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
Staff Divisi Neurologi. Dept Ilmu Kesehatan Anak-FKUI
Muscle weakness, relatively common clinical presentation in infants or young children,
result from many different conditions including PNS and CNS

Paralysis in children

Brain
Motor neuron

AHC
muscle

Brainstem

Nerve fiber

Spinal cord

Dwi Putro Widodod, MD, PhD, MMed (clin neurosci)

 Question !

1. Is neurologic disease present

2. Where is the lesion
3. What is the nature of the lesion
Main Points
§ Using the history and diagnostic studies to answer ‘
what is the lesion ? And neurological examination to
answer where is the lesion ?
§ Many neurological deficits can be detected by
watching the child walk, talk and play

3
 Conditions presenting as gait disorder (mimic
weakness)
Non neurologic disorder
• Chikungunya
• Arthritis post infectious
streptococcus
• Henoch-Schonlein purpura
• Toxic transient synovitis
(hip)
• Diskitis (spine)
• Growing pain
Neurologic disorder
• Acute viral myositis
• Hypotonia
• Dopa responsive dystonia
• Ataxia cerebellar post
infection atau ataxia
spinocerebellar
• Conversion disorder -
malingering !
 Definition
(Migita R et al. 2019. Etiology and evaluation of the child with weakness)

• Weakness is a decreased ability to voluntary and actively move muscles against

resistance.
• Weakness can be confused with hypotonia or ataxia. Hypotonia is a decreased
resistance to passive range of motion . Ataxia refers to decreased muscular
coordination
• Most children who are weak, are hypotonic (not all)
• Exception is spastic cerebral palsy (spatic quadriplegia, spastic diplegia)
• Most children who are hypotonic, are not weak
• Ligamentous laxity is the most common cause of hypotonia
• Genetic condition are not always associated with weakness (Down syndrome,
Prader willi syndrome, William syndrome, )
 Features differentiating central and peripheral
problems

Central Peripheral

Developmental delay Developmental delay

In the acute phase
Seizure Weakness
GCS PNS CM
and CNS
CK n Lesions
CK
DTRs LookDTRs
similar
Paresthesia Paresthesia
Athena

Fenichel’s clinical pediatric neurology’ 2013

 Cannot miss diagnoses
THE FIRST STEP IN DIAGNOSIS IS TO DETERMINE WHETHER THE DISEASED LOCATION IS

• CNS • NM • MUSCLE
• SPINAL • P Nerve
CORD Junction
• ADEM • DMD
• GBS • LGMD
• MS • Infection • MG
• CIDP • PP
• CP • Tumor • Botulism
• ALS (UMN • Transverse
• CMT • Myotonia
& LMN) myelitis • Erb’s • Myositis
• Bell’s • Myopathy
• Motor
neuron

• SMA
• POLIO
 Neuromuscular disorder in pediatric
In CMH ‘2017
179 149

Anterior horn cell • SMA (11) History and

neurological
examination
• GBS /CIDP (16)
Peripheral nerve • CMT (Distal neuropathy) (3)
• BELL’S PALSY (5), ERB’S PALSY (4) CK
• OTHERS NEUROPATHIES (68)

Neuromuscular • Ocular-generalized MG (7)

junction EMG ?
• DMD (16)
• LGMD (4)
Muscles • PP (1)
DNA analysis
• Myotonia congenital (2)
• Dermatomyositis (3)
 Motor neuron

NMJ
NERVE FIBER
UMN
Muscle
AHC
• 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

Characteristics of Spinal Muscular Atrophy :

• SMN protein deficiency
• Motor neuron loss and muscle atrophy
• Degenerative motor neuron disease
• SMA clinical manifestations

