Genetic Diseases: Is it sometimes benefits?

‫الرحيم‬‫الرحمن‬‫هللا‬ ‫بسم‬

GENETIC DISEASES: IS IT
SOMETIMES BENEFITS?
By
DR: Awad M. Elabd
Prof. Of Medical Biochemistry & Molecular Biology
Biochemical Endocrinology Unit (BEU) & Information
Technology Unit (IT) Founder & Manager

INTRODUCTION
Some genetic conditions can confer resistance to specific
infectious diseases.
 It is theorized that these genotypes are preferentially
maintained in populations regularly exposed to certain infectious
agents, especially those with high virulence.
 The protection afforded by these conditions has provided the
impetus for understanding these genetic mechanisms of
resistance that can potentially be exploited for developing novel
therapies or improving current therapies.

Diseases
Genetics
Non-
Genetics

GeneticDiseases
Resistance to
malaria
Resistance to
cholera
Resistance to T.B
Resistance to
mycotic abortion
Resistance to
enveloped viruses

Resistance to
Malaria
Examples
Thalassemia, Sickle
cell trait
G-6-P dehydrogenase
deficiency
Duffy antigen receptor
First: Genetic disease
Hemoglobinopathy Enzymopathy
No erythrocytes
surface protein

HEMOGLOBINOPATHY
 It is a kind of genetic defect that results in abnormal structure of one of
the globin chains of the hemoglobin molecule.
 Hemoglobinopathies are inherited single-gene disorders; in most cases,
they are inherited as autosomal co-dominant traits.
 Common hemoglobinopathies include sickle-cell disease.
 It is estimated that 7% of world's population (420 million) are carriers,
with 60% of total and 70% pathological being in Africa.
 Hemoglobinopathies are most common in populations from Africa, the
Mediterranean basin and Southeast Asia.

THALASSEMIAS
 Thalassemias are genetic disorders inherited from a person's
parents.
 There are two main types, alpha thalassemia and beta
thalassemia.
 The severity of alpha and beta thalassemia depends on how
many of the four genes for alpha globin or two genes for beta
globin are missing.
 Diagnosis is typically by blood tests including a complete blood
count, special hemoglobin tests, and genetic tests.
 Diagnosis may occur before birth through prenatal testing.

PATHOPHYSIOLOGY
 The thalassemias are classified according to which chain of the hemoglobin molecule is
affected.
 In α-thalassemias, production of the α globin chain is affected, while in β-thalassemia,
production of the β globin chain is affected.
 The β globin chains are encoded by a single gene on chromosome 11; α globin chains are
encoded by two closely linked genes on chromosome 16.
 Thus, in a normal person with two copies of each chromosome, two loci encode the β
chain, and four loci encode the α chain.
 Deletion of one of the α loci has a high prevalence in people of African or Asian descent,
making them more likely to develop α-thalassemia.
 β-Thalassemias are not only common in Africans, but also in Greeks and Italians.

α-THALASSEMIAS
 The α-thalassemias involve the genes HBA1 and HBA2, inherited
in a Mendelian recessive fashion.
 Two gene loci and so four alleles exist. It is also connected to the
deletion of the 16p chromosome.
 α Thalassemias result in decreased alpha-globin production,
therefore fewer alpha-globin chains are produced, resulting in an
excess of β chains in adults and excess γ chains in newborns.
 The excess β chains form unstable tetramers (called hemoglobin
H or HbH of 4 beta chains), which have abnormal oxygen
dissociation curves.

BETA THALASSEMIAS
 Beta thalassemias are due to mutations in the HBB gene on
chromosome 11, also inherited in an autosomal, recessive fashion.
 The severity of the disease depends on the nature of the mutation
and on the presence of mutations in one or both alleles.
 Mutated alleles are called β+ when partial function is conserved
(either the protein has a reduced function, or it functions normally
but is produced in reduced quantity) or βo, when no functioning
protein is produced.
 The situation of both alleles determines the clinical picture:

BETA THALASSEMIAS
 β thalassemia major (Mediterranean anemia or Cooley anemia) is caused
by a βo/βo genotype. No functional β chains are produced, and thus no
hemoglobin A can be assembled. This is the most severe form of β-
thalassemia;
 β thalassemia intermedia is caused by a β+/βo or β+/β+ genotype.
 In this form, some hemoglobin A is produced.
 β thalassemia minor is caused by a β/βo or β/β+ genotype.
 Only one of the two β globin alleles contains a mutation, so β chain
production is not terribly compromised and patients may be relatively
asymptomatic.

