Dwi Putro Widodo has extensive medical training and experience in neurology. He obtained degrees in general medicine and pediatric specialties. Additionally, he has a Master's in clinical neuroscience and has worked in neurology departments. His background qualifies him as an expert in the neurology field, specifically in areas like the neuromuscular system, spinal muscular atrophy, and potential treatments.

1. Daftar Riwayat Hidup
• Nama : Dwi Putro Widodo
• Pendidikan
• Dokter Umum FKUI, 1983
• Dokter Spesialis Anak FKUI, 1992
• Dokter Spesialis Konsultan Neurologi 1998
• Doktor Ilmu kedokteran 2010
• Pendidikan Tambahan
• Master of Medicine in Clinical Neuroscience
Univ. Melbourne, 1996 – 1998
. Course in clinical neurophysiology, RCH-Melbourne 1998
• Pekerjaan
Staf Div Neurologi. Dept Ilmu Kesehatan Anak-FKUI

2. NEUROMUSCULAR SYSTEM –
MOTOR NEURON IN THE SPINAL ANTERIOR HORN
Brain
Spinal cord
Motor neuron
Motor Neuron control muscles used for activities such as breathing, crawling,
walking, head and neck control, and swallowing. 2
Update SMA and the role of
valproic acid

3. Fukuyama- type congenital muscular dystrophy
1. Symptoms
Delayed milestones (mostly can sit alone)
CNS abnormalities (MR, convulsion)
Contracture of multiple joint
Slowly progressive
2. Brain CT/MRI: polymicrogyria, delayed myelin
High CK: 10-20 times normal

4. Pathophysiology
• In healthy individuals, most functional SMN protein is produce by the
SMN1 gene
• In patients with SMA, deletion or mutation of the SMN1 gene leads to
reduce levels of SMN protein
• Small amounts of functional SMN protein are still produced by the SMN2
gene
• SMN protein deficiency
• Motor neuron loss and muscle atrophy
• SMA clinical manifestations

5. THE DIAGNOSIS
OF SMA IS BASED
ON MOLECULAR
GENETIC TESTING1
CORE
DIAGNOSTIC
SIGNS
HYPOTONIA
§ Truncal
§ Proximal
§ Lower limb more commonly
than upper limb
AREFLEXIA
SMA manifestations
In neonates
• Areflexia
• Weakness-
Hypotonia
• Tongue fasciculation
• Bell shaped thorax
• Paradoxical breath
• Weak cry
• Feeding problem
• Dysautonomic
• Hypoglycemia
• Hypercalcemia
• Joint contracture
• Osteopenia/fracture

6. Genetic cause of SMA
• Autosomal recessive mutation of SMN 1 gene on
chromosome 5 (96% homozygous deletion exons 7 (+8)
• 2% of general population are heterozygote for SMN 1 deletion
(1:50).
Homologue SMN 2 gene in direct vicinity
. In healthy people SMN2 gene has no function
. In patients with SMA, SMN2 leads to partial rescue of
of phenotype, SMN 2 copy number correlates with disease
severity.

7. SMA INHERITANCE 9,10
PARENTS
SMA CARRIER SMA CARRIER
CHILDREN
UNAFFECTED SMA CARRIER SMA
RISK OF SMA RISK OF SMA
25% 50% 25%

8. SPINAL MUSCULAR ATROPHY
SMA TYPE 1
The #1 genetic cause of infant
mortality, 2 SMA type 1
typically presents within the
first six months of life and
those affected :
§ Never sit without support 2
§ Have poor head control 3
§ Have dificulty breathing &
swallowing 2,4
SMA TYPE 2
Presents between six and 18
months of age 2
In natural history sudies ,
those affected will never walk
without support 2
SMA TYPE 3 & 4
Presents between six and 18
Typically presents in early
childhood to early adulthood 2
Those affected may lose the
ability to walk over time 2
MORE THAN
90%
WILL DIE OR
NEED PERMANENT
VENTILATORY SUPPORT
BY THE AGE OF 2 4
MORE THAN
30%
1 IN 10,000 AFFECTED
Caused by a genetic defect in
the SMN1 gene that codes
SMN, a protein necessary
for survival of motor
neurons1
EPNS, Greece Athena, 2019
OF PATIENTS WILL DIE
BY 25 YEARS OF AGE 5

