SINGLE GENE DISORDERS

Asist. Univ. Dr. Radu URSU

GENETIC DISORDERS
HUMAN DISEASE CLASSIFICATION:
1. Non-genetic disorderds (echological)
produced exclusively by factors in the
environment
2. Genetic disorders caused exclusively
by genetic factors
3. Multifactorial disorders caused by the
combined action of ecologic and
genetic factors

SINGLE GENE
Huntington Disease (HD)
DISORDERS
Huntington's disease (HD) is an autosomal dominant disease
Incidence >1 in 10,000.
Huntington's disease is caused by a genetic defect on
chromosome 4. The defect causes a CAG triplet repeat to occur
many more times than it is supposed to. (normally, the CAG
triplet is repeated 10 to 28 times, but in HD patients - 36 to 120
times)
As the gene is passed down through families, the number of
repeats tend to get larger. The larger the number of repeats, the
greater your chance of developing symptoms at an earlier age.
Therefore, as the disease is passed along in families, symptoms
develop at younger and younger ages.
There are two forms of Huntington's disease.
The most common is adult-onset Huntington's disease.
Persons with this form usually develop symptoms in their mid
30s and 40s.

Huntington Disease (HD)

Physical features/signs
- involuntary movements
- weight loss
- abnormal gait
- speech & swallowing difficulties.
- Abnormal reflexes
Psychiatric Manifestations:
- personality/behavior changes
- Depression
- Aggression
- early onset dementia.
Complications
Loss of ability to care for self
Loss of ability to interact
Injury to self or others
Increased risk of infection
Depression
Death

Structure of the Huntington disease gene

Short vertical bars represent exons.

Fig. 3.7 Scion Publishing Ltd

Huntington disease
a triplet repeat disease

AG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG ... CAG
11-34 CAG triplet repeats are normal:
encodes a run of 11-34 glutamine
amino acid residues in the protein.

A run of > 34 glutamine residues

causes the protein to aggregate in
the brain cells and
cause progressive cell death.

Runs of >34 CAG repeats in the HD gene expand further (particularly during male meiosis)
causing earlier age of onset in children of men who have the gene anticipation.

1 ttg
ggg
61 gca
tgc
121 cgc
gga
181 cgg
tgc
241 att
cgg
301 ggg
aag
361 tcc
cag
421 cag
ccg

ctg
gcg
gag
tgg
ggc
cgc
gtc
ttt
gcc
ccc
cgg
ctg
ttc
cag
cag
ccg

tgt
ggc
tcc
ccg
ccc
aag
caa
tac
ccg
gag
gag
atg
cag
cag
cag
ccg

gag
tgg
gca
gcg
gcc
gcg
gat
ctg
gtg
gcc
acc
aag
cag
cag
caa
ccg

gca
ttc
ggc
tgg
tcc
ccg
gga
cgg
ctg
tcc
gcc
gcc
cag
cag
cag
cct

gaa
cct
tag
ccc
gcc
tgg
cgg
ccc
agc
ggg
atg
ttc
cag
cag
ccg
cct

cct
ggc
ggc
cgc
ggc
ggg
ccg
aga
ggc
gac
gcg
gag
cag
cag
cca
cag

gcg
cag
tgt
ctc
gca
ctg
ctc
gcc
gcc
tgc
acc
tcc
cag
cag
ccg
ctt

ggg
cca
caa
cgc
cgt
ccg
agg
cca
gcg
cgt
ctg
ctc
cag
cag
ccg
cct

gca
ttg
tca
cgg
ctg
gga
ttc
ttc
agt
gcc
gaa
aag
cag
cag
ccg
cag

21 CAG repeats in a normal/usual Huntington disease gene

Huntington disease
A patient in the advanced stages of the disease showing involuntary movements of the head
and face. Photos courtesy of Professor Peter Harper, Cardiff.
(b) Post mortem sections comparing normal brain (left) with brain from Huntington disease
patient (right); note the loss of tissue in the Huntington disease brain. Photos courtesy of Dr
David Crauford, St Marys Hospital, Manchester.

Fig. 1.1 Scion Publishing

Photos courtesy of (a) Prof. Peter Harper and (b) Dr David Crauf

Familial
Hypercholesterolemia
Autosomal dominant disorder
High levels of low density lipoprotein cholesterol
(LDL)
Early coronary artery disease (CAD)
Heterozygous ~1 in 500
Homozygous ~1/1,000,000
Greater risk of heart disease (100x for males 20-40 yrs)

Familial
Hypercholesterolemia
Physical symptoms
Xanthomas fatty skin
deposits
Xanthelasmas Cholesterol deposits in
the eyelids
Angina chest pain

Familial
Hypercholesterolemia
Heterozygous Familial
Hypercholesterolemia (HeFH)
Monogenic disorder
Heterozygous mutations in the LDLR
gene
Cholesterol deposits in the corneas,
eyelids and extensor tendons
Elevated plasma concentrations of LDL

