LA TER ONSET birth 6 months 18 months 30 years 2 weeks

(6)

After an initial period of acquisition,

motor capacity reaches a plateau, and then begins to decline,

marking the start of SMA. Infantile-onset forms of the disease progress more quickly.

By the time symptoms appear, a significant proportion of motor neurons have already been lost.

Without treatment, people with SMA will see their disease progress over time.

A PROGRESSIVE DISEASE, REGARDLESS AGE AND TYPE

NEUROMUSCULAR

DEVELOPMENT

MILESTONES AND

TRAJECTORIES

SMA TYPE II SMA TYPE III

PRE-SYMPTOMATIC PHASE ACUTE PHASE Walking N eur omuscular developmen

t milestones and trajectories

Adult life Adolescence Birth Sitting unaided Head control NORMAL SUBACUTE PHASE CHRONIC PHASE SMA TYPE I

(7)

DIFFERENT GOALS DEPENDING ON THE CLINICAL PHENOTYPE

PREVENTING

phenotypic expression of the disease

Goal: Enables motor development.

LIMITING

phenotypic expression of the disease

Goal: Improves motor development.

STABILISING

phenotypic expression of the disease

Goal: Preserves acquired motor functions,

as a minimum.

BEFORE

SYMPTOMS

EARLY

SYMPTOMS

LATER

SYMPTOMS

(8)

IDENTIFY

THE SYMPTOMS

1

l

Type I: In very young babies, onset is before they are able to sit up (< 6 months);

infantile-onset type I begins before they can hold up their head.

l

Type II: Onset is after the baby can sit up but before the normal age at which they

learn to walk (< 18 months).

l

Type III: Onset is after the child learns to walk.

Moderately elevated CK is sometimes observed (2 to 5 times the normal level).

l

Type IV: Onset is in adulthood. Mild symptoms: increasing difficulty to walk.

CONFIRM

THE DIAGNOSIS

1

If the clinical presentation appears to indicate spinal muscular atrophy, the child

must be referred as quickly as possible to their reference or specialist centre for

neuromuscular disease to undergo genetic analysis of the SMN1 gene (+ identification

(9)

EARLY WARNING SIGNS OF SMA

RED FLAGS FOR 0-6 MONTHS

13

• Progressive hypotonia and low muscle power

• Poor or progressive loss of anti-gravity movement especially in proximal limb muscles

• Sparing of extraocular muscles (“bright eyes”) Facial weakness is often minimal or absent • Some tongue fasciculations

• Commonly assumes frog leg position • Reduced or absent tendon reflexes

• Patients appear alert, no apparent cognitive deficit • Tachypnea for age

• Potential diaphragmatic breathing (“see-saw or paradoxical”) leading to respiratory failure

• Bulbar dysfunction: poor suck/swallow. Potentially unsafe swallow • May have bell-shaped chest

• Does not reach or delayed milestones (cannot sit without support, cannot hold on to a toy, cannot roll over)

• Milestone loss: has lost the ability to do things he/she was able to do before • Failure to thrive “seems smaller than other children his/her age”

• If very severe may have reduced movements even in utero and are born with contractures

(10)

EARLY WARNING SIGNS OF SMA

RED FLAGS FOR 7-24 MONTHS

 14

• Symptoms may present anytime over this period. Child initially appears normal

• Fails to reach or delayed milestones: sit without support but are unable to stand

• Milestone loss: has lost the ability to do things he/she was able to do before

• Poor or progressive loss of movement initially in proximal limb muscles

• Progressive hypotonia and low muscle power • Fails vertical suspension test:

When child picked up slips through hands • Sparing of extraocular muscles (“bright eyes”)

Facial weakness is often minimal of absent • Commonly assumes frog leg position • Poor phonation: cry is weak

• Tachypnea for age; hypoventilation in sleep • May have a bell-shaped chest

• Bulbar dysfunction: poor suck/swallow. Potentially unsafe swallow. Prolonged feed • Failure to thrive “Seems smaller than other

(11)

EARLY WARNING SIGNS OF SMA

RED FLAGS FOR 24 MONTHS

TO 18 YEARS

 15

ADULTS ONSET

RED FLAGS FOR

 15-17

Scoliosis develops

Trouble completing everyday

activities such as walking up stairs

more prone to respiratory illness

• Symptoms may present anytime over this period

Child initially appears normal

• Proximal leg muscles are most often affected first, with a tremor seen in the hands • Fails to reach or delayed milestones:

walks but can’t run, or can’t do squats • Progressive milestone loss

• Bulbar dysfunction occurs very late in the disease

Waddling gait is common

Finger trembling and fasciculation

Calf hypertrophy may occur

Muscle weakness predominantly

affecting the legs and hip muscles then

progresses to the shoulders and arms

Percieved weaker after infections

Joint contractures leading to reduced

range of movement due to perceived

fatigue with standing and walking

(12)

ADULT SMA PATIENTS ARE LOOKING FOR STABILISATION WITH A TREATMENT 

18

ACTIVITIES THAT PATIENTS MOST WANT

TO SEE IMPROVED OR STABILISED*

HOW WOULD YOU RATE A TREATMENT THAT

STABILISED YOUR CLINICAL CONDITION?*

Answers (%) - Number of pa tients surveyed: 822 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

