Genetic Disorders
Etiolgy of Mental Retardation
Syndromes with Mental Retardation
Mental Retardation
Mental retardation is a particular state of
functioning that begins in childhood and is
characterized by limitation in both
intelligence and adaptive skills (daily living,
communication, social).
Classification of MR
Severity
IQ Range
[Borderline]
70-90
Mild
50-70
Moderate
35-50
Severe
20-35
Profound
< 20
Specific Causes of Mental
Retardation
Causes of mental retardation classified by IQ level
Cause
IQ<50
IQ 50-70
Genetic
47
10
Down syndrome
33
5
Autosomal aneuploidy
2
1
Sex Chromosome aneuploidy
<1
1
FragileX
2
<1
Single gene disorders
6
2
Environmental
19
10
Prenatal
4
3
Perinatal
10
4
Postnatal
5
3
Unknown
34
80
The Diagnostic Process:
Clinical Evaluation

Clinical history, prenatal and birth
history
◦ birth measurements extremely important

Family pedigree
◦ 3-generation, learning problems, psychiatric disorders, autism,
mental retardation

Physical and neurological
examination
◦ assess minor anomalies, growth, development
Major categories of genetic
disorders include;
◦ Chromosomal -Aneuploidy, Deletions,
Duplications/Insertions
◦ Single Gene -Autosomal Dominant, Recessive, X-linked
-Nonmedelian inheritance ( Triplet repeat
disorders, Imprinting, Mitochondrial )
◦ Multifactorial – central nervous system abnormalities
Diagnostic Tests
Chromosome analysis
 Molecular analysis

Normal Female Karyotype
Normal Male Karyotype
Down Syndrome
Trisomy 21—Down Syndrome
Most common chromosomal
abnormality
Most common cause of
mental retardation
◦ 1:700
◦ Associated with maternal
age
1/625 at 33
1/30 at 45
Trisomy 21—Down Syndrome
Clinical Features
Typical facial features
Flat face, upslanting
palpebral fissures,
epicanthus,
Smian crease (%45) – sandal
gap (%50)
Atrioventricular septal defect
(Endocardial Cushion Defect)
most common !!!
VSD, PDA
Growth and Mental Retardation
Hypotonia
Trisomy 21—Down Syndrome
Hearing problems
Duodenal Atresia
Acute Lymphoblastic
Leukemia
Hypothyroidy
Diabetes
Immune Deficency
Early Alzheimer Dz
Trisomy 21—Down Syndrome
94% Trisomy 21 (regular type)
47,XX,+21
4% Robertsonian Translocation
(inherited form)
46,XX,rob(14;21),+21
1-2% Trisomy 21 Mosaicism
46,XX/47,XX,+21
Attention !!! Mosaic froms don’t mean mild MR. Mosaic trisomy 21
can be more severe than other forms.
Regular type
Robertsonian translocation (inherited
type)
Mosaic type
Trisomy 21—Down Syndrome
Down Syndrome can be diagnosed 95% at
clinical level.
 Karyotype analysis is important for
genetic counseling of recurrence risk.

Recurrence risks for regular type and
mosaic forms are lower than 1 %.
 Recurrence risk for Down syndrome due
to robertsonian translocation is much
higher. (10-15 %)

Edward’s Syndrome
Trisomy 18-Edward’s Syndrome





Incidende 3/1000
Head and Face
◦ Microcephaly, prominent occiput,
micrognathia, cleft lip and palate
Chest
◦ Congenital Heart Disease, Narrow
chest and Short Sternum, Small
and widely spaced nipples
Extremities
◦ Limited hip abduction, overlapping
fingers, rocker bottom feet.
General
◦ Severe developmental delay and
growth retardation.
◦ Only 5% live beyond 1 year.
Patau Syndrome
Trisomy 13-Patau Syndrome
Incidence 1/5000
 Head and Face

Scalp defects, microcephaly
◦ Microphthalmia,
◦ Cleft lip and palate (60-80%),
◦ Holoprosencephaly
◦

Chest
◦

Congenital Heart Disease 80% (VSD,
PDA, and ASD)
Abdomen
◦ Omphalocele

Extremites
◦ Overlapping fingers and toes,
polydactyly

General
◦ Severe developmental delay and mental
retardation, only 5% live longer than 6
months.
Prenatal Diagnosis