• 8 type of SMA Ia,b,c; IIa,b; IIIa,b; IV

• Associated with deletion SMN1 gene
 SPINAL MUSCULAR ATROPHY (SMA)
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
§ Have poor head control 3
1 IN 10,000 AFFECTED § Have dificulty breathing &
swallowing 2,4
MORE THAN
90%
HYPOTONIA
(Truncal, proximal) WILL DIE OR
LL >> UL NEED PERMANENT
VENTILATORY SUPPORT
AREFLEXIA BY THE AGE OF 2 4
EPNS Congress, Greece Athena, 2019
SMA TYPE 2
Presents between six and 18
months of age 2
In natural history studies ,
those affected will never walk
without support 2
MORE THAN
30%
OF PATIENTS WILL DIE
BY 25 YEARS OF AGE 5
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
 The role of SMN in spinal muscular atrophy (SMA)
Healthy individual SMA patient

SMN1 SMN2
DNA 6 7 6 7

Pre-mRNA 6 7 6 7 6 7

100% FL-SMN1 7 SMN ?

6 7 6 6 7
mRNA

FL-SMN ?
Functional SMN Unstable SMN protein Functional SMN
protein rapidly degraded protein

90% of SMN transcript 90% truncated SMN 10% SMN transcript

 Genotypes of people affected and unaffected
by SMA
Unaffected people People with Type 1 SMA
--SMN-1 ----- SMN-2 deletion --SMN-1 ----- SMN-2

--SMN-1 ----- SMN-2 deletion --SMN-1 ----- SMN-2

90% 10-20% zero 10-20%
SMN protein SMN protein SMN protein SMN protein

People with Type 2 SMA People with Type 3 SMA

deletion --SMN-1 ----- SMN-2 --SMN-2 ----- SMN-2

Gene conversion
--SMN-2 ----- SMN-2
--SMN-2 ----- SMN-2 Gene conversion
Gene conversion

40% SMN protein

30% SMN protein
 Continuous spectrum of phenotypes in SMA

SMN1 absence or mutations

SMA manifestations

More Negative Positive Less

severe modifiers modifiers severe

M
1a 1b 1c 2a 2b 3a 3b 4
M

SMA2 copies / Amount of SMN protein

 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)
 Suspected SMA with
typical or atypical
clinical features
DIAGNOSTIC ALGORITHMA FOR SMA4
SMN1 gene
deletion test

Homozygous SMN1 Homozygous SMN1

deletion detected deletion NOT delected

Repeat clinical Results typical

exam, EMG, for SMA
NCS, CK

Results NOT SMN1 gene copy One copy

typical for SMA count Of SMN1

Two copies SMN1 gene

of SMN1 sequencing

No SMN1 SMN1 mutation

mutation found found

SMA diagnosis Consider other Consider other SMN-related SMA diagnosis

Confirmd disorders disorders diagnosis confirmed
unconfirmed

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
33 (94) children with Spinal Muscular Atrophy (Biologi
Moleculer Eijkman, Jakarta)
(2004-2018)

§12 patients SMA I with

homozygous deletion of exon 7
SMN-T (SMN-I) gene.

Genetic §21 patients SMA I with

Diagnostic homozygous deletion of exon 7
(PCR & MLPA) and 8 SMN-T gene.

§3 patients SMA II with no

deletion of exon 7 SMN-T and
SMN-C (or SMN II) gene
 Characteristic of advance therapeutic specific SMN
dependent

Nusinersen (spiranza) AVXS-101 (Zolgensma) RG7916 (Risdiplam)

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

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)

 Guillain-Barré syndrome
• Post-infectious rapidly progressive polyneuropathy
• Incidence 1.4/100.000 = 7.000/yr in EU = 100.000/yr world
• Large heterogeniety and severity

Diagnostic criteria (Asbury and Cornblath, Ann Neurol 1990)

Required
§ Progressive bilateral paresis of legs and arms
§ Reduced tendon reflexes

Supportive
§ Progressive phase 4 < weeks
§ CSF; protein increased, cell normal (< 50 /µ)
§ EMG

Exclude other diagnosis

Willson and Good fellow

GBS100 Celebrating a Century of Progress in Gullain-Barré Syndrome

BRAIN
DORSAL COLUMN
Grey Matter
Guillain-Barré syndrome in the 100 years since
its description by Guillain, Barré and Strohl
Richard A.C. Hughes,1 David R. Corblach2 and High J, William3