9. Frequency of phenotypes
age of onset < 6 months
Characteristic
< 18 months
Frequency
> 18 months
Never sits
without support
Never stand without
support
Stand alone, my
walk
30%
20%
50%
Type 1 Type 2 Type 3
Adulthood
Ambulatory
5%
Type 4

10. Linking pathophysiology with the clinic
• Weakness is axial and proximal, and predominantly
affect the lower limbs
• The severity of the SMA phenotypes mainly depend
on the number of copies of the SMN 2 gene
• Patients with type 1 SMA (infantile form) typically
have 1-2 SMN 2 copies while patients with type 3
(adult form) have > 3 copies

11. Natural history type 1
> 90% of SMA Type 1 patients will not survive to the age of 2
Holds heads steady
alone, brings
hands to mouth
Rolls over in
both
directions
Sits
alone
crawls
Cruises; may
stand alone
Walks alone; may run
and walk up stairs;
outs with a spoon
Climbs furniture
alone; kicks and
throws a bail
8 % survival*
20 MOS
25 % survival*
13.6 MOS
50 % survival*
10.5 MOS
Phil Child RESNET Finkel 2014
Survival Predictions
0 2 4 6 8 10 12 14 16 18 20 22 24
Onset of SMA Type 1 by 6m
SURVIVAL CURVE
Age (mos)
Milestone for a
healthy infant
SMA Type 1
survival rates

12. Spinal muscular atrophy
• Classical SMA
• Autosomal recessive form of SMA linked to chromosome 5 (SMN
gene)
• Homozygous SMN 1 deletion (exons 7 and 8) of the SMN gene on
chromosome 5
• Other form not linked to chromosome 5
• Distal SMA
• Diaphragmatic SMA
• Dominant forms predominantly affecting the lower limbs

13. PHASES OF DISEASE PROGRESSION IN SMA1
PRE-CLINICAL SUB-ACUTE CHRONIC PHASE
Motor neuron/muscle loss, is
progressing but has not
reached a critical threshold
Motor neuron/muscle loss
reaches a critical threshold
ongoing motor neuron repair
Infants appear normal Ongoing motor
neuron/muscle loss is fairly
rapid
Motor neuron/muscle loss
appears to plateau
Clinical symptoms develop
TIME
Functional motor abilities
may remain stable for
months/years

14. DIAGNOSTIC ALGORITHMA FOR
SMA4
Suspected SMA with
typical or atypical
clinical features
SMN1 gene
deletion test
Homozygous SMN1
deletion NOT delected
Repeat clinical
exam, EMG,
NCS, CK
Results NOT
typical for SMA
Results typical
for SMA
SMN1 gene copy
count
One copy
Of SMN1
Two copies
of SMN1
SMN1 gene
sequencing
No SMN1
mutation found
SMN1 mutation
found
SMA diagnosis
Confirmd
Homozygous SMN1
deletion detected
Consider other
disorders
Consider other
disorders
SMN-related
diagnosis
unconfirmed
SMA diagnosis
confirmed
Althogh newborn screening is not yet standart practice, time to diagnosis is critical. Based on the natural history of the
disease, earlier diagnosis and intervention may help improve outcomes for children with SMA.3

16. DNA testing for SMA
• SMN gene deletion test
• Via molecular genetic PCR-based testing (2-3 weeks for result; now
quicker)
• 95% sensitivity, 100% specitivity
• 95% will have homozygous of SMN1
– 90% homozygous absence of exons 7 and 8
– 10% show homozygous absence of exon 7 but not 8
• 4% of SMA patients exhibit intragenic SMN1 mutation instead of
deletion
• EMG less used as first line; possibly more in later onset cases
• Prenatal diagnosis
• Carrier testing/screening in expectant mother
• Via CVS (10-12th week GA) or amniocentesis (14-16th week GA)

17. The role of SMN in spinal muscular atrophy (SMA)
6 7
6 7
6 7
DNA
Pre-mRNA
mRNA
SMN1
6 7
6 7
6
6
6
7
7
SMN2
Unstable SMN protein
rapidly degraded
Functional SMN
protein
Functional SMN
protein
90% of SMN transcript 10% SMN transcript
90% truncated SMN
100% FL-SMN1 7 SMN ?
FL-SMN ?
Healthy individual SMA patient

18. Continuous spectrum of phenotypes in SMA
SMN1 absence or mutations
SMA manifestations
SMA2 copies / Amount of SMN protein
More
severe
Less
severe
Negative
modifiers
Positive
modifiers
1a 1b 1c 2a 2b 3a 3b 4
M
M

