Psychomotor development Mental retardation€¦ · • Psychomotor development • Mental retardation Viktor Farkas M.D. First Dept. of Pediatrics Semmelweis University, Budapest.

• Psychomotor development• Mental retardation

Viktor Farkas M.D. First Dept. of PediatricsSemmelweis University, Budapest

Brain development

4 weeks adult

Proliferation of Neural Stem CellsMigration of Neuronal Precursor Cells

Differentiation into Neurons

What makes us human?

The unfortunate 'rat people' of Pakistan could providethe answer:

Gul A et al. Neurogenetics 2006

Mutations in autosomal recessive primary microcephaly (MCP H)

Comparison of MRI and Post-mortem SectionComparison of MRI and Post-mortem Section

van der Knaap and Valk, 1995T2-weighted MRI myelin stained section

1. Bulbus oculi2. Cavum nasi3. N. opticus4. Sinus sphenoidalis5. M. rectus med.6. Lobus temporalis

7. Art. ophthalmica8. Sella turcica9. Pons10. Ventriculus quartus11. Vermis cerebelli12. Lobus occipitalis

Csillag A, Atlas of Medical Imaging,

Koenemann, Cologne, 1999

T1 súlyozott axialis MRI felvétel

Development of the cerebral cortex

Couillard-Despres S et al. (2001) Curr. Mol. Med. 1: 677-688

I

II

V

EVZ

PPCP

5w 6,5w 7,5w 16 w8,5w Adult

III

VI

IV

Ventricularzone

10-14w

Development of the Human Brain

Development of the Human Brain

Development of Human Brain

Development of Human BrainMyelinisation

Formation of the cerebral cortex

2. Migration of post-mitotic immature neurons from the ventricular

zone to the edge of the cerebral cortex

3. Development of a mature cortex through the formation of cortical

layers, synapse formation and apoptosis

Shortly after the closure of the rostral end of the neu ral tube:

1. Proliferation of neuronal precursor cells

and their differentiation into “immature”

neurons and glial cells

Disorders of cortical development

1. Disorders of proliferation and differentiation of theneuronal progenitorcells

2. Disorders of migration

3. Disorders of corticalorganisation (layering)

Migratory patterns of interneuronsand pyramidal neurons converge in the

dorsal cortex

Development of the cerebral cortex

Couillard-Despres S et al. (2001) Curr. Mol. Med. 1: 677-688

I

II

V

EVZ

PPCP

5w 6,5w 7,5w 16 w8,5w Adult

III

VI

IV

Ventricularzone

10-14w

Genes involved in neuronal migration

FLNA X-linked periventricular nodular heterotopia

ARFGEF2 a.-r. periventricular nodular heterotopia

LIS1 isolated lissencepahly (lissencephaly type I )

DCX X-linked isolated lissencephaly (lissencephaly type I )

ARX X-linked lissencepahly with abnormal genitalia (XLAG)

Reelin lissencephaly with cerebellar hypoplasia (LCHb)

VLDLR simplified gyration with cerebellar hypoplasia

POMT1 Walker-Warburg-Syndrome (lissencephaly type II )

POMT2 Walker-Warburg-Syndrome (lissencephaly type II )

POMGnT1 Muscle-Eye-Brain Disease (lissencephaly type II )

Fukutin Fukuyama Congenital Muscular Dystrophy (liss. type II )

FKRP congenital muscular dystrophy with cerebellar cysts

LARGE congenital muscular dystrophy with cortical malformation

GPR56 bilateral frontoparietal polymicrogyria

PN

H

DC

S

LIS

I

LIS

II

BF

PP

LCH

b

XLA

G

• subependymal / periventricular nodular heterotopia (PNH)

• lissencephaly type I (LIS I) / Double Cortex Syndrome (DCS)

• lissencephaly with abnormal genitalia (XLAG)

• lissencephaly with cerebellar hypoplasia (LCHb)

• lissencephaly type II (LIS II)

• bilateral frontoparietal polymicrogyria (BFPP)

Periventricular Nodular Heterotopia (PNH)