Table I Guillain-Barré syndrome subtypes, related Antiganglioside antibodies can activate

disorders and associated antiganglioside antibodies complement and induce disruption of

Syndrome Associated antiganglioside § Nodes of Ranvier

antibodies § Neuromuscular junction
§ Other neuronal and glial membranes
ACP None
AMSAN GMI, GMIb, GDIa nAChR C3c MAC
AMAN GMI, GMIb, GDIa, GaNac-GDIa
Acute sensory neuropathy GDIb
Fisher syndrome GQIb, GTIa
Fisher GBS over bp syndrome GQIb, GMI, GMIb, GDIa
GaNac-GDIa
Carvico-brachial-cropharyngeal GTIa
syndrome

AMSAN + active motor and memory axomal neuropathy

 Guillain-Barré
syndrome

Clinical presentations Neurophysiology study, CSF analysis

Typical ascending form Atypical presentations

MRI Study Prominent cranial

nerve involvement

Demyelination Axonal form

Form (AMAN, AMSAN) MFS, BBE, PCB, Pandys autonomia
(AIDP) PCN ASN

Figure 1. A diagnostic flowchart for Gullai-Barré syndrome and variants

Cranial neuropathies (variant GBS)
 Diagnostic criteria for Bickerstaff brainstem
encephalitis (variant GBS)
• Probable BBE
• Diagnosis can be made when both of the following criteria have
been met:
1. Subacute onset (rapid progression of less
than 4 weeks) all the following symptoms:
. Decreased level of consciousness
. Bilateral external ophthalmoplegia
. Ataxia
2. Reasonable exclusion of alternative causes
. Definitive BBE
Diagnosis can be made in the presence of positive IgG anti GQib antibody
even if bilateral external ophthalmoplegia is not completed or ataxia
cannot be assessed or if recovery has occurred within 12 weeks after onset.
 IVIG versus plasma exchange
IVIG
Adverse events in
25,5%
§ 196 children
§ Advedrse events in 25.5%
§ 0% into life-threatening
§ 2% severe / medically significant but not
immediately life-treatening complications
(aseptic meningitis, hypotension)
Plasma
exchange
Adverse events in
66%
§ 58 children
§ Advedrse events in 66%
§ 3% life-threatening (septic shock secundary
27% severe / medically significant but not
immediately life-treatening complications
(anaemia, hypotension, thrombocytopaenia,
bradycardia, hyperkalaemia, suspected line
infection, complications of anaesthetic)
CMT subtypes and disease burden in patients enrolled in the
Inherited Neuropathies Consortium natural history study: a
cross-sectional analysis

CMT Diagnosis: 2018

. Single gene analysis ( usually Sanger)
. Targeted diseases specific gene panels
. Exome sequencing
. Whole genome sequencing

225
CMT1
36
53 CMT2
47 CMT4
CMTX
107
61% CMT1A 910
CMTN
32
HSN
HNPP
287
UNKNOWN

J Neurol Neurosurg Pschiatry 2015,86:873-878

Characteristics of Myasthenia Gravis :
• uncommon;
• Fluctuating of weakness;
• fatiguability;
• reflexs normal;
• positive response to anticholinesterase.

NEUROMUSCULAR
JUNCTION

Motor neuron

Brain

Spinal cord
Clinical feature
• Ocular symptoms (53%)
– 25% ptosis, 25% diplopia, 3 % blurred visio
• Bulbar symptoms 16%
– 6% difficulty swallowing, 5% slurred, 4% difficulty chewing,
1% dyspnea
• Most patients exhibit progession of disease 86%
– 40% purely ocular, 35% generalized, 15% bulbar or ocular-bulbar
• If an ocular MG is going to develop general symptoms
– 56% by 6 months
– 78% by the first years
– 85% by the second years
– 92% by the third years

26
 Infantile Botulism
• Background
• Due to consumption of botulinum spores (usually from honey)
– Higher GI tract pH of infants makes them more susceptible
• Most cases occur in <1yr, 90% occur in < 6 m
• Clinical feature
– GI
• Constipation, poor feding
– Lethargy, weak cry, floppy infant
 Muscle
NMJ
Peripheral
UMN nerve
Is a degenerative muscle disorder, which Muscle

result from a lack of AHCdystrophin protein.

