Intellectual Disability

**Intellectual Disability** = significantly sub-average intellectual functioning with related limitations in 2< adaptive skills

**Adaptive Skills** = communication; self-care; home living; social skills; leisure; community use; self-direction; health and safety; functional academics; work

 Mild
 Moderate
Dress, toilet, food prep independent
 Severe
Toilet independent; Dress with Help
 Profound
Might toilet independently; dress with help
Work very limited

Formal IQ testing not possible until 5 years of age

* Incidence = 1.14% of school age children, 1.8/1000 males, 30% more Males than Females
* Identified Cause = 50%

**Autism Spectrum Disorder/Pervasive Developmental Delay** = broad spectrum of disease which includes deficiencies in three areas

* Social Interaction
* Communication
* Restrictive, repetitive & stereotypic patterns of behavior, interests, or activities

### **Molecular Etiology of Intellectual Disability**

* 10-12% X-Linked Intellectual Disability
* 12% Down Syndrome
* 5% Chromosome Structure
* >2% Subtelomeric
* 15% Pathogenic CNVs
* 3% Fragile X
* 1.4% 16p13.11 deletion
* 1% Inborn Errors of Metabolism
* Also: AR, AD Disorders, Environmental Exposures
* Unknown

### **X-Linked Intellectual Disability**

* 153 syndromes, 90+ genes
* Syndromic vs. Nonsyndromic (1:2)
* Molecular Mechanisms
	1. Rho/Rab GTPase signaling pathways = involved in neuronal differentiation, synaptic plasticity
	2. Regulation of gene expression
	3. Other processes = cell adhesion, transcription regulation, posttranslational modification, signal transduction, ubiquination, actin cytoskeleton modification, sodium transport

### **Intellectual Disability Evaluation**

* **Benefits of Evaluation**
	+ identification of appropriate medical and nonmedical therapies
	+ identification of indicated medical intervention/referrals
	+ presymptomatic screening for associated complications/functional disabilities
	+ educational planning
	+ elimination of unnecessary testing and evaluations
	+ anticipatory guidance
	+ education and advocacy
	+ referral to appropriate medical/social services
	+ reproductive counseling, carrier testing, prenatal diagnosis
	+ family networking
* **Approach to Evaluation**
	+ Medical History
		- prenatal, birth history, birth stats
		- neonatal period, hospitalizations
		- developmental history = attainment of milestones, progression vs regression
		- growth history
		- review of systems
		- behavior patterns
	+ Family History
		- 3 Generation Pedigree
		- Sweep Questions = ID? Learning Disabilities? Psychiatric problems?
		- Family Resemblance
	+ Physical Exam
		- growth parameters
		- skin findings (with Woods lamp)
		- minor anomalies
		- measurements
		- facial features
		- What is the most unusual feature?
		- head size - congenital or progressive?
	+ Neurological Exam
		- weakness
		- muscle tone
		- extrapyramidal signs = hyperreflexia, gait, movements
		- cerebellar signs = ataxia
		- behavior
		- Acute Neurological Changes
			* aminoacidopathies
			* organic acidurias
			* energy production disorders
			* lysosomal storage disorders
			* peroxisomal disorders
		- Loss of skills/Regression/Plateauing
			* All of the Above
			* Rett Syndrome
			* Lesch-Nyhan Syndrome
	+ Review of Medical Records, Photographs
	+ Testing
		- audiology (*always rule out hearing loss)*
		- ophthalmology
		- psychometric assessment
		- X-rays
		- Neuroimaging
			* High frequency of brain abnormalities with ID
			* CT best for craniosynostosis, intracranial calcifications
			* Useful for: macrocephaly, microcephaly, seizures, loss of psychomotor skills, spasticity
		- Metabolic Testing Indications
			* FTT
			* Recurrent illness
			* Seizures
			* Ataxia
			* Hypotonia
			* Coarse Features
			* Eye abnormalities
			* Recurrent coma/lethargy
			* Metabolic Acidosis
			* Abnormal Sexual Differentiation
			* Hepatosplenomegaly
			* Hyperuricemia
			* Hyperammonemia
			* Low cholesterol
			* Structural hair abnormalities
			* Unexplained deafness
			* Bone abnormalities
				+ dysostosis, occipital horns, punctate calcifications
			* Skin abnormalities
				+ angiokeratoma, ichthyosis
	+ Test of Time = Diagnoses Increase 5-20% with return visits; phenotypic evolution

## Syndromes/Conditions Associated With Intellectual Disability

* Trisomy 21 = Avg IQ ~50
* Trisomy 18 = Severe
* Trisomy 13
* 47, XXX = Mild, IQ ~85-90
* Mosaic Trisomy 8 (Warkany Syndrome) = IQ ~40-75, to normal
* Mosaic Trisomy 9 = Severe
* Tetrasomy 12p = Profound
* Ring X Syndrome
* Cat-Eye Syndrome = Borderline
* Deletion 4p- (Wolf Hirschhorn Syndrome) = Severe
* Deletion 5p- (Cri-du-Chat Syndrome) = Moderate - Severe
* WAGR
* Williams Syndrome = Mild - Moderate; exceptional verbal ability
* Miller-Dieker Syndrome = Profound
* Cornelia de Lange Syndrome = IQ <30-100, average 53
* Angelman Syndrome
* Coffin-Lowry Syndrome
* ARX Gene & Associated Syndromes
* Fragile X
* Bardet-Biedel
* Hypomelanosis of Ito
* Smith-Magenis Syndrome
* Rett Syndrome
* Lesch-Nyhan Syndrome
* Homocystinuria
* Tuberous Sclerosis
* Smith-Lemli-Opitz
* Kabuki Syndrome
* Menke's Disease