Genetics of FH

Mutations in 3 genes
Low-density lipoproteins receptors gene (LDLR)
Apoliprotein B-100 gene (APOB)- involved in LDLR binding
Proprotein convertase subtilisin/kexin type (PCSK9)
cholesterol homeostasis

Genetics of FH

93% of all mutations occur in the LDLR

Coding region of 5kb, 18 exons
Over 1000 mutations reported
5% mutations may be due to large deletions or duplications

FH Inheritence (Autosomal Dominant)

Familial
Hypercholesterolemia
Early identification
Reduction in morbidity through changes in the
lifestyle
Diet and exercise
No smoking

Use of statins to lower cholesterol

Life expectancy now is equal to the general
population
(85%) of affected individuals remain undiagnosed

Marfans Syndrome

Marfan
syndrome
is
a
genetic
disorder arising from mutations in the
fbn1 GENE on chromosome 15 that
affect the structure of connective tissues
throughout the body.
The fbn1 gene encodes for fibrillin 1, a
protein
molecule
essential
for
the
formation of elastin. Elastin is the basis of
the fibers that form the connective tissues.
In Marfan syndrome the elastin is too soft,
allowing connective tissues to stretch more
than normal.
Fibrillin formation of extracellular matrix
Main protein of CT Microfibils including
elastic fibers
Abundant in the aorta, ligaments,
cilliary body of the eye
MFS: mutation in the fibrillin-1 gene (FBN1)
Chromosome 15
The inheritence pattern for Marfan
syndrome is autosomal dominant.

Epidemiology
Incidence

at least 1 in 5,000 in the US

Inheritance

Autosomal Dominant, Variable Penetrance

Gender

men, women, children

Risk

Child of parent with MFS: 50% chance

Prenatal testing available but given unpredictable phenotype not widely
used

Two unaffected parents: 1 in 10,000

~ 25% from a spontaneous mutation

Diagnostic Criteria

Major criteria: highly specific & rarely occur in the general

population

aortic root enlargement (aortic aneurysm)

aortic dissection
lens dislocation
dural ectasia
at least 4 major skeletal features
Chest wall deformities
Long, thin arms/legs
Scoliosis greater than 20 degrees

Minor criteria: features with Marfans but may also occur in

the general population

Diagnosis requires:

+ FamHx: only 1 Major criteria

FamHx: at least 2 Major criteria

Diagnostic Criteria

Organ Systems Affected

Skeletal
Oral Cavity
Eyes
Cardiovascular
CNS
Skin
Pulmonary

Skeletal
Tall, slender stature
Joint hypermobility
Thumb sign
Wrist sign

Reduced elbow extension

<170 degrees

Affects long bones

arms/legs/fingers/toes may be disproportionately long

Arm span > Height

ratio >1.05

Long, narrow face

Sternal deformity

Pectus escavatum (funnel chest)

Pectus carinatum (pigeons chest)

Scoliosis
Pes plantus (flat feet)

Eyes
Lens dislocation
Superior lens disolocation (ectopia lentis)

Lens position changes

slightly higher/lower and may be shifted to one side

Retinal detachment
Myopia
Early glaucoma or Cataracts

Oral Cavity
Arched palate

crowded dentition

Mandible malocclusion

Cardiovascular System
Heart
Mitral Valve Prolapse
60-80% of pts
SOB, fatigue, palpitations

Vascular
Ao dilation
Ao dissection/rupture
Type I or Type A

Types of Aortic
Dissection

CNS
Dura surrounds brain/spinal cord
made of connective tissue

Dural Ectasia with age the dura

weakens/stretches
progressive ectasia of dura/neural
foramina and erosion of verterbrae
enlargement of the spinal canal
Radiculopathy
CT, plain films, MRI

Skin
Stretch marks
appear at sites subject to stress
shoulders, hips, lower back

Increased risk of an abdominal or

inguinal hernia

Pulmonary
Marfan fibrillin1 deficiency: affects lung
development & homeostasis

Restrictive lung disease

pectus abnormalities and/or scoliosis

~ 70% of people with MFS

Spontaneous pneumothorax
Early emphysema
Sleep-related breathing disorders
snoring and sleep apnea

Follow-up

Annual Echo

monitor the size and function of heart and aorta

Periodic follow up with ophthamology

Monitoring of the skeletal system

chest and back x-rays

BB to lower BP and regulate heart rhythm

reduced strain on the aorta and slowing the widening of the

aorta

Physical exercise

stay fit to improve muscle tone

avoid strenuous exercises and activities, avoid contact sports or
generally exhausting sports, to prevent injury to the Aorta

Treatment
Beta Blockers
TGF
Aortic Surgery

Duchenne Muscular Dystrophy

(DMD)
Clinical Features:
Progressive muscle weakness.
Mainly in a wheelchair by early teens.
Respiratory muscles eventually involved.
Death usually in late teens, early twenties.
Inheritance:
X linked recessive condition, hence males affected
and females are carriers (see pedigree on next slide).