This lack of functional protein is due to a

number of
Characteristics mutation
of Duchenne in the
Muscular dystrophin
dystrophy:
gene. muscle weakness disease
• Progressive
• Many medical issue (a complex disease)
• No cure, premature death
• Genetic implication.
 Early signs and sysmptoms of DMD1-5 (1/2)

Motor abnormalities include :

:
Gross motor delay1-4 Gait problems1-4 Difficulty keeping up with peers
- Sitting - Toe walking / fat-footedness while playing3,5
- Crawling - Wadding gait - Muscle weakness
- Standing - Falling / clumsiness - Gowers sign
- Walking - Trouble climbing
- Trouble running

Birth 1,5 3 5 patient age years

Early signs are variable and can be Gowers sign

subtle, but close monitoring may lead
to another diagnosis and specialist
care5
Source royalty-tree image from www.shulterstock.com
Bushby K et al. lancet neurol 2010;9:77-93
DIAGNOSIS OF DUCHENNE MAY BE DELAYED

A retrospective chart review of 20 patients in England found that the mean age at first reported
symtomps was 32.5 months (range 8-72 months).2
§ First contact with a healthcare professional occurred at a mean age of 42.9 months (range
10-90 months).2
§ Diagnosis was confirmed at a mean age of 51.7 months (range 16-90 months).2
§ Total delay from parental concern to diagnosis was 19.2 months (range 4-50 months).2

First reported symptoms 32.5 months

First contact with healthcare professional 42.5 months 19.2 months

Diagnosis was confirmed 51.7 months

 DMD is caused by mutations in the DMD gene1

§ Several different Large deletions

mutation types can
prevent the creation ~15%
of a full-length, Nonsense mutations
functional dystrophin
10-15%
protein 2-4
60-80%
7-11% Other small mutations
§ It is important to
identify the type of
mutation to help
Large duplications
inform medical
management option
1,5
 Genetic diagnostic pathway of DMD1-9

Genetic testing Elevated CK

DNA isolated from s
confirms diagnosis in blood or saliva sample
1. Detects gene deletions and duplications
over 95% of cases3 1. MLPA Detects -70-80% of mutations
and is required to
identity small
mutations 1,4-6
Multiple deletion / Single exon deletion No mutation found
duplication mutations mutation
2. Detects
remaining
2. Gene sequencing mutations
DMD

Genetic testing Small mutation found No mutation found

identifies the type 3. Muscle
of disease-causing biopsy detects
abnormalities in
mutation DMD 3. Dystrophy analysis the dystrophin
muscle biopsi protein

No dystrophyn
detected
In addition some
laboratories may use RNA
Adapted from references 1,7-9 DMD sequencing to identity
intronic of complex
variants
 Medical therapy
Mutation specific treatment

Recently 3 drugs (officially marketing approved)

Atalurent@ that induces dystrophin production
from the nonsense-encoding m RNA
Eteprilsen@ that induce skipping of dystrophin
exon 51 during splicing.
Golodirsen @ vyondys 53

In Japan, have developed an anti-sense therapy for

DMD that induce dystrophin exon 45 skipping.