Cortex

Ependym

Cortex

EpendymHeterotopia

normal PNH

ARFGEF2 gene autosomal-recessive microcephaly

FLNA gene X-linked

• associated with epilepsy– up to 80%– freq. begin after age 20– mostly focal seizures

• cognitive impairment

• coagulopathy / vasculopathy(stroke / patent ductus art. Botalli)

• abortions


Mutations of Filamin A gene (FLNA), Xq28

[ X Xmut ]- cause in heterozygous females PNH

[ Xmut Y ]- are in hemizygous male fetuses lethal


Periventricular heterotopia: a disorder at the start of migration

• Subsets of neurons fail to migrate from theperiventricular region duringcorticogenesis

• PVNH due to mainly loss-of-function mutations in FLNAon Xq28

• FLNA is an actin-bindingprotein

Brain malformations

PN

H

DC

S

LIS

I

LIS

II

BF

PP

LCH

b

XLA

G

• subependymal / periventricular nodular heterotopia (PNH)

• lissencephaly type I (LIS I) / Double Cortex Syndrome (DCS)

• lissencephaly with abnormal genitalia (XLAG)

• lissencephaly with cerebellar hypoplasia (LCHb)

• lissencephaly type II (LIS II)

• bilateral frontoparietal polymicrogyria (BFPP)

Walker-Warburg-Syndrome

Muscle-Eye-Brain-Disease

Fukuyama congenital muscular dystrophy

- lissencephaly

- congenital muscular dystrophy

- malformations of the eyes

„Cobblestone“ lissencephaly (lissencephaly type II)

Fukuyama congenital muscular dystrophy

Fukutin gene

Silan et al.(2003), Ann Neurol

Aida et al.(1996), AJNR

pachygyriapolymicrogyriacerebellar hypoplasia

cerebellar cysts

eye abnormalities lessprominentlife expectancy 10-20 years


SialinsäureGalaktoseGlcNAcO-Mannose

Ross (2002), Nature


Ross (2002), Nature

O-glycosylation failure


Ross (2002), Nature


Autosomal recessive primary microcephaly

• Primary / true microcephaly is a subclass of microcephaly: - significant reductions in cerebral cortical size withoutdisplaying other gross abnormalities

• Affected individuals can have mild to moderate mental retardation and infrequently, epilepsy

Normal brain Patient with microcephaly

Autosomal recessive primarymicrocephaly (MCPH)

Chromosome Gene

MCPH1 Microcephaly + PVNH 8p22-pter Microcephalin

MCPH2 M icrocephaly 19q13.1-13.2 -

MCPH3 Microcephaly 9q34 CDK5RAP2

MCPH4 Microcephaly 15q15-q21 -

MCPH5 Microcephaly 1q31 ASPM

MCHP6 Microcephaly 13q12.2 CENPJ

Microcephaly + PVNH 20q11.21 ARFGEF2

Mutations in autosomal recessiveprimary microcephaly (MCPH)

• Linkage study in 33 unrelatedconsanguinous Pakistani families– Head circumference 4-9 SD below

population age- and sex-relatedmean

– Mild to moderate mental retardation

Tested 6 known MCPH lociLinkage: 18 families linked to MCPH5 (ASPM gene)

2 families linked to MCPH2 (chr. 19q)2 families to MCPH4 (chr. 15q)1 family to MCPH6 (CENPJ gene)

Mutations in ASPM found in 9 of 18 familiesMutations in regulatory regions or another gene ?

Gul A et al. Neurogenetics 2006

A corticalis malformációk diagnosztikája

anamnezis /családi anamnézisepilepsziamentális retardáció, .....spotán abortuszconsanguitás

koponya MRI: vékony szeletek inversion recovery sequenciák

Genetikai tanácsadáscytogenetika / moleculáris genetikai analízisprenatális analízis„polar body” analízis

Development of locomotion

• Mothers are usually (but not always) right

• Social, cultural and ethnic factors

• Normal variations in development


• A, ventral suspension• B, prone position• C, sitting• D. standing and walking• E. manipulation (evolution of graps)• F. sphincter control


• Moro reflex• Parachute reaction• ………

Moro reflex:

Ventral suspensionA, normal

B, pathological

Development oflocomotion

Ventral position: Abnormalnewborn

Abnormal newborn


Prone position


• Sitting

Sitting: normal newborn

Primitive Reflexes – Steppingnormal newborn

Primitive Reflexes - Stepping• Primitive Reflexes - Stepping

With the baby held in vertical suspension and his feet touching the mat, he does nothave the expected reciprocal flexion and extension of the legs. The stepping or

walking reflex is absent in this baby .