Symptoms of DMD
Delayed developmental milestones
Loss of motor skills
Characteristic gait
Calf hypertrophy
Clumsiness/frequent falls

More Symptoms of DMD

Muscle weakness
Difficulty climbing stairs or hills
Difficulty rising (Gowers sign)
Difficulty walking/running

Duchenne Muscular
Dystrophy Inheritance
Mother carries the recessive gene
and passes it to her child
Trait is usually expressed in males
only

DMD Pedigree

The X chromosome carrying the disease-causing mutation can be tracked through the family.
Note: Shaded squares = affected males: dots in circles = carrier females.

Prevalence of DMD
Affects one in
3500 to 5000
newborn males
1/3 of these with
previous family
history
2/3 sporadic

Duchenne muscular dystrophy

(a) Affected boys stand up by bracing their arms against their legs (Gowers manoeuvre)
because their proximal muscles are weak.
(b) and (c) Muscle histology (Gomori trichrome stain). Normal muscle (b) shows a regular
architecture of cells with dystrophin (brown stain) on all the outer membranes. (c) Shows
muscle from a 10-year-old affected boy. Note the disorganisation, invasion by fibrous tissue
and complete absence of dystrophin.
Histology photos courtesy of Dr Richard Charlton, Newcastle upon Tyne.

Fig. 1.4 Scion Publishing L

Histology photos courtesy of Dr Richard Charlto

A muscle biopsy from a female carrier of Duchenne muscular

dystrophy stained with an antibody against dystrophin
Note the patchy distribution of staining around the outer membranes of cells (compare with
the sections from an affected boy and a normal control in next slide).

Fig. 7.11 Scion Publishing Ltd

Photo. courtesy of Dr Richard Charlton

Immunolabeling of Muscle
Biopsy Sections

Dystrophin
antibody
staining of
muscle cells

Normal Control

4 year old boy with DMD No

detectable dystrophin

A deletion of part of the dystrophin gene

This figure shows a 500 kb region containing exons 41-50. These exons are all 100-200 bp
long, and so if drawn to scale each exon would be represented by a line occupying less than
0.05% of the width of the figure. Random deletion breakpoints therefore almost always fall in
introns. Their effect is to remove one or more complete exons from the mature mRNA. The
deletion shown removes exons 45-47 from the mature mRNA, while leaving all the other
exons intact.

Fig. 3.9 Scion Publishing Ltd

Where is This Gene?

X CHROMOSOME

The dystrophin molecule

anchors the cytoskeleton
of muscle cells to the
extracellular matrix, via
the dystrophin
glycoprotein complex.
This includes the
sarcoglycans (mutations in
which cause limb-girdle
muscular dystrophies) and
dystroglycans.
Muscle cells that lack
dystrophin are mechanically
fragile, and fail after a few
years, hence progressive
muscle weakness.

Fig. 6.4 Scion Publishing

Ltd

Treatments for DMD

To improve breathing:
O2 therapy
Ventilator
Scoliosis surgery
Tracheotomy

Treatments
To improve mobility:
Physical therapy

Surgery on tight joints

Prednisone
Non-steroidal medications
Wheelchair

IN RESEARCH GENE THERAPY

Cystic fibrosis
Cystic fibrosis is an inherited disease that causes thick, sticky
mucus to build up in the lungs and digestive tract. It is the most
common type of chronic lung disease in children and young
adults, and may result in early death.

Cystic fibrosis
The most common lethal inherited disease affecting
Caucasians (not uncommon in Asians)
Autosomal recessive
Incidence 1:2500 Caucasian populations
Carrier frequency 4%
Single gene disease (CFTR 7q)
Gene discovered 1989

Cystic fibrosis

Clinical Features
Cystic fibrosis is a heterogeneous
recessive
genetic
disorder
with
features that reflect mutations in the
cystic
fibrosis
transmembrane
conductance regulator (CFTR) gene.
Classic cystic fibrosis is characterized
by chronic bacterial infection of the
airways and sinuses, fat maldigestion
due
to
pancreatic
exocrine
insufficiency, infertility in males due to
obstructive azoospermia, and elevated
concentrations of chloride in sweat.
Patients with nonclassic cystic fibrosis
have at least one copy of a mutant
gene that confers partial function of
the CFTR protein, and such patients
usually have no overt signs of

CF CLINICAL
FEATURES (LUNG)
Thick viscid secretion in
respiratory tract
Bacterial
colonization
Mucosal inflammation
Mucosal hypertrophy
Recurrent LRTI
Bronchiectasis

CF CLINICAL FEATURES
(PANCREAS)
Thick viscid secretions in
Pancreas

Pancreatic insufficiency
Meconium ileus
Meconium peritonitis
Steatorrhea
Failure to thrive

CF Clinical Features
Increased chloride content
in sweat
Salty taste on kissing
Increased salt wasting
Dehydration in hot weather
Salt craving

Salties and Wrinklies

Beware the salty child for they will
surely die (German folklore)

Beware the wrinkly child as well.