Screening tests for common aneuploidies ;
1- First trimester screening: Nuchal
translucency + biochemical parameters
(hCG+PAPP-A)
2- Second trimester screening (triple test )
Only biochemical parameters (hCG,AFP,E3)

If the risk above the cut-off value (>1/250) ,
we can offer invasive prenatal diagnosis such
as chorion villus biopsy or amniocenthsis or
cordocenthesis.
Chromosomal deletion
Chromosomal Deletions (and
microdeletions)
5p deletion Syndrome

Best known deletion
is at 5p-, Cri du Chat
◦ Characteristic cry, hypotonia,
microcephaly, round face,
hypertelorism, high and flat
nasal bridge, high arched
palate and mental retardation.
◦ Prognosis- 10% mortality in
first year of life then a
normal life span.

Other common deletions;
◦ 1p-,4p-, 5p-, 9p-, 11p-, 13p-, 18p-,
21q-
Chromosomal Microdeletion
Microdeletions are small chromosomal
deletions which can not be detected
by convetional karyotype analysis.
(only high resolution banding
procedures or FISH)
These deletions produce syndromes
that are usually clinically recognizible.
Williams Syndrome
Chromosome 7q11.23
• Round face with full checks,
• Thick lips
• strabismus,
• supravalvular aortic
stenosis,
• friendly personality,
• hyperactivity
• varying degrees of
mental retardation (IQ 4180)
Velocardiofacial-DiGeorge
SyndromeChromosome 22q11.2





conotruncal anomalies
(tertrology of fallot),
hypoplasia or agenesis of the
thymus and parathyroid gland
resulting in frequent infections
and hypocalcemia,
hypoplasia of the auricle and
external auditory canal,
cleft palate, short stature,
behavior problems.
Miller-Dieker Syndrome
Chromosome
17p13.3




Lissencephaly
Microcephaly
Severe mental
retardation and
developmental delay
Hypotonia
Prader-Willi Syndrome
Paternal deletion of Chromosome
15q11q13
◦
◦
◦
◦
◦
Mental retardation
Obesity
short stature
small hands and feet
Typical facial features
 Round face
 Almond shape eyes
 Small chin
Angelman Syndrome
Maternal deletion of
chromosome 15q11q13
◦ behaviour like excessive
laughter,
◦ apparent happiness with
tremulous movements
◦ gait ataxia (lack of
coordination of muscle
movement)
Genomic Imprinting
Two copies of most
genes are functionally
equivalent but in a
small number only one
the pair is
transcribed.
Therefore, the active
gene will be inherited
from a specific
parent and the other
copy is silenced by
methylation- this is
Genomic imprinting
Fragile X
Most common form of inherited MR
 1 in 1,200 males
 Single gene disorder but nonmendelian
inheritance
 Caused by increased CGG repeats of
FMR1 gene on X chromosome (triple
nucleotide repeat disorder)
 Premutation 50-200 repeats (not
affected)
>200 are affected individuals
50% of carrier females have
some developmental delay

Fragile X




Males affected more
severely
Males have moderate MR,
characteristic face;
◦ Elongated face
◦ Flattened Nasal Bridge
◦ Protruding Ears
large testicles, joint
mobility
Girls may have mild MR
Behavior in Fragile X







Hyperactivity, impulsivity
Social anxiety
Poor eye contact
Self-injury, usually hand-biting
in response to anxiety or
excitement
Delayed imitative and social
play
Stereotyped and repetitive
behaviors
1 in 3 with Fragile X syndrome
have autism
Rett syndrome



Neurodevelopmental disorder characterized by normal
early development followed by loss of purposeful use
of the hands, distinctive hand movements,
slowed brain and head growth, gait abnormalities,
seizures, and mental retardation.
Hypotonia is usually the first symptom.
As the syndrome progresses, the child loses
purposeful use of her hands and the ability to speak.
Other early symptoms may include problems crawling
or walking and diminished eye contact.
Rett syndrome