I:

Standing and walking


II:

Standing and walking


• Manipulation(evolutaion ofgrasp)

Head Circumference

• Another very important part of assessing braindevelopment is measuring the growth of the brain. Thisis accomplished by measuring the head circumference, which is an accurate reflection of brain size . The braingrows to 80% of its adult volume during the first 2 years of life so many neurological diseases that occurearly in life will impact the growth of the brain. A smallhead (microcephaly ) or a large head (macrocephaly orhydrocephalus ) can be key findings in explaining theneurological abnormalities of a child.

• It is essential to plot head circumference on a standardized head growth chart such as the Nellhauschart.

Head Circumference

SPECIAL PROGRAMSNeurodevelopment Assessment

• Attentional based disorders• Dyslexia and language related learning

difficulties• Study and organizational problems• Non-verbal learning disabilities• Emotional/Behavioral problems• Written Expression problems

Developmental Milestones

• The neurological examination of the pediatric patientmust be couched in the context of neurodevelopmentalmilestones. The normal neurological findings one wouldexpect for a newborn are certainly different than a 2, 6 or12-month-old infant. Obtaining developmentalmilestones is an important reflection of the maturation ofthe child’s nervous system and assessing developmentis an essential part of the pediatric neurologicalexamination. Delay in obtaining developmentalmilestones and abnormal patterns of development areimportant indicators of underlying neurological disease.

Diseases - Therapies• Speech Therapy• Occupational Therapy or Physical Therapy• Vision Therapy• Applied Behavioral Analysis Therapy• Neurodevelopment Therapy• Specific Educational Therapy• ADD/ADHD• The Ritalin-Free Child: Managing Hyperactivity & Attention Deficits Without Drugs by Diana Hunter (ISBN 0962833681

• Autism (also PDD)• Asperger Syndrome• Auditory Processing Dysfunction• Dysgraphia• Dyslexia• Mental Retardation• Sensory Processing Dysfunction• Speech Disorders• Vision Impaired

Cerebral Palsy

a persistent disorder of

- movement and

- posture

Risk factors for CP

• multifactorialpreterm birth

multiple gestation

intrauterine growth restriction

male sex

low Apgar scores

intrauterine infections

maternal thyroid abnormalities

prenatal strokes

birth asphyxia

maternal methyl mercury exposure

maternal iodine deficiency

Risk factors for CP

• prenatal factors result in 70-80% of cases of CP

• In most cases:the exact cause is unknown but is most likelymultifactorial

Clinical course of CP

CP generally is considered to be

static encephalopathy or

nonprogressive in nature !!!!

Practice Parameter: Diagnostic Assessment of

the Child with Cerebral Palsy (CP )Neurology 2004; 62:851-863

Prevalence• Worldwide incidence of CP is approximately 2 to 2.5 per

1000 live births.

• Each year about 10,000 babies born in the US develop CP.

• Data from the Northern Ireland Cerebral Palsy Registry revealed that ½ the children with CP were of low birth weight (i.e., less than 2500 grams

Practice Parameter: Diagnostic Assessment of

the Child with Cerebral Palsy (CP )Neurology 2004; 62:851-863

Economic Impact:A California study (1992) of the extra economic

costs associated with CP and 17 other congenital disorders (e.g., Down syndrome, spina bifida) showed that CP had the highest lifetime costs per new case, averaging $503,000 in 1992 dollars

Rate of Cerebral Palsy

• Rate of cerebral palsy per 1000 live births across

Europe by year and severity

Psychomotor development Mental retardation€¦ · • Psychomotor development • Mental retardation Viktor Farkas M.D. First Dept. of Pediatrics Semmelweis University, Budapest.

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