Classical Clinical Features

ENT:

Chronic Sinusitis
Nasal Polyps

Lungs:

Cough and sputum

Airflow obstruction
Recurrent infection (Pseu, S. aureus)

GI:

Pancreatic insufficiency (malnutrition)

Pancreatitis (PS)
Meconium ileus and DIOS
Biliary cirrhosis and portal hypertension

Sex organs: Obstructive azoospermia (CBAVD)

Adapted from Welsh and Smith. Sci Am. 1995;273:52-59.

Unusual
Manifestations
Severe
hypokalemia,
hyponatremia
with
alkalosis:
pseudobarter syndrome
Meconium ileus equivalent
Sterility in males: Azoospermia
alone

Genotype and Phenotype

Cystic fibrosis (CF) is caused by mutations in the CF

transmembrane conductance regulator (CFTR) gene which
encodes a protein expressed in the apical membrane of
exocrine epithelial cells.
This genotypic variation provides a rationale for phenotypic
effects of the specific mutations. The extent to which
various CFTR alleles contribute to clinical variation in CF is
evaluated by genotype-phenotype studies.
The poor correlation between CFTR genotype and severity
of lung disease strongly suggests an influence of
environmental and secondary genetic factors (CF
modifiers).
Several candidate genes related to innate and adaptive
immune response have been implicated as pulmonary CF
modifiers. In addition, the presence of a genetic CF modifier
for meconium ileus has been demonstrated on human
chromosome 19q13.2.
The phenotypic spectrum associated with mutations in the
CFTR gene extends beyond the classically defined CF.
Besides patients with atypical CF, there are large numbers
of so-called monosymptomatic diseases such as various

Molecular Genetics and Gene

Function

Locus: 7q31.2 - The CFTR gene is found in

region q31.2 on the long (q) arm of human
chromosome 7.
Gene Structure: The normal allelic variant
for this gene is about 250,000 bp long and
contains 27 exons.
mRNA: The intron-free mRNA transcript for
the CFTR gene is 6129 bp long.
Coding Sequence (CDS): 4443 bp within
the mRNA code for the amino acid sequence
of the gene's protein product.
Protein Size: The CFTR protein is 1480
amino acids long and has a molecular
weight of 168,173 Da.
Protein Function: The normal CFTR protein
product is a chloride channel protein found
in membranes of cells that line
passageways of the lungs, liver, pancreas,
intestines, reproductive tract, and skin.
CFTR is also involved in the regulation of
other transport pathways.
Associated Disorders: Defective versions
of this protein, caused by CFTR gene

Protein Function and

Biochemistry
CFTR controls
chloride ion
movement in
and out of
the cell.

Protein Function

Protein Structure and

Function

CFTR transports chloride ions

(Cl-) ions across the
membranes of cells in the
lungs, liver, pancreas, digestive
tract, reproductive tract, and
skin.
CFTR is made up of five
domains:
two membrane-spanning domains
(MSD1 and MSD2) that form the
chloride ion channel
two nucleotide-binding domains
(NBD1 and NBD2) that bind and
hydrolyze ATP (adenosine
triphosphate)
and a regulatory (R) domain.

Delta F508, the most common

CF-causing mutation, occurs in
the DNA sequence that codes

Changes in Protein
structure
CFTR functions principally as a cAMP-induced
chloride channel and appears capable of
regulating other ion channels.
Besides the most common mutation, F508,
accounting for about 70% of CF chromosomes
worldwide, more than 850 mutant alleles
have been reported to the CF Genetic
Analysis Consortium.
These mutations affect CFTR through a
variety of molecular mechanisms which can
produce little or no functional CFTR at the
apical membrane.

3D Image of Protein
When a CFTR protein with the delta
F508 mutation reaches the ER, the
quality-control mechanism of this
cellular component recognizes that
the protein is folded incorrectly and
marks the defective protein for
degradation. As a result, delta F508
never reaches the cell membrane.
People who are homozygous for delta
F508 mutation tend to have the most
severe symptoms of cystic fibrosis
due to critical loss of chloride ion
transport.
This upsets the sodium and chloride
ion balance needed to maintain the
normal, thin mucus layer that is
easily removed by cilia lining the
lungs and other organs. The sodium
and chloride ion imbalance creates a

Disease

Mucous in the airways cannot be easily cleared from the lungs.

Presentation of Disease
Colo
n

Pancreas
Sticky mucus secretion

Ducts are filled with sticky mucus. Scaring of

tissue.

Treatment

The only way to cure CF would be to use gene therapy to replace the
defective gene or to give the patient the normal form of the protein before
symptoms cause permanent damage.
The major goal in treating CF is to clear the abnormal and excess
secretions and control infections in the lungs, and to prevent obstruction in
the intestines.
For patients with advanced stages of the disease, a lung transplant
operation may be necessary.
Although treating the symptoms does not cure the disease, it can greatly
improve the quality of life for most patients and has, over the years,
increased the average life span of CF patients to 30 years.

Gastrointestinal Treatment
Modified diet
Due to pancreatic disorders, children with CF require a modified diet,
including vitamin supplements (vitamins A, D, E, and K) and pancreatic
enzymes. Maintaining adequate nutrition is essential. The diet calls for a
high-caloric content (twice what is considered normal for the child's age),
which is typically low in fat and high in protein. Patients or their caregivers
should consult with their health care providers to determine the most
appropriate diet.

Gene Therapy
Gene therapy is the use
of normal DNA to
"correct" for the damaged
genes that cause disease.
In the case of CF, gene
therapy involves inhaling
a spray that delivers
normal DNA to the lungs.
The goal is to replace the
defective CF gene in the
lungs to cure CF or slow
the progression of the
disease.

THALASSEMIAS
Heritable, hypochromic anemiasvarying degrees of severity
Genetic defects result in decreased or
absent production of mRNA and
globin chain synthesis
At least 100 distinct mutations
High incidence in Asia, Africa,
Mideast, and Mediterrenean countries

Hemoglobin Review
Each complex consists of :
Four polypeptide chains, non-covalently
bound
Four heme complexes with iron bound
Four O2 binding sites

Globin Chains
Alpha Globin
141 amino acids
Coded for on Chromosome 16
Found in normal adult hemoglobin, A1 and A2

Beta Globin
146 amino acids
Coded for on Chromosome 11, found in Hgb A1

Delta Globin
Found in Hemoglobin A2--small amounts in all adults

Gamma Globin
Found in Fetal Hemoglobin

Zeta Globin
Found in embryonic hemoglobin

Hemoglobin Types

Hemoglobin
Type
Hgb A1
92%--------Hgb A2
2.5%-------Hgb F
<1%--------Hgb H
------------------

Globin Chains





gluval
glulys

Genetics
Alpha globins are coded on chromosome 16
Two genes on each chromosome
Four genes in each diploid cell
Gene deletions result in Alpha-Thalassemias

Also on chromosome 16 are Zeta globin

genesGowers hemoglobin (embryonic)
Beta globins are coded on chromosome 11
One gene on each chromosome
Two genes in each diploid cell
Point mutations result in Beta-Thalassemias

Also on chromosome 11 are Delta (Hgb A2)

and Gamma (Hgb F) and Epsilon (Embryonic)

Alpha Thalassemias
Result from gene deletions
One deletionSilent carrier; no
clinical significance
Two deletions Thal trait; mild
hypochromic microcytic anemia
Three deletionsHgb H; variable
severity, but less severe than Beta
Thal Major
Four deletionsBarts Hgb;
Hydrops Fetalis; In Utero or early

Alpha Thalassemias
Usually no treatment indicated
4 deletions incompatible with life
3 or fewer deletions have only mild
anemia

Beta Thalassemias
Result from Point Mutations on
genes
Severity depends on where the
hit(s) lie
0-no -globin synthesis;
+ reduced synthesis

Disease results in an
overproduction of -globin chains,
which precipitate in the cells and
cause splenic sequestration of

-Thal--Clinical
-Thalassemia Minor
Minor point mutation
Minimal anemia; no treatment indicated

-Thalassemia Intermedia
Homozygous minor point mutation or
more severe heterozygote
Can be a spectrum; most often do not
require chronic transfusions

-Thalassemia Major-Cooleys Anemia

Severe gene mutations
Need careful observation and intensive
treatment

Beta Thalassemia Major

Reduced or nonexistent production of -globin
Poor oxygen-carrying capacity of RBCs
Failure to thrive, poor brain development

Increased alpha globin production and precipitation

RBC precursors are destroyed within the marrow

Increased splenic destruction of dysfunctional

RBCs
Anemia, jaundice, splenomegaly

Hyperplastic Bone Marrow

Ineffective erythropoiesisRBC precursors destroyed
Poor bone growth, frontal bossing, bone pain

Increase in extramedullary erythropoiesis

Iron overloadincreased absorption and

transfusions
Endocrine disorders, Cardiomyopathy, Liver failure

-Thalassemia MajorLab
findings
Hypochromic, microcytic anemia

Target Cells, nucleated RBCs, anisocytosis

Reticulocytosis
Hemoglobin electrophoresis shows
Increased Hgb A2delta globin
production
Increased Hgb Fgamma globin
production

Hyperbilirubinemia
LFT abnormalities (late finding)
TFT abnormalities, hyperglycemia
(late endocrine findings)

-Thalassemia Major Treatment

Chronic Transfusion Therapy

Maximizes growth and development

Suppresses the patients own ineffective
erythropoiesis and excessive dietary iron
absorption
PRBC transfusions often monthly to maintain Hgb
10-12

Chelation Therapy
Binds free iron and reduces hemosiderin deposits
8-hour subcutaneous infusion of deferoxamine, 5
nights/week
Start after 1year of chronic transfusions or
ferritin>1000 ng/dl

Splenectomy--indications

-Thalassemia Major
Complications and
Emergencies

SepsisEncapsulated organisms
Strep Pneumo

Cardiomyopathypresentation in
CHF
Use diuretics, digoxin, and
deferoxamine

Endocrinopathiespresentation in
DKA
Take care during hydration so as not
to precipitate CHF from fluid overload

Anticipatory Guidance and

Follow Up
ImmunizationsHepatitis B,
Pneumovax
Follow for signs of diabetes,
hypothyroid, gonadotropin
deficiency
Follow for signs of cardiomyopathy
or CHF
Follow for signs of hepatic
dysfunction
Osteoporosis prevention
Diet, exercise
Hormone supplementation

On The Horizon
Oral Chelation Agents
Pharmacologically upregulating
gamma globin synthesis, increasing
Hgb F
Carries O2 better than Hgb A2
Will help bind globins and decrease
precipitate

Bone Marrow transplant

Gene Therapy
Inserting healthy genes into stem cells
and transplanting

PHENYLKETONURIA (PKU)
PKU
(phenylketonuria),
in its "classic"
form, is a rare,
inherited metabolic
disease that results
in mental
retardation and
other neurological
problems when
treatment is not
started within the

Causes
1. A single mutant recessive allele of the
Phenylalanine Hydroxylase (PAH) gene
Locus : Long arm of Chromosome 12
2. Dietary excess of plant proteins which
results in the exhaustion of a protein
cofactor (pterin) needed by the enzyme

2008 Paul Billiet ODWS

PKU Genetics

Phenylalanine
PKU is
characterized by
the inability of the
body to utilize the
essential amino
acid phenylalanine.

The normal metabolism of phenylalanine

(pathways a and b)
BREAKDOWN

Dietry
sources,
particularly
plant
proteins

PHENYLALANINE

PHENYLALANINE
HYDROXYLASE

(a)

TYROSINE

(b)
BODY
PROTEINS
2008 Paul Billiet ODWS

The abnormal metabolism in phenylketonuric subjects

(pathway c)
HYDROXYPHENYLACETIC
ACID

Dietry
sources,
particularly
plant
proteins

(c)
PHENYLALANINE*

PHENYLALANINE
HYDROXYLASE

(a)

(c)
(b)
PHENYLACETIC
ACID*

*Agents, thought to be responsible for mental retardation

2008 Paul Billiet ODWS

BODY
PROTEINS

Enzymatic activity
In cases of PKU, the enzyme that breaks down
phenylalanine, phenylalanine hydroxylase, is
completely or nearly completely deficient.
This enzyme normally converts phenylalanine
to another amino acid, tyrosine, which is
utilized by the body.
When this enzyme, phenylalanine
hydroxylase, is absent or deficient,
phenylalanine and its breakdown chemicals
from other enzyme routes, accumulate in the
blood and body tissues.

Levels of blood phenylalanine

A normal blood phenylalanine level is
about 1mg/dl.
In cases of PKU, levels may range
from 6-80mg/dl, but are usually
greater than 30mg/dl.

What happens when there

is too much blood
phenylalanine?
Chronically, high levels of phenylalanine
and some of its breakdown products can
cause significant brain problems.
There are a number of other disorders
of hyperphenylalaninemia, but classic
PKU is the most common cause of high
levels of phenylalanine in the blood.

What happens when there is too

little blood phenylalanine?
It is important to remember that
some phenylalanine is needed to
maintain normal body function.
Insufficient
phenylalanine intake
may cause mental and physical
sluggishness, loss of appetite,
anemia, rashes, and diarrhea.

PKU Inheritence

PKU is inherited
as an
autosomal
recessive
trait.

Incidence of PKU
PKU affects about one out of every
10,000 to 20,000 Caucasian or
oriental births.
The incidence in
African Americans is far less.
The PKU disorder is as frequent in
men as it is in women.

PKU Symptoms
(About 50% of untreated infants have the
following early symptoms)

Vomitting
Irritability
Eczema-like rash
Unusual odor to urine
Nervous System
Problems(increased muscle
tone, more aactive muscle
tendon reflexes)
Microcephaly
Decreased body growth

Other symptoms of PKU

Prominent cheek and jaw bones
widely spaced teeth
Poor development of tooth enamel.

Treatment
If PKU goes
untreated or
undetected, severe
brain problems
occur such as
seizures and
mental retardation.
This can occur as
early as the second
month of life, if not
detected and
treated.

Treatment
Every state now screens the blood
phenylalanine level of all newborns
at about 3 days of age.
This test is one of several newborn
screening tests performed before or
soon after discharge from the
hospital.

Treatment
Usually a few drops of
blood are obtained by a
small prick on the heel,
placed on a card and
then
sent
for
measurement.
If the screening test is
abnormal, other tests
are needed to confirm or
exclude PKU.
Newborn
screening
allows
early
identification and early

Fragile X Syndrome
The worlds leading cause of
inherited mental impairment
Symptoms ranging from learning
problems to mental impairment and
autism
Can be accurately diagnosed with a
simple blood test or DNA

Prevalence
Affects 1 in 3,600 males & 1 in
4,000- 6,000 females
1 in 260 women are carriers
1 in 800 men are carriers
Fragile X appears in all
socioeconomic background
In Alabama, carriers and full
mutations are estimated at 15,978

Fragile X Syndrome
Second only to Downs Syndrome
as a genetic cause of mental
retardation
Unlike Downs Syndrome, maternal
age is not a factor

Fragile X Syndrome
The most common known cause of
autism
About 30% of individuals with
Fragile X Syndrome have autism
2-6% of individuals with autism
have Fragile X Syndrome

Fragile X Chromosome

46,Y,fra(X)(q27.3)

SCAN in page 14

Both Males and Females

Can Have Fragile X
Syndrome
BOYS
Approximately 85%
of boys with F.M.
have cognitive
defects in the MR
range (below 70)
The production of
FMR1 protein is
usually shut down

GIRLS
Approximately 70%
of girls with F.M.
have cognitive
defects in borderline
to M.R. range (below
70)
Girls with more
protein-producing
cells tend to have
higher IQs

Father
XY

Pre-mutated Female
XX

Pre-mutated Male
XY

XX

XY
Unaffected

4
5

XY
XX

Mother
XX

XY

XX

Unaffected

CGG
Repeats

Unaffected Female

XY
Unaffected

XX

XX

X Pre-mutation
X Full Mutation

6
XX

I
N
C
R
E
A
S
I
N
G

INHERITENCE
The inheritance is different from common dominant or
recessive inheritance patterns.
A fragile area on the X chromosome (FMR1) has
repeats in the genetic code. The more repeats, the
more likely there is to be a problem.
Boys and girls can both be affected, but because boys
have only one X chromosome, a single fragile X is likely
to affect them more severely.

CLINICAL FEATURES

Physical Characteristics

Large ears
Long, narrow face
Prominent forehead
Prominent, square chin
High palate (roof of mouth)
Hand calluses
Mitral valve prolapse (a leaky heart valve)
Seizures
Eye problems

Physical Characteristics
Often Seen in Young
Children:
Numerous ear infections
Flat feet
Hyper extensible joints
Eye problems in 20%-25%:
Refractive errors
Strabismus
Astigmatisms

Seizures
Missing developmental milestones

Common Difficulties

Sleeping
Toilet training
Socialization
Play (spinning objects, play with
exclusive toy, or part of toy)

Cognitive
The Fragile X mutation affects brain
development and leads to a range of
cognitive delays.
Developmental delays
Mental impairment
Learning disabilities

Difficulties with
frontal lobe functions
(executive functions)
Organization of information
Acting on that information in an
effective manner
Focusing attention
Forming a plan and carrying it out

Behavior

Attention deficits
Hyperactivity
Impulsivity
Autistic-like behaviors

Repetitive behaviors
Hand flapping
Hand biting
Gaze aversion

Extreme anxiety, shyness

Transition problems, difficulty adjusting
to change

Cognitive/ Behavioral Strengths

Strong visual memory

Long term memory
Good verbal imitative skills
Desire to be social
Strong appreciation of humor
Often receptive to helping or working
cooperatively

Speech and Language

Characteristics

Delayed speech
Problems with intelligibility
Rapid, repetitive speech
(perseveration)
Echolalia
Poor conversation skills
Good verbal imitative skills

Sensory Processing
Characteristics

Tactile defensiveness
Visual defensiveness
Olfactory defensiveness
Oral defensiveness
Gravitational/ postural insecurity

Sensory processing often seen

in infants and young children

Excessive mouthing and drooling

Mouth stuffing
picky eaters
Difficult to calm and comfort
Over sensitivity to sounds

Gross Motor Characteristics

Low muscle tone
Delays in gross motor skills
Uncoordinated, clumsy

Fine Motor Characteristics

Low muscle tone
Hyper extensible finger joints
Difficulties with fine motor joints
Self feeding
Dressing
handwriting

Characteristics Often Seen

in Females With FX

Attention deficits
Shyness and anxiety
Selective mutism
Problems with math
Increased risk for mental health issues
such as depression, bipolar disorder,
and obsessive compulsive disorder
25% premature ovarian failure (early
menopause)

A FEW MORE CHROSOME

DISORDERS

Cri-du-Chat syndrome

First recognized syndrome due to a deletion

(1963)
Involves a missing piece of the short arm of
chromosome 5 (5p-)
Only deletion syndrome currently listed in ICD-9CM

Quick Facts

Hereditary Congenital Syndrome

Deletion of short arm of chromosome 5
No Known Cure
One of Most Common Human Deletion
Syndromes
1 in 20,000 to 1 in 50,000 births
Less than 1% are profoundly retarded
Also known as LeJunes Disease

Cri-du-Chat syndrome

Cri-du-Chat Syndrome

Cri-du-Chat syndrome

Mental retardation
Microcephaly
Round face
Congenital Malformations
Laryngeal anomaly leading
to cry sounding like cat
(infants)
High palate or possible cleft
Ptosis (epicanthic folds)
Chronic otitis media
Delayed
motor
development
Normal life expectancy
Picture from Cri-du-Chat
Syndrome Website

Physical Features
Babies
o
o
o
o
o
o

High Pitched cry at birth

Low Birth Weight
Poor Muscle Tone
Developmental Delay
Small Head
Round Moon Face
http://members.tripod.com/~yen
ial/confpics98.html

Physical Features
Children
o
o
o
o

Small Thin Build

Short Stature
Small Chin, Long Nose
Delay in Mobility, Speech,
Toilet Training
o Protruding Teeth
o Some Internal Abnormalities such
http://www.cridchat.uas Heart
net.com/
Defects or Absent Kidneys

Treatment
No Current Cure
Intervention from Speech Therapists,
Physiotherapists and Occupational
Therapists
Some Drugs control behavioral or
sleep problems

ANGELMAN Syndrome
(AS)
and
PRADER-WILLI Syndrome
(PWS)
Usually caused
by large
(megabase+) deletions of 15q11-q13
Delete maternal chromosome = AS
Delete paternal chromosome = PWS

Angelman Syndrome
Angelman Syndrome is a genetic disorder
caused by abnormal function of the gene
UBE3A, located within a small region (q11q13) on chromosome #15.
Maternal Inheritance
This region is deleted from the maternally
derived chromosome in approximately
80% of individuals with Angelman
Syndrome.
There are estimated to be between 1000
and 5000 cases in the U.S. and Canada.

Angelman Syndrome
Severe developmental delay or
MR
Severe speech impairment
Movement
disorder-ataxia,
jerky limb movements
Unique behavior:
Frequent,
inappropriate
laughter, excitability, happy
demeanor, hand-flapping,
Acquired microcephaly by age
2 years
Seizures, starting before 3
years of age-of any type
Strabismus
Wide
mouth,
wide-spaced
teeth
Flexed,
lifted
arms
with
ambulation
Affinity for water

Angelman Syndrome

Prader-Willi Syndrome
Prader-Willi syndrome is caused
by the deletion of normally
active genetic material on the
long arm of chromosome 15.
Prevalence: 1:12,000- 15,000
(both sexes, all races)
In Prader-Willi syndrome this
absence may occur in three
different ways.
deletion on the paternal
chromosome 15
mutation on the paternal
chromosome 15
maternal uniparental disomy--i.e.,
both chromosome 15s from the
mother and none from the father

Prader-Willi Syndrome

Visible deletion
Chromosome 15

Microdeletion (absence
of a FISH signal)

 Physical
Holm et al established the following diagnostic criteria
for Prader-Willi syndrome. Based on these guidelines,
the diagnosis of Prader-Willi syndrome is highly likely
in children younger than 3 years with 5 points (3 from
major criteria) or in those older than 3 years with 8
points (4 from major criteria).
Major criteria (1 point each)
CNS Infantile central hypotonia
GI Infantile feeding problems and/or failure
to thrive
Nutrition Rapid weight gain in children aged
1-6 years
Craniofacial Characteristic facial features
such as narrow bifrontal diameter, almondshaped palpebral fissures, narrow nasal
bridge, and down-turned mouth
Endocrine Hypogonadism

Minor criteria (one half point each)

Neurologic Decreased fetal movement and/or infantile
lethargy
Pulmonary Sleep disturbance and/or sleep apnea
Endocrine Short stature for predicted height by mid
adolescence
Dermatologic Hypopigmentation
Orthopedic Small hands and feet
Orthopedic Narrow hands with straight ulnar border
Ophthalmologic Esotropia and/or myopia
Dental Thick viscous saliva
Otolaryngology Speech articulation defects
Psychiatric Skin picking (Some patients with Prader-Willi
syndrome have become anemic from chronic rectal bleeding
secondary to skin picking.)
Supportive criteria (no points)
Neurology High pain threshold and normal neuromuscular
evaluation for hypotonia
Gastroenterology Decreased vomiting
Endocrinology Ineffective thermoregulation, early
adrenarche, and/or osteoporosis, adrenal insufficiency

Prader-Willi Syndrome
Neonatal
and
infantile
central hypotonia with poor
suck leading to feeding
problems and/or failure to
thrive.
Hyperphagia
(begins
between ages 2-6 years)
Obesity (due to hyperphagia)
Characteristic facial features:
narrow bifrontal diameter,
almond-shaped
palpebral
fissures, down turned mouth
Hypogonadism
Developmental delay/mild to
moderate mental retardation
Small hands and feet for
height age
Esotropia, myopia (60-70%
of individuals)

Child at Age
1

Same child at
Age 2