Paediatrics JC125: Paediatric Neurological Diseases With Neurodisabilities

Question 1

Neurological disorders and Neurodisability

Answer 1

Neurological disorders:
- Diseases of brain, spine, nerves, muscles (CNS + PNS)

Neurodisability:
- A consequence of impairment of brain, CNS, PNS that creates activity limitation
- Examples:
1. **Physical difficulties (e.g. cerebral palsy, neuromuscular diseases)
2. **Learning difficulties (e.g. intellectual disorder)
3. ***Social communication difficulties (e.g. autism)

Question 2

Neurodevelopmental disorders

Answer 2

Group of disorders with disabilities in brain functions that noticed at birth / during early childhood
- predominantly affect individual **behaviours, **memory, **concentration, **ability to learn

Common characteristics:
- ***Defined in terms of behaviour
- Tend to run in families
- No single biological cause can be found
- Male preponderance

DSM4 classification:
1. Communication disorders
2. **Autism spectrum disorders
3. ADHD
4. **Intellectual disabilities
- Global developmental delay
5. Specific learning disorder
6. Motor disorder
7. Other neurodevelopmental disorder

Question 3

Global developmental delay (GDD)

Answer 3

Child development:
- Refers to how a child becomes able to do more complex + skillful things in different developmental domains as they grow older

Developmental delay:
- Child does not reach their milestones at the expected times
- Child develops at his/her own pace
- Delay can occur in >=1 areas:
1. Language
- comprehension
- expression
2. Motor
- gross
- fine
3. Social communication skills
4. Thinking skills

Global developmental delay:
- Significant delay >=2 SD below mean on age appropriate standardised tests
- in >=2 developmental domains
—> Gross / Fine motor
—> Speech / Language
—> Cognition
—> Social / Personal
—> ADL
- Wide variety of causes
- Reserved for children <5 yo

Question 4

Developmental Quotient (DQ)

Answer 4

Estimate severity of global developmental delay

***DQ = Developmental age / Chronological age x 100

Interpretation:
- 100 —> Age appropriate performance
- Lower DQ —> More severe delay

Management:
- DQ >85: Routine developmental screening
- DQ 75-85 (borderline): Close developmental **follow-up + some support
- DQ <75: Refer **Comprehensive evaluation for ***early intervention

Question 5

***Possible causes of GDD

Answer 5

1. Prenatal
   Intrinsic
   - Genetic
   - **CNS malformation
   - **Metabolic (Underlying conditions: ***Inborn errors of metabolism)

Extrinsic (complications during pregnancy)
- **Infections (e.g. **TORCH infection: Toxoplasmosis, Rubella, CMV, HSV, Other organisms)
- ***Teratogens / Toxins (drugs of abuse, alcohol, medications etc.)

2. Perinatal
   - **Asphyxia
   - **Prematurity
   - ***Neonatal complications (e.g. intracranial haemorrhage)
3. Postnatal
   - ***Neglect / Psychosocial environment (e.g. child abuse)
   - Infections
   - Trauma
   - Toxins

Question 6

Approach to GDD / Intellectual disability (ID)

Answer 6

1. History
   - **Family history (3 generations review)
   - Psychosocial history
   - **Prenatal history
   - **Birth history
   - Red flags suggestive of **inborn errors of metabolism
   - ***Developmental milestones
2. Examination
   - Physical exam
   —> growth parameters
   —> head shape
   —> fontanelle
   —> cutaneous stigmata
   —> spine
   —> heart abnormalities
   —> abdomen check for organomegaly
   —> limb abnormalities
   —> genital abnormalities

• Neurodevelopmental exam
  —> neurological exam
  —> congenital abnormalities
  —> **dysmorphic features
  —> **current developmental level

3. ***Vision + Hearing assessment

Algorithm:
—> Exogenous cause suspected —> Monitor + Investigate selectively
—> Suggestive of etiology (a more specific Dx suspected) —> Tailor investigations according to etiology
—> No clues to etiology —> Stepwise approach —> 1st line / Tier 1 investigations —> Individually tailored to 2nd line investigations

Tier 1 investigations (**記: Genetic, Metabolic, MRI):
1. **Genetic test (Fragile X, Chromosomal microarray)
2. Baseline metabolic testing (esp. if no metabolic newborn screening)
3. +/- Brain imaging (MRI) (for abnormal neurological sign, microcephaly, macrocephaly, seizures)