19. Genotypes of people affected and unaffected by SMA
--SMN-1 ----- SMN-2
--SMN-1 ----- SMN-2
100% 10-20%
SMN protein SMN protein
--SMN-1 ----- SMN-2
--SMN-1 ----- SMN-2
zero 10-20%
SMN protein SMN protein
--SMN-1 ----- SMN-2
--SMN-2 ----- SMN-2
(Gene conversion)
30% SMN protein
--SMN-2 ----- SMN-2
Gene conversion
--SMN-2 ----- SMN-2
Gene conversion
40% SMN protein
Unaffected people People with Type 1 SMA
People with Type 3 SMA
People with Type 2 SMA
deletion
deletion
deletion

20. Lembaga Biologi Molekuler Eijkman
Sekitar 96% kasus SMA tipe 1, 92% kasus SMA 2, dan 90% dengan SMA tipe 3
menunjukkan delesi homosigot ekson 7 atau delesi homosigot ekson 7 dan 8
gen SMN1 (SMN-T)
Pada umumnya, individu normal memiliki 2 copi ekson 7 pada gen SMN1 dan
2 copi ekson 7 pada gen SMN2
Individu yang tidak memiliki copi ekson 7 gen SMN1, namun memiliki 3 copi
ekson 7 gen SMN2 bermanifestasi klinis SMA.
Genetic diagnosis in 33 (92) children spinal
muscular atrophy (2004-2018)

21. Approach for drug treatment of SMA
• Increased production of SMN protein through SMN2 gene
• Splicing modifiers Antisense oligonucleotides (Nusinersen)
(prevents skipping of exon 7)
• Oral splicing modifiers (Risdiplam)
• Gene therapy
• ScAAV9 with SMN 1 gene (replacement of SMN 1)
• Neuroprotection
• Olesoxime
• Increase of muscle mass
• Myostatin blockade
• IGF-1/growth hormone
• Stem cells
Finkel RS, et al. Lancet 2016; 38:3017-26

22. SMN upregulating SMN independent
SMN gene
replacement
SMN2 splicing modified
Muscle
enhancer
Gene Therapy ASO Small molecule
IV intrathecal Oral
Systemic CNS only Systemic
Type 1-2 Type 1-3 Type 1 Type 2-4
Mechanism
Strategy
Drug type
Delivery
method
Body
distribution
Patient
population
AVXS-101 Spiranza Risdiplam Bramaplam Reldesemtiv
I I I I
SMN- Targeted therapies

23. Spinraza*(nusinersen)
• Modifies the transcription of SMN2 to produce a FL SMN
protein
• Only effective for SMA caused by deletions/point mutation of
SMN1
• Approved for use in patient of all ages with 5q SMA
• Given via intrathecal injection, 12 mg ( in 5 ml solution) –
single dose vial
• Induction phase, then maintenance every 4 months for life
2 wks 2 wks 30 days 4 months 4 months
Induction Maintenance

24. AVXS-101 gene therapy
addresses the genetic root cause of SMA
Normal individual SMA-affected individual
SMN gene ---- SMN1----- SMN---
primary back up
SMN protein 90% 10%
SMN gene ---- SMN1----- SMN---
primary back up
SMN protein 90% 10%
SMA –affected individual treated with onasemnogene abepravovec
SMN gene ---- SMN1------------SMN------------------- 0nasemnogene A
primary back up primary
SMN protein 90% 10% 90%
(functional SMN protein) (non-functional) (functional)
Mendell JR et al. NEJM 2017

25. Risdiplam * (RG7916; RO7034067): An Oral, Small
Molecule SMN2 Splicing Modifier
6 7
6 7
6 7
DNA
Pre-mRNA
mRNA
SMN1
6 7
6 7 Risdiplam
6
6
6
7
7
SMN2
Unstable SMN protein
rapidly degraded
Functional SMN protein
Functional SMN protein

26. Drug treatment for SMA types II and III
Meta-analysis. Cochrane database syst Rev. 2020
• 10 randomized, placebo-controlled trial of treatment (duration 3-24
months)
• Creatine (55 participant)
• Gabapentin (84)
• Nusinersen (126)
• Olesoxime (165)
• Phenylbutyrat (107)
• THR (9)
• Valproic acid (33)and valproic acid plus acetyl-L-carnitine(61)
• Conclusion: (clinical important effect on motor function)
1. Moderate –certainty evidence: (nusinersen)
2. Low-certainty: Creatine, gabapentin, phenylbutyrat, valproic acid and
valproic acid plus creatine
3. Very low-certainty : Olesoxime, somatotropin