• Sickle cell trait describes a condition in which a person has one abnormal
allele of the hemoglobin beta gene (is heterozygous), but does not display
the severe symptoms of sickle-cell disease that occur in a person who has
two copies of that allele (is homozygous).
• Those who are heterozygous for the sickle cell allele produce both normal
and abnormal hemoglobin (the two alleles are codominant with respect to
the actual concentration of hemoglobin in the circulating cells).

• Sickle cell disease is a blood disorder in which there is a single
amino acid substitution in the hemoglobin protein of the red
blood cells, which causes these cells to assume a sickle shape,
especially when under low oxygen tension.
• Sickling and sickle cell disease also confer some resistance to
malaria parasitization of red blood cells, so that individuals with
sickle-cell trait (heterozygotes) have a selective advantage in
environments where malaria is present.

HEMOGLOBIN GENETICS
 Normally, a person inherits two copies of the gene that produces beta-
globin, a protein needed to produce normal hemoglobin (hemoglobin A,
genotype AA).
 A person with sickle cell trait inherits one normal allele and one abnormal
allele encoding hemoglobin S (hemoglobin genotype AS).
 The sickle cell trait can be used to demonstrate the concepts of co-
dominance and incomplete dominance. An individual with the sickle cell
trait shows incomplete dominance when the shape of the red blood cell is
considered.

• This is because the sickling happens only at low oxygen concentrations.
• With regards to the actual concentration of hemoglobin in the circulating
cells, the alleles demonstrate co-dominance as both 'normal' and mutant
forms co-exist in the blood stream.
• It is interesting to note that unlike the sickle-cell trait, sickle-cell disease is
passed on in a recessive manner.
• The sickle cell gene has five haplotypes, which are named after its core
geographical areas of distribution: Bantu, Benin, Cameroon, Senegalese and
Saudi-Indian.

Mechanism of resistance
of sickle patients
to
Malaria
This vein (4) shows the interaction between the malaria sporozoites (6) with sickle cells (3) and regular
cells (1). While malaria is still affecting the regular cells (2), the ratio of sickle to regular cells is 50/50 due
to sickle cell anemia being a heterozygous trait, so the malaria can’t affect enough cells with schizonts (5)
to harm the body.

• Sickle cell trait provides a survival advantage over people with normal hemoglobin in
regions where malaria is endemic.
• The trait is known to cause significantly fewer deaths due to malaria, especially when
Plasmodium falciparum is the causative organism.
 Although the precise mechanism for this phenomenon is not known, a several factors
are believed to be responsible.
1. Infected erythrocytes (Red Blood cells) tend to have lower oxygen tension, because it
is significantly reduced by the parasite. This causes sickling of that particular
erythrocyte, signaling the phagocytes to get rid of the cell and hence the parasite
within.
2. Since the sickling of parasite infected cells is higher, these selectively get removed by
the reticulo-endothelial system, thus sparing the normal erythrocytes.

3. Excessive vacuole formation occurs in those parasites
infecting sickle cells.
4. Sickle trait erythrocytes produce higher levels of the
superoxide anion and hydrogen peroxide than do normal
erythrocytes, both are toxic to malarial parasites.
The sickle cell trait was found to be 50% protective against
mild clinical malaria, 75% protective against admission to the
hospital for malaria, and almost 90% protective against
severe or complicated malaria.

Introduction
• G6PD deficiency is the most common disease producing enzyme
abnormalities in humans, affecting more than 200 million
individuals worldwide.
• The highest prevalence in the Middle East, tropical Africa & Asia.
• G6PD Deficiency is caused by 400 different mutations in gene
coding for G6PD, only few of them causes the clinical symptoms
of the disease.

What is G6PD?
• G6PD is an metabolic enzyme is involved in pentose
phosphate pathway, especially important in red blood cell
metabolism
• It also protects red blood cells from the effects of potentially
harmful molecules called REACTIVE OXYGEN SPECIES

G6PD Deficiency
• The G6PD gene is located on the telomeric region of the long arm of
X-chromosome (band Xq28).
• Mutation of the X-linked G6PD gene (approximately 127 have been
reported with a single base substitute leading to amino acid
replacements) results in many variants of protein with varying
enzyme activity that result in different patterns of clinical
manifestations.

Male to Female ratio
• Male cases are overrepresented compared with female cases.
• Males are hemizygous for the G6PD gene; therefore the expression is
either normal or deficient.
• In contrast, in females who have two copies of the gene on each
chromosome, the gene expression can be normal or heterozygous.
• Homozygous inheritance in females can occur; whereas, heterozygous
females have genetic mosaicism secondary to X-chromosome
inactivation and