Other investigations:
- Lead level (e.g. Pica) + Fe studies (e.g. Ferritin considered when dietary restriction present)
- Whole-exome / genome sequencing (NOT recommended now)

If Dx not established with Tier 1 investigations —> Referral to Genetics / Metabolic / Neurology specialist

Question 7

Consider referral to specialist in Metabolic, Genetic, Neurology

Answer 7

History:
1. **Regression (cognitive decline / significant change in behaviour)
2. Seizures (possible / definite)
3. **Movement disorder (e.g. dystonia)
4. Recurrent episodes of vomiting, ataxia, seizures, lethargy, coma
5. Significant decline in visual acuity (e.g. cataracts, retinopathy) / hearing / other sensory systems
6. ***Family history of IEM, unexplained neonatal / sudden infant death

Examination:
1. **Cerebral palsy like picture without clear cause from history
2. Neurological signs (e.g. dystonia, ataxia, chorea)
3. MSS signs (e.g. arthrogryposis / joint contractures)
4. Ocular / Other signs (e.g. nystagmus, sensorineural deafness)
5. Neurocutaneous features
6. **Organomegaly (e.g. Cardiomegaly) / Multiple congenital anomalies
7. ***Coarse / dysmorphic facial features

Question 8

Investigations of GDD

Answer 8

1st line:
1. ***Chromosomal Microarray (Fragile X)
- detect tiny deletion mutations

Blood tests:
1. **TFT
2. CBC
3. U+E
4. CK
5. **AA, Homocysteine, Acylcarnitine profile

Urine tests:
1. ***Organic acids
2. GAG (glycosaminoglycans)
3. Oligosaccharides
4. Creatine / GAA (guanidinoacetate)
5. Purine + Pyramidines

Question 9

Management of GDD

Answer 9

1. Ongoing monitoring + support
2. Referral to ***Early intervention programs + Multidisciplinary team training
3. GDD is a “provisional” Dx until child is old enough to participate in ***standardised intellectual assessment for diagnosis
4. Some children can catch up their developmental performance after training
5. Other children will have GDD diagnosis ***replaced by IDD (Intellectual disability disorder)

Question 10

Intellectual disabilities (IDD)

Answer 10

Significant limitation in both intellectual functioning + adaptive skills
- A learning disorder
- Must meet following 3 criteria:

1. Deficits in ***intellectual functions
   - reasoning, problem-solving, abstract thinking etc.
   - confirmed by both clinical assessment + individualised, standardised intelligence testing
2. Deficits in ***adaptive functioning
   - results in failure to meet developmental + socio-cultural standards for personal independence + social responsibility
   - limit functioning in >=1 ADL, e.g. communication, social participation, independent living, across multiple environments e.g. home, school, work, community
3. Onset of intellectual + adaptive deficits during the ***developmental period

Question 11

Autism spectrum disorder (ASD)

Answer 11

A continuum / Spectrum of presentations
- each individual has variations in symptoms, behaviours, severity (mild - severe)

Manifests in early childhood

Deficits in (記):
1. **Socialising
2. **Language + communication

Have (記):
1. ***Restricted repetitive behaviours (RBB), interests, activities

Result in:
1. ***Isolation
2. Autism
3. Remove self from social interaction + communication

Prevalence:
- Dramatic increase during last decade
- Now: 1 in 59
- Boys: 1 in 37
- Girls: 1 in 151

Reasons:
1. Broadening of diagnostic concepts that ↑ diagnosis in milder spectrum
2. ↑ Awareness including milder cases with normal intelligence

Other associated comorbidities:
1. **Cognitive (e.g. intellectual, language)
2. Genetics (e.g. fragile X, tuberous sclerosis, Rett)
3. **Behavioural (e.g. anxiety, hyperactivity)
4. Medical (e.g. seizure disorder)
5. Biomarkers (e.g. abnormal EEG, hyperserotonaemia)

Question 12

ASD from DSM5

Answer 12

Was under Pervasive Developmental disorders (PDD) in DSM4:
Other diseases:
1. Asperger syndrome (some characteristics of autism, but language and cognition not as affected —> “high functioning autism”)
2. Childhood disintegrative disorder (late onset, normal initial development, lost skills between 2-10 yo)
3. Not otherwise specified (PDD-NOS) (meet some but not all of above categories)
—> BUT inconsistent diagnosis ∵ share similar S/S

