Download Global developmental delay and Intellectual Disability

Global developmental delay and
Intellectual Disability
Myriam Srour
Outline
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Definitions
Etiology
Pathways
Evaluation
Definitions
Global developmental delay?
• Significant delay in 2 or more developmental domains (gross/fine
motor; cognitive, language, personal/social, activities of daily living)
Intellectual disability?
3 criteria
(1) Limitation in intellectual functioning
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IQ 2SD below mean (i.e. 70)
(2) Limitation in 2 or more adaptive behaviours (communication, selfcare, social, community use, health and safety)
(3) Onset before age 18 years
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Mild: 50-70
Moderate: 35-49
Severe: 20-34
Profound: below 20
Epidemiology
• ID: 2% prevalence
• Mild: 1.5%
• 30-50% more common in males than females
• Syndromic vs non-syndromic
Etiology
• Prenatal
– Genetic: chromosomal, single gene
– Acquired: infectious (TORCH), toxins (ETOH, substance abuse), nutritional (PKU, iodine
deficiency), ischemic
• Perinatal
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Birth asphyxia
Infectious
Metabolic
Stroke
• Post-natal
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Toxic
Infectious
Trauma
Stroke
Toxic (lead)
Yield of testing
• Moderate to severe: conclusive genetic or
metabolic abnormalities detected in 50-60%
• Mild: conclusive genetic or metabolic
abnormalities detected in 20%
Genetic causes
• Macro to micro
– Chromosomal
– Single gene
Disorders you should know:
• Down’s
• Rett syndrome
• Angelman
• Prader-Willi
• William
• Fragile X
• Rubenstein-Taybi
• Sotos syndrome
• 22q11/DiGeorge
Inheritance patterns
• Dominant
• X-linked
• Recessive
• De novo
• Exome sequencing of trios
Pathway approach
• Recognized molecular and cellular mechanisms
underlying intellectual disability:
• Neurogenesis
– Microcephaly
– Defective centrosomal function and DNA repair
• Neuronal migration
• Synaptic functions
– Synapse formation
– Plasticity
– Cellular signaling
• Transcription and translation
Vesicle shuttling in the pre-synaptic space
Post-synaptic density (PSD)
• Disruption of excitatory glutamatergic and inhibitory
GABAergic neurons
• What are the 2 main types of glutamatergic receptors?
– NMDA
– AMPA
• Main pathways at the PSD
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Organization of PSD
Regulation of post-synaptic protein levels
Cytoskeletal dynamics
Cellular signaling cascades
Epigenetic regulation of transcription
Post-synaptic protein networks and pathways
involving ID proteins
AMPA
NMDA
SYNGAP de novo mutations
responsible for 3-5% of
isolated NSID
Regulation of Post-synaptic protein
levels
• FMRP (Fragile X)
– RNA-binding proteins that regulates local
translation of mRNAs, especially local synthesis of
synaptic proteins
• Ubiquitin-mediated protein turnover
– UBE3A (Angelman syndrome), UBE2A, HUWE1…
Cellular signaling cascades
• Ras-MAPK pathway
– Neuro-cardio-facio-cutaneous syndromes
– Noonan
– Costello
– NF
– LEOPARD
– CFC- cardio-facio-cutaneous
Clinical Features of Rasopathies
Cellular signaling cascades
• P13K-PTEN-mTOR pathway
Main features: tumors and overgrowth
– TS
– Cowden syndrome (PTEN)
Multiple Hamartomas
Multiple benign and malignant tumours
Mucocutaneous manifestations
Megalencephaly
– Proteus syndrome (AKT1)
Epigenetic regulation of transcription
– CREBBP
– MECP2
–…
Prospects for therapy
• mGLUR5 antagonists in Fragile X
– FMRP normally represses transcription of GLUR5
– Restoration of memory performance in fragile X
drosophila flies
– Experiments done in mice
– Clinical trials in humans
• Clinical trials for compounds that modulate
pathways (Ras, mTOR…)
– Improvement of cognition in TSC mice on rapamycin
Clinical evaluation
• History should include:
– Family history
– Consanguinity
– Perinatal history
– Maternal exposures
– Age at first concern
– Regression
– Detailed developmental history
– Co-existing medical problems (Seizures…)
Clinical Evaluation
• Exam:
– General exam- cardiac, HSM
– HC, height, weight
– Skin
– Dysmorphisms
– Neuro exam
Some clues…
• Café au Lait?
– NF, TS, AT
• Sensorineural deafness?
– Mitochondrial
• Fine hair:
– Menkes
– Arginosuccinic aciduria
– CFC
• Short stature
– Mucolipidoses,
Mucopolysacch
– Mitochondrial
– Prader-Willi
– Cockayne syndrome
• Hepatosplenomegaly?
– Gaucher, GM1,
Mucoplysacchaidoses, NPC
– Glycogen storage diseases
• Broad thumbs and toes
– Rubinstein-Taybi syndrome
• Abnormal fat pad
distribution
– CDG
– Cornelia de Lange syndrome
Evaluation
In cases where history and exam does not give
underlying etiology:
• First tier:
– Microarray testing
• Yield 10-20%
• Yield higher wit severe delay, dysmorphisms, multiple
congenital anomalies
– Followed by MRI if negative (MRS)
– Fragile X in mild-moderate ID (2% yield)
Second tier genetic testing
• MECP2 in girls with moderate to severe ID
(1.5% yield)
Second-tier genetic testing
Screening for inborn errors of
metabolism?
• Controversial- Most physicians/consortiums
feel they are not justifiable, unless something
suggestive on exam, or high risk
– Consanguinity, family history…
• Yield 0.4-4.6% depending on presence of
clinical indicators
• CDG- yield 1.4%
• Creatine synthesis and transport disordersyield 2.8%
Future
• Whole exome sequencing…