27. Muscular atrophy: a systematic review and
Meta-Analysis
• Total n=704
• 1. Pubmed: n=55 5. clinicaltrial: n=6 9. SIGLE: n=0
• 2. Scopus: n=203 6. POPLINE: n=0 10. mRCT; n=0
• 3. google scholar: n=296 7. WHO GHL: 55 11. NYHAM:n=0
• 4. ISI: n=26 8. Virtual health library: n=63
10 articles were included for final analysis
5 clinical trials were included for
meta-analysis
Conclusion: study suggests that VPA treatment results in an improvement in
gross motor function for SMA patient, but not in other assessment of motor
function, or possibly, in respiratory function. VPA appears to be relatively safe
drug.
21 include for full text reading

28. Phase II open label study of valproic acid
in SMA
• 37 (42) subject SMA II-III, age > 2 years, continued on
treatment for a full year.
• Primary outcome were laboratory safety and adverse event.
Exploratory outcome, motor function, pulmonary function,
degree of denervation
• In conclusion, this study provides good evidence that VPA can
be used safely in SMA subjects over 2 years of ages in the
setting of close monitoring of carnitine status
• This study provides evidence in support of improvement in
gross motor function in younger non-ambulatory type II
children

29. Novel therapeutic approached in SMA : current clinical
and preclinical trials
(Pediatr Neuro 2019;46:1-12)
SMN 1 replacement Zolgensma (AVXS-101) FDA-Approved
Therapeutic Therapeutic target Therapeutic agents Trial status
pathway (completed or ongoing/results)
Upregulation of SMN2 transcript . HDACIs, e.g., PBA,VPA VPA: completed placebo-controlled
; negative
PBA: completed-placebo-controlled;
negative
. Albuterol completed open-label; positive but
lacking large data
Stabilizing SMN protein . Aminoglycoside
. Indoprofen All are preclinical
. polyphenols
Promote exon 7 inclusion . Nusinersen FDA -approved
. Risdiplam FDA-Approved
. Branaplam Ongoing
SMN-
Depend
ent
SMN- In
dependent
1998

30. SMA classification and standards of care
Standards of care guidelines
Part 1 Diagnostic and
genetics
Physical
Therapy and
rehabilitation
Orthopaedic
care
Nutritional
care
Part 1
Pulmonary
And acute
care
Medication
Other organ
systems
Ethics and
Palliative care
• Non-sitters
• Sitters
• Walkers
Firkel R.S, et al, Neuromuscul Disord, 2018, 28:.197-207
Mercuri E, et al, Neuromuscul Disord, 2018, 28: 103-15

31. 3 6 9 12 15 18
Normal development
SMA TYPE 3
SMA TYPE 2
SMA TYPE 1
Age (months)
Acquisition
of
motor
skills

32. Characteristic of advance therapeutic specific SMN
dependent
Mechanism Increase amount of complete SMN protein production of SMN protein from Increase a mount of
Of action from SMN2 SMN1 complete SMN protein from
SMN2
Nusinersen(spiranza) AVXS-101(Zolgensma) RG7916(Risdiplam)
Administration Intrathecally (IT) Intravenously Oral
Dose four loading doses (12 mg each) and one dose of 2.0 vg/kg 5 mg/day or 0.25/kg
maintenance every 4 months
Approval FDA & EMA all SMA type FDA FDA
Cost 125.000 per inj 2.125 m per inj 340.000/yr
(j.earlhuman dev. 2019;138)

33. Paper by years
Conclusion
33
2007
Preclinical trial
• Protocol treatment
• Newborn screening
and
presymptomatic
intervention
• Combined
therapies
• Evaluation of long
term impact of
these treatment
1992
Clinical
classification type
I,II,III
1995
SMN gene
discover
2017
FDA/EMA approval of
nusinersen
2019
FDA approval of
ZolgenSMA, SMN1
AAV gene therapy 2020
FDA approval of
Risdiplam
2011
Clinical trial
program
>150 >350 >400 Near future
1. Thompson RA, Nelson CA. Am Psychol. 2001;56:5-15; 2. Lenroot RK, Giedd JN. Neurosci Biobehav Rev. 2006;30:718-29.