DSM5:
- ALL counted into ASD: 2 problems
1. **Social communication + **Social interaction
- deficit in social + emotional reciprocity
- deficit in non-verbal communication
- deficit in developing + maintaining social relationships

2. ***Restricted / repetitive behaviours / interests / activities
   - fixed on certain routines / excessive resistance to change
   - restricted thinking, fixed interest of abnormal intensity / focus
   - stereotyped / repetitive speech, motor movements / use of objects
   - hyper / hyposensitivity to sensory input
   - unusual interest in sensory aspect of environment

Question 13

Diagnosis of ASD

Answer 13

1. Observed behaviours
   - best known by parents / teachers
2. Relies on listening to caretakers’ observations
3. Give severity score (do assessment by standardised tests)

Flowchart:
Suspicious of ASD by parents / others
—> **Developmental screening
—> Referral to Assessment centre for diagnostic
—> **Comprehensive diagnostic evaluation (involving multidisciplinary team on ASD, global development, hearing, vision)
—> ***Early intervention program, Family support, Follow up for progress

Mild:
- Social communication: able to speak in full sentences but conversation still difficult
- Repetitive / restrictive behaviours: difficulty to switch activities but can still participate in most activities
- need some support

Severe:
- Social communication: speak a few words, rarely interact
- Repetitive / restrictive behaviours: extremely resistant to change, interferes with daily life
- need substantial support

Question 14

***Common presentations of ASD

Answer 14

• Little / No eye contact
• ***Not respond to name
• Not share interest in object / activity with others
• ***Prefers to be alone
• Weak in initiation of joint attention (directs the attention of another person towards a shared target)
• ***Weak in use / interpret of non-verbal communications (e.g. facial expression, gestural cues)
• ***Language delay (understand / expression)
• Use repetitive words / phrases (odd use of language, echolalia (模仿言語))
• ***Rigidity / fixed on certain routines (e.g. same school route, wear same shoes everyday)
• ***Restricted thinking: narrow specific interest (e.g. names of all planet, dinosaurs, MTR stations)
• ***Insistence on sameness + resistance to change
• Lines up toys / objects in obsessive manner
• ***Weak symbolic play / inappropriate play with toys
• Displays self-injurious behaviours
• Absent of typical response to pain / physical injury
• Tantrums (暴躁) easily
• ***Motor mannerism
  —> Displays hand falling / toe walking
  —> Rocks / bang head
  —> Spin self / objects
  —> Odd hand + finger movements

***Regular screening of infants / toddlers for ASD critical —> early referral —> early evaluation + treatment

Question 15

Causes of ASD

Answer 15

1. ***Genetics (vast majority)
   - causative gene unknown
2. Advanced maternal (>40) / paternal age (>50)
   - independently associated with ASD risk
3. Siblings
   - 7-20% subsequent children after 1st ASD child
4. Twins
   - identical: 36-95%
   - non-identical: 31%
5. Preterm birth (<32), Low birthweight (<1.5 kg), Small / Large for gestational age
6. Environmental factors?
   - no clear risk factors
   - but Vaccines do ***NOT cause autism

Question 16

Cerebral palsy

Answer 16

Group of disorders:
- of development of **movement + posture
- causing **activity limitations
- attributed to **non-progressive disturbances occurring in **developing fetal / infant brain
- motor disorders of cerebral palsy often accompanied by disturbances of **sensation (e.g. vision, hearing), **cognition (e.g. learning), **communication perception / by a **seizure disorder

Classification
Types:
1. ***Spastic (most common)
- Hemiplegia
- Diplegia
- Quadriplegia

2. ***Ataxic (predominant cerebellum affected)
3. ***Dyskinetic
   - Athetoid (whole body have involuntary movement)
   - Dystonic (whole body have abnormal muscle tone)
4. Mixed

Question 17

Risk factors / Causes of Cerebral palsy

Answer 17

1. Prenatal
   - **Congenital infection
   - **Stroke
   - ***Congenital malformation
2. Perinatal
   - Birth process related: Asphyxia, Brain injury from traumatic delivery
   - Prematurity related (e.g. **Intraventricular haemorrhage) (related to Spastic palsy esp. Diplegic type)
   - Severe neonatal jaundice (*Kernicterus)
3. Postnatal
   - Acquired conditions (e.g. **brain infection, head injury, progressive **hydrocephalus, hypoxic ischaemic injury in near drowning)