81.3%

Important progress

15.2%

Moderate progress

3.2%

No progress

0.3%

Don’t know

IMPROVEMENT

48%

Use toilet on own

39%

Wash on own

34%

Turn in bed

33%

Dress on own

32%

Transfer on own 22% Self feeding 17% Write with a pen

13%

Use a keyboard 10%

Brush own teeth

8%

Brush own hair

STABILISATION

37%

Self feeding

28%

Wash on own

26%

Use a keyboard

25%

Use toilet on own

24%

Write with a pen

22% Turn in bed

20% Transfer on own

18% Brush own teeth

18% Dress on own

9%

Brush own hair

*Participants were asked to choose the 3 functions, ranked 1–3 in decreasing order of priority, they would most like to stabilise. All numbers are the number of the respective answers received. The percentages given express the proportion of the total answers selecting the given function, irrespective of the priority order, among the 822 replies to the questionnaire.

(13)

ADULT SMA PATIENTS ARE LOOKING FOR STABILISATION WITH A TREATMENT 

18

ADDITIONAL RESSOURCES

For more information on SMA & treatment centres, please visit

the UK patient society websites such as SMA UK, Treat SMA

https://smauk.org.uk/

https://treat-nmd.org/

https://www.treatsma.uk/

https://www.musculardystrophyuk.org/

NHS information on SMA:

https://www.nhs.uk/conditions/spinal-muscular-atrophy-sma/

Results are from a survey aiming to obtain the view on the current clinical stat of EU Type II and III SMA patients conducted in 2015

Impact of SMA on quality of life and expectations regarding clinical development was captured

(14)

DIAGNOSTIC ALGORITHM

19

Consider other

disorders diagnosis not confirmedSMN-linked SMA SMA diagnosis confirmed

SMA diagnosis

confirmed Consider other disorders

Typical results for SMA Number of copies of SMN1 Two copies of SMN1 Homozygous SMN1 deletion detected One copy of SMN1 SMN1 gene sequencing No SMN1 mutation

detected SMN1 mutation detected

SMA suspected based on

typical or atypical clinical characteristics

SMN1 deletion test

Homozygous SMN1 deletion NOT detected

Repeat clinical examination, EMG, NCS, CK

NON-typical results for SMA

(15)

REFERENCES

1 • Farrar MA, et al. Ann Neurol. 2017;81:355-368.

2 • Norwood FL, et al. Brain 2009: 132;3175–3186.

3 • SMA UK.org. Available at: http://smauk.org.uk/what-is-spinal-muscular-atrophy. [Accessed September 2020].

4 • SMA UK.org. Available at: https://smauk.org.uk/summary-information-about-sma#:~:text=At%20any%20one%20time%20 it,is%20affected%20by%20the%20condition. [Accessed September 2020].

5 • Tisdale S, Pellizzoni L. J Neurosci. 2015;35:8691-700.

6 • SMA UK.org. Available at: http://smauk.org.uk/the-genetics-of-5q-sma. [Accessed September 2020].

7 • Butchbach ME, et al. Front Mol Biosci. 2016;3:7.

8 • Lunn MR, et al. Lancet. 2008;371:2120-33.

9 • Faravelli I, et al. Nat Rev Neurol. 2015;11(6):351-359.

10 • TREAT-NMD. Diagnostic testing and care of new SMA patients. Available at: http://www.treat-nmd.eu/downloads/file/ standardsofcare/sma/english/sma_soc_en.pdf. [Accessed September 2020].

11 • Munsat TL, et al. Neuromusc Disorders. 1992;2:5-6.

12 • Serra-Juhe C, Tizzano EF. European Journal of Human Genetics 2019;27(12): 1774-1782.

13 • CureSMA SMArt Maves Checklist for Motor Delays (Infant 0-6 months). Available at: http://events.curesma.org/site/ DocServer/0-6_SMArt- Moves_Checklist.pdf?doc1D=2574. [Accessed September 2020].

14 • CureSMA SMArt Maves Checklist for Motor Delays (0-12 months). Available at: http://events.curesma.org/site/DocServer/7-12_ SMArtMOves_Checklist.pdf?doclD=2575. [Accessed September 2020].

15 • SMA UK.org. Available at: http://smauk.org.uk/symptoms-diagnosis-effects-of-5q-sma. [Accessed September 2020].

16 • NIH. Available at: https://rarediseases.info.nih.gov/diseases/564/spinal-muscular-atrophy-type-4. [Accessed September 2020].

17 • Types of SMA. Available at: https://www.nhs.uk/conditions/spinal-muscular-atrophy-sma/types/ [Accessed September 2020].

18 • Rouault F, et al. Neuromuscul Disord. 2017;27(5):428-438.

(16)

Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie.

For the UK, reporting forms and information can be found at https://yellowcard.mhra.gov.uk/

or via the Yellow Card app available from the Apple App Store or Google Play Store.

Adverse events should also be reported to Biogen Idec on 1800 812 719 in Ireland

and 0800 008 7401 in the UK.

Biogen Idec Limited

Innovation House 70 Norden Road

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