Caused by change in MECP2 gene on
X chromosome - insufficient amounts
or structurally abnormal forms of the
protein are formed – Mutation found
in about 80%
X-linked dominant
Affects females almost exclusively.
1% of children with autism have
MECP2 gene change.
Mitochondrial Inherited Diseases
Mitochondrial diseases are a clinically heterogeneous
group of disorders that can be caused by mutations
of nuclear or mitochondrial DNA (mtDNA). Often
present with prominent neurologic and myopathic
features.
MELAS- Myopathy, Encephalopathy, Lactic Acidosis,
and Stroke like episodes.
LHON - Subacute bilateral visual failure, Dystonia,
Cardiac pre-excitation syndromes
MERRF- Myoclonic epilepsy associated with ragged red
fibers.
Kearns-Sayre Syndrome- ophthalmoplegia, pigmentary
retinopathy, and cardiomyopathy.

Neurocutaneous Syndromes
Familial/ primitive ectoderm
 All AUTOSOMAL DOMINANT

◦
◦
◦
◦
◦
◦
◦
◦
Neurofibromatosis I/II
Tuberous Sclerosis
Sturge-Weber
Von Hippel-Lindau
Ataxia Telengiectesia
Linear Nevus Syndrome
Hypomelanosis of Ito
Incontinentia Pigmenti
Environmental factors
Infectious agents
 Radiation
 Chemical Agents
 Hormones
 Maternal Disease
 Nutritional Deficiencies
 Hypoxia

Infectious Agents
Rubella
◦ Malformations of the
eye
 Cataract (6th week)
 Microphthalmia
◦ Malformations of the
ear (9th week)
 Congenital deafness
 Due to destruction of
cochlea
◦ Malformations of the
heart (5th -10th week)
 Patent ductus arteriosis
 Atrial septal defects
 Ventricular septal defects
◦ May be responsible for
some brain abnormalities
 Mental retardation
◦ Intrauterine growth
retardation
◦ Myocardial damage
◦ Vascular abnormalites
◦ Incidence
 47%- during 1st four
weeks
 22% - 5th – 8th weeks
 13% - 9th – 16th week
Infectious Agents
Cytomegalovirus
◦ Malformations
 Microcephaly
◦ Cerebral calcifications
◦ Blindness
 Chorioretinitis
◦ Kernicterus (a form of jaundice)
◦ multiple petechiae of skin
◦ Hepatosplenomegaly
◦ Mother asymptomatic
Radiation

Teratogenic effect of ionizing
radiation well established
◦
◦
◦
◦
◦



Microcephaly
Skull defects
Spina bifida
Blindness cleft palate
Extremity defects
Direct effects on fetus or
indirect effects on germ cells
May effect succeeding
generations
Avoid X-raying pregnant
women
Drugs
Thalidomide
◦ Antinauseant &
sleeping pill
◦ Found to cause
amelia & meromelia
 Total or partial
absence of the
extremities
◦ Intestinal atresia
◦ Cardiac abnormalities
◦ Many women had
taken thalidomide
early in pregnancy (in
Germany in 1961)
Anticonvulsants
◦ Diphenylhydantoin
(phenytoin)
 Craniofacial defects
 Nail & digital hypoplasia
 Growth abnormalities
 Mental
retardarion
 The above pattern is know
as “fetal hydantoin
syndrome”
◦ Valproic acid
 Neural tube defects
 Heart defects
 Craniofacial & limb
anomalies
Alcohol
Relationship between
alcohol consumption &
congenital abnormalities
◦ Growth deficiency
Disproportional low weight to height
◦ Craniofacial abnormalities
 Short palpebral fissures
 Hypoplasia of the maxilla
◦ Limb deformities
◦ Cardiovascular defects
 Ventricular septal abnormalites
◦ Structural brain abnormalities
◦ Head circumference < 10%
(microcephaly)
◦ Mental retardation
Fetal Alcohol Syndrome
Cigarette Smoking

Has not been linked to major birth
defects
◦ Smoking does contribute to intrauterine growth retardation &
premature delivery
◦ Some evidence that is causes behavioral disturbances
Maternal Disease
Maternal Phenylketonuria (PKU)
◦ Enzyme phenylalanine hydroxylase is deficient 
phenylalanine (PA) concentrations
 Developmental delay and Mental retardation
 Microcephaly
 Congenital heart disease
 Facial dismorphism
◦ Risk can be  with low PA diet