33
 EXAMPLE OF A DELETION AMENABLE TO EXON SKIPPING

DELETION
MUTATION

14 15 16 17 18 20 21 22

! EXONS OUT OF
FRAME

20

EXONS 20 15 HIDDEN

14 15 16 17 18 20 21 22

READING FRAME
RESTORED

14 15 16 17 18 21 22 23 24
 Exon skipping in development for Duchenne
(eterplirsen)

Exon 51 │ May not be

13% amenable to
exon skipping │
Exon 45 │ ~ 20%
8%

Exon 53 │
8%
Other exon skips │ ~
Exon 44 │ 30%
6%
Exon 52 │
4%
Exon 50 │
4%
Exon 55 │ Exon 8 │ 2%
2%

About 13% of DMD patients Available data suggest up to 80% of DMD

may be treated with patients have genotypes amenable to
an exon 51-skipping therapy exon skipping)
 Direct MPLA (total number of sample)
(2011-2020) Lembaga Biologi Molekuler Eijkman,
N:144 Jakarta

mPCR (2003-2010) MPLA (2011-2020)

N:58 (40,3%) N:86 (59,7%)

Deletion positive Deletion or

(N:44) + (3 promotor) Duplication negative
Duplication positive (N:6) (N:33)

Promotor Duplication Single deletion Multiple deletion

1. Muscle, ex 1- 1. Ex 2-6 OF 1. Ex 46-47 OF 1. Ex 50-52 OF
2OF 2. Ex 1&40 IF 2. Ex 45-52 OF 2. Ex 8-18 OF
2. Brain, ex 3. Ex 72 IF 3. Ex 46-52 OF 3. Ex 3-20 IF
38,72(-), deletion 4. Ex 55 OF 4. Ex 45-53 OF 4. Ex 49-50 OF
5. Ex 45 OF 5. Ex 53-54 OF 5. Ex 18-19 OF
6. Ex 48-50 6. Ex 3-7 OF
The most frequent sites for single exon 7. Ex 53-55 OF
deletion ex 44 (5/12) 41,6%. 8. Ex 30-48 OF
9. Ex 3-7 OF
In general, deletion were mostly found in 10. Ex 49-52 OF
exon 19-52.
 Limb-girdle Muscular Dystrophies

LGMD type Gene product clinical features

2A Calpain 3 0nset at 8-15 years,

progression variable
2B Dysferlin adolescence, mild
weakness
2C Sarcoglican Duchenne -like
2D A-sarcoglican Duchenne -like
2E B-sarcoglican Duchenne-Becker like

2F Sarcoglican slowly progressive, growth

retardation

Fenichel’s clinical pediatric neurology’ 2013

 Hypokalemic periodic paralysis
• CACNA1S calcium channel (2/3)
• SCN4A sodium channel (1/3)
• Prevalence about 1:100,000
• AD or AR
• Onset < 20 years
– Highest frequency of attacks
between 15 and 35 years
– Attack frequency decreases with age
– Fixed limb girdle weakness later in
life
• Attacks range from mild
weakness to paralyzed
– Rarely involves ocular, bulbar, and
respiratory muscles
• Frequency 8 attacks/month,
lasting from hours to days
• Carbohydrate-rich food, stress,
alcohol and rest after exercise
• K+ can drops < 3.0 mmol/L
• Transient elevation on serum CK
• Patophysiology
– Abnormal gating pore current for
both calcium and sodium mutation in
the context of low K+
– sustained depolarization
– Sodium channel to an inactive
configuration
Dubai, 24th World Congress of Neurology 2019
 Acquired demyelinating syndromes of
childhood
• Clinically isolated syndrome (CIS)
The clinical
• Transverse •myelitis (TM) feature are more important
• Optic neuritis than
(ON) radiological feature
The most
• Brainstem /• cerebellar common cause of transverse
syndrome
myelitis
• Acute disseminated is demyelination .Dale(ADEM)
encephalomyelitis RC, Vincent A,
inflammatory and autoimmune disorder of the CNS in children. 2010

• Multiple sclerosis (MS)

• Neuromyelitis optica (NMO)

Tillerna and McKeon 2012. J Child Neurol 27: 1437-47

 Common signs and symptoms
of TM by location

67% . Weakness in the upper and or lower

extremities
. Sensory loss and sensory level
27% . Flaccid or hyper-reflexia
. Difficulty walking
. Muscle cramps
6%
. Bowel/bladder dysfunction
. Fever 50%
. Preceding illness 50%