Question 18

Early signs of Cerebral palsy

Answer 18

記: Neurobehavioural, Reflex, Tone, Milestone

1. ***Neurobehavioural signs
   - excessive irritability, lethargy, poor sleep
   - vomit frequently
   - difficult to handle / cuddle
   - poor visual attention
2. Developmental reflexes
   - ***persistence of primitive reflex
   - delay appearance of protective reflex
   - brisk deep tendon reflex
   - clonus
   - upgoing babinski
3. ***Motor tones + Posture
   - tone in all / part of extremities / trunk may be ↓ / ↑ (eventually ↑)
   - poor head control, persistent / asymmetric hand fisting
   - abnormal oromotor patterns (e.g. tongue thrusting, grimacing)
   - ↑ neck extensor / axial tone —> make head control seem better than it actually is
4. ***Motor milestones
   - serial examination of motor milestones —> effective screening to pick up CP early —> gives idea severity of physical disability
   - delay in motor development +/- other developmental domains
   - Gross motor function classification system (GMFCS: level 1-5)

Treatment:
Hypertonia, Weakness, Incoordination
- GM + FM training
- rehab equipment needs
- neuromotor treatment with oral medications, **Botox
- casting
- intrathecal **baclofen pump
- selective dorsal ***rhizotomy (selectively destroys problematic nerve roots —> improve lower limb spasticity)

Associated symptoms:
1. Visual / Hearing impairment —> hearing + visual aids, glasses, squint corrective surgery
2. Speech / Swallowing impairment —> oromotor training, nutritional supplement
3. Acid reflux, constipation —> anti-reflux medication
4. Breathing difficulties (frequent aspiration pneumonia) —> inhalation / oral medical treatment for chronic lung disease, non-invasive ventilation
5. Spinal deformity, joint dislocation, weak bones (∵ abnormal truncal, limb tone) —> orthosis, orthopaedic surgery
6. Seizures + Intellectual disability —> anticonvulsants
7. Sleep disorder
8. Mental health issues —> early diagnosis + management

Question 19

Protective reflex + Primitive reflex

Answer 19

Protective reflex:
Should be present in ALL children >12 months —> delayed / absent in CP
1. Sideward parachute reflex
2. Forward parachute reflex
3. Backward parachute reflex

Primitive reflex (age of disappearance):
1. Moro reflex (supine) (6m) (達落地伸直雙手)
2. Asymmetrical Tonic Neck reflex (ATNR) (supine) (***Fencing posture) (3m)
3. Galant reflex (prone) (4m) (掃腰兩邊)
4. Palmer grip (supine) (6m)
5. Plantar grip (supine) (15m)
6. Barbinski (supine) (12m)

Question 20

Investigations of CP

Answer 20

1. CT
   - **congenital malformation
   - intracranial bleeding
   - periventricular leukomalacia
   - **hydrocephalus
2. MRI
   - congenital brain malformation
   - **grey / white matter disease
   - **cortical dysplasia
3. X-ray
   - **hip surveillance: 1st X-ray hip: 2-3 yo —> subsequent frequency guided by clinical findings
   - **spine: for scoliosis
   - chest: if suspect chronic lung disease

Question 21

Developmental / Motor regression

Answer 21

Need to consider other DDx (CP-like condition with developmental / motor regression) than CP:
1. ***Inborn error of metabolism (Neurometabolic disorder)
- urea cycle disorder
- glutaric academia type 1
- mitochondrial disease

2. ***Neurodegenerative disorder
   - Pelizaeus-Merzbacher disease
   - adrenoleukodystrophy
   - metachromatic leukodystrophy
   - Rett sydnrome
   - hereditary progressive spastic paraplegia
3. ***Brain / Spinal cord tumour
   - basal ganglia germinoma

If motor impairment / abnormal tone accompanied by unusual symptoms:
- unexplained hypoglycaemia
- recurrent emesis
- progressively worsening seizure
- family history of unexplained neurological symptoms / infant deaths
—> consider possibility of underlying ***metabolic disorder

Question 22

Floppy infant

Answer 22

Generalised hypotonia:
- ↓ resistance to passive movement
- unusual posture (e.g. ***frog like posture)
- ↑ range of joint movement

Causes:
Central causes (some ~ to GDD / CP) (Non-paralytic (Felix Lai))
1. **Hypothyroidism
2. **Neonatal asphyxia
3. **Intracranial haemorrhage
4. **Infection (congenital e.g. TORCH, acquired, sepsis)
5. ***Cerebral malformation
6. Spinal cord lesions
7. Chromosomal disorders
8. Metabolic diseases
9. CT diseases
10. Drugs (e.g. BDZ)

