Bio 37 Lecture 11

Neurodevelopmental disorders 1-
Down Syndrome or trisomy 21

Learning objectives:

• To define neurodevelopmental disorders, mental retardation, intellectual

disability and their general characteristics

• To understand the genetic defects that cause Down syndrome (trisomy 21)
and the main characteristic of the syndrome and current treatment
modalities available

• To acquire general knowledge about different aspects of research being

conducted in DS

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 Neurodevelopmental disorders

appear during childhood and represent some alteration in development

developmental intellectual disability (DID) affects approximately 1% of

the population.

4 main conditions:

•Mental Retardation (MR)

•Dyslexia (reading difficulties)

•Autistic Spectrum Disorders (ASD)

•Attention-Deficit Hyperactivity Disorder (ADHD)

MR

• failure to acquire intellectual abilities across cognitive domains at a normal rate

• difficulties in adaptive functioning (e.g. self care)

• not associated with specific lesions but rather affect several brain systems

There are many causes of MR:

genetic disorders, infections, toxins, oxygen deprivation, etc

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 Mental Retardation is divided into 4 categories Based on Severity

Many genetic disorders cause mental retardation
Genetic causes include :
‐chromosomal abnormalities such as Down syndrome (DS), 
‐copy number variations (CNVs) involving a few to tens of genes, and 
‐single gene mutations identified in >300 genes. 

We will study 2 of these conditions:

Down syndrome and fragile X syndrome

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 Down syndrome is the most common cause of intellectual disability in humans

In 1958, Gautier and Lejeune

discovered the chromosomal
abnormality that causes Down
syndrome

First described by
Langdon Down in 1866

Down syndrome (trisomy 21)

Karyotype: a profile of
a person’s
chromosomes

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 How is Down syndrome diagnosed?

Amniocentesis – Prenatal screening

Amniocentesis is a procedure in which amniotic

fluid is removed from the uterus for testing or
treatment. Amniotic fluid is the fluid that surrounds
and protects a baby during pregnancy. This fluid
contains fetal cells and various proteins.

Three different chromosomal abnormalities can

cause Down syndrome

Trisomy 21: error in cell division called “non-disjunction,”

results in an embryo with three copies of chromosomes
instead of two.

Translocation: the total number of chromosomes in the

cells remains 46; however, an additional full or partial
copy of chromosome 21 attaches to another
chromosome, usually chromosome 14.

Mosaicism: the individual has a mixture of two types of

cells, some containing the usual 46 chromosomes and
some containing 47.

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 Chromosomal Translocation in a DS karyotype:

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Mosaicism- condition in which different cells within the

same person have a different genetic makeup

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 Down syndrome (DS) or trisomy 21

• Most common autosomal aneuploidy that

survives birth
• ~ 1 in 800 live births.
• > 300,000 subjects with DS in the USA.

DS is characterized by:

• flattened facial features

• congenital heart and gastrointestinal defects
• high incidence of leukemia
• increased incidence of seizures
• increased susceptibility to infections
• immune and endocrine deficiencies
• hypotonia
• higher incidence of diabetes

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Neuroanatomical abnormalities in DS brain:

Macroscopic
•decreased brain weight
•diminished gyral size
•simplified convolutional pattern

Microscopic
•decreased neuronal number/density
•synaptic degeneration
•alterations in dendritic spine structure
•Alzheimer’s neuropathology in adults with DS

Cognitive
•Pronounced deficits in language and verbal memory
•Preserved visuospatial and social abilities
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 Current therapies for people with Down syndrome

-Special Ed
-Speech therapy
-Physical therapy
-Occupational therapy
-Treatments for other medical symptoms
(anti-seizure, hormone replacement
therapy, treatment for sleep apnea, surgery
to correct congenital defects, etc)

“An increasing number of adults with Down syndrome in the U.S. are living independently
with limited assistance from family members or the state. A small percentage are able to
live entirely independently”

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DS mouse models replicate several features of DS including impaired learning

and memory, alterations in brain structure, synaptic alterations, etc

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 Dendritic spine alterations in Down syndrome brain and in DS mouse model
consistent changes in dendrite and
spine structure in cortex and
hippocampus:
1. long, tortuous, thin spines
2. short spines
3. very large spines
•4. decreased numbers of
spines (15% decrease; larger
decrease in DS/AD patients).

E N P DS

E:embryonic,N:newborn; P:postnatal, DS:postnatal DS

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www.mind.uci.edu Universidad de California-Irvine

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 Mitochondria provide energy for cellular work in the form of ATP

Mitochondrial function is
impaired in DS and
affects neuronal function

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Neurons require a lot of energy in the form of ATP for proper

axonal transport and synaptic function.

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 Trisomy 13: Patau syndrome Trisomy 18: Edwards syndrome

• 1 in 5,000
• 1 in 16,000
• Full trisomy, translocation or mosaicism
• Full trisomy, translocation or mosaicism
• Severe developmental abnormalities
• Severe developmental abnormalities
• 5-10% survival after 1st year of life
• 5-10% survival after 1st year of life
• Intellectual disability
• Intellectual disability

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