Peripheral causes (LMN from anterior horn cells to distally) (Paralytic)
1. Anterior horn cell diseases
- Genetic: ***Spinal muscular atrophy (SMA) type 1, 2, 3 (Type 1 most severe, infant onset (Felix Lai))
- Acquired: Poliomyelitis

2. Peripheral neuropathies
   - Hereditary: **Charcot-Marie-Tooth disease
   - Acquired: **GBS, toxin, nutritional, metabolic cause
3. NMJ disorder
   - MG
   - ***Congenital myasthenic syndrome
   - Infant botulism (Vinson Cheng)
4. Muscle disease
   - **Congenital myopathies
   - **Muscular dystrophies (Myotonic dystrophy a type of Muscular dystrophy) (e.g. Duchenne muscular dystrophy (DMD))
   - Mitochondrial myopathies
   - ***Inflammatory myopathies

General causes:
1. Prematurity
2. Intercurrent illness

Diagnosis by exclusion:
- Benign hypotonia (after exclusion of central, peripheral, general causes)

Question 23

History taking of Floppy infant

Answer 23

1. How / When hypotonia first noticed
2. ***New onset? Acute (infective, trauma causes) / Subacute / Chronic (genetic, metabolic causes)
3. ***Progression of hypotonia?
4. Body part involved: Truncal / Limbs
5. Developmental history
6. Antenatal history (poor fetal movement, breech, maternal drug use)
7. Birth history (trauma, birth asphyxia, poor APGAR score)
8. Family history (weakness, parents consanguinity, previous early death / recurrent miscarriage)
9. Systemic review (feeding difficulties, respiratory problem, seizures)

(***APGAR: Appearance (Cyanosis), Pulse, Grimace (Reflex irritability), Activity (Tone), Respiration)

Question 24

P/E of Floppy infant

Answer 24

Shake hands with parents (possible involvement in ***Myotonic dystrophy (e.g. myotonic hand grip —> cannot relax))

Inspection:
1. ***Dysmorphic features, Head size + shape
- Down’s, Prader-Willi, Mucopolysaccharidosis
- measure OFC

2. Facial features
   - Alert face with tongue fasciculation in SMA
   - Obtunded tongue in evolving CP
   - Ptosis, Ophthalmoplegia (congenital myopathy)
3. Need for **NG tube, **O2 supplementation, ***Ventilation support
4. Posture, Hypotonia
   - Frog-like posture: hip externally rotated, flexed knee
5. Respiratory
   - Paradoxical breathing, ***bell shape chest in SMA
6. ***Paucity of limb movement
   - minimal, subgravity, antigravity, against resistance

180 degree maneuver (Supine —> observe posture + antigravity movement)
1. Pull to sit (head lag)
2. Sitting (head / trunk control, able to sit unsupported as expected age)
3. Vertical suspension, attempt weight bearing (slipping through hand, lower limb scissoring)
4. Ventral suspension (***inverted U shape)
5. Prone

Neurological examination to localise lesions
1. UMN / Central: less weak, normal / hyperreflexia +/- upgoing babinski +/- persistent primitive reflexes

2. LMN: very weak, hyporeflexia / areflexia, downgoing plantars
3. **Recognised typical patterns
   - SMA: **proximal muscle weakness + ↓ reflex + **tongue fasciculation + **alert face
   - Congenital muscular dystrophy / myopathy, Myotonic dystrophy: **facial weakness + ptosis + **proximal muscle weakness + ↓ reflex
   - Peripheral neuropathy: **distal muscle weakness + ↓ reflex
   - Generalised MG: facial weakness + **variable ptosis + ***ophthalmoplegia + weakness
4. Look for presence of hepatosplenomegaly / cardiac failure (may suggest metabolic cases e.g. Pompe disease: a form of glycogen storage disease, Zellweger’s)

Question 25

Recognised typical patterns

Answer 25

1. SMA
   - **Proximal muscle weakness
   - ↓ Reflex
   - **Tongue fasciculation
   - ***Alert face
2. Congenital muscular dystrophy / myopathy, Myotonic dystrophy
   - **Facial weakness
   - Ptosis
   - **Proximal muscle weakness
   - ↓ Reflex
3. Peripheral neuropathy
   - ***Distal muscle weakness
   - ↓ Reflex
4. Generalised MG
   - Facial weakness
   - **Variable ptosis
   - **Ophthalmoplegia
   - Weakness

Question 26

Investigations of Floppy infant

Answer 26

Central causes:
1. **TFT
2. **CT / MRI
3. **Karyotype + genetic review (e.g. Dysmorphism)
4. **TORCH screen
5. Infective screen
6. ***Metabolic screen (if metabolic cause suspected)
- newborn screening
- serum a.a.
- lactate
- NH3
- urine organic acid

Peripheral causes:
1. CK level
2. **Nerve conduction study
3. **Electromyography
4. **Muscle biopsy
5. **Genetic study
- **SMN1 (SMA)
- **CTG repeats (Myotonic dystrophy)
- Neuromuscular disorder gene panel

Progress:
- Serial neurological examination
- Monitor progress of child’s weakness
- Watch for respiratory / feeding difficulties

Question 27

Important points to rmb

Answer 27

1. Ensure patient is stable
   - may require emergent ***airway management (if floppy infant with intercurrent illness)
2. Narrow down DDx by determining if hypotonia is **central vs **peripheral cause
3. Observe for presence of **antigravity movement
   - floppy but strong —> more likely **central cause
4. Check OFC
   - abnormal head size / shape —> ***central cause
5. Detailed family history important

Question 28

Spinal muscular atrophy (Vinson Cheng)

Answer 28

Etiology:
- Autosomal recessive
- Genetic mutation in *Chromosome 5q13
—> A telomeric copy SMN1
—> A centromeric copy SMN2 (SMN2 gene is a disease phenotype modifier, more number of SMN2 genes —> more SMN protein produced to compensate for loss of SMN1 gene —> less severe the disease is (SpC Paed))

4 types (some say 5)
(1. SMA0 (Prenatal onset, respiratory support at birth (Felix Lai))
2. SMA1 (Infantile, Werdnig-Hoffman disease, onset <6 months) (唔識坐 (Felix Lai))
3. SMA2 (Intermediate, Dubowitz disease, onset 6-18 months) (most in examination) (識坐唔識行)
4. SMA3 (Juvenile, Kugelberg-Welander disease, onset >18 months) (識行但成日跌)
5. SMA4 (Adult onset)

Investigations (Felix Lai):
1. CK level (should be normal, DMD / BMD: abnormal)
2. Molecular genetic testing (homozygous deletions of exon 7 of SMN1 gene located on chromosome 5)
3. Muscle biopsy +/- Sural nerve biopsy

Management:
1. Breathing
- Ventilation
- PT
- Sputum clearance

2. Nutrition (e.g. ***gastrostomy)
3. Orthopedics
   - PT
   - OT
   - Orthotic device
   - Electric wheelchair
   - Assistive technologies
4. Drugs
   - Nusinersen (new drug: antisense nucleotide that modifies the alternative splicing of the SMN2 gene —> more SMN protein produced)
   - Gene therapy (Onasemnogene abeparvovec (Zolgensma))

Question 29

Duchenne muscular dystrophy (SpC Revision)

Answer 29

• ***X-linked recessive
• ***DMD gene mutation —> Loss of Dystrophin protein

Clinical features:
- **Proximal muscle weakness (Gowers’ sign)
- **Waddling gait (weakness in gluteus medius, swaying of hip (SpC Paed))
- **Marked lordosis
- **Weakness of pelvic girdle muscle
- **Pseudohypertrophy
- **Elevated CK level

Treatment: ***Oral Steroid

Natural history:
- **Unaffected at 2-3 yo (Honeymoon period)
—> Start to have **motor clumsiness at 8 yo (e.g. Waddling gait)
—> ***Loss of ambulation at 8-12 yo

From MSS30:
- 1 in 3500 in live male birth

Stages:
- At birth: no physical indication
- 1st year: rare for any delay in development to be noticed
- 18 months - 4 years: become evident
- 8/9 years: weakness progresses rapidly
- 12 years: lose ability to walk independently
- 15-25 years: death

Progressive symptoms:
Shoulder, pelvic areas
–> shortening of muscles and loss of muscle tissue
–> upper trunk and arm muscles

**Becker Type Muscular Dystrophy (BMD):
- less severe form of DMD
- onset > 7 yo
- **muscle hypertrophy esp. Calves
- slowly progressive
- failure to walk 16 - 80 yo

Outlier:
- intermediate between DMD and BMD (severity, onset etc.)
- failure to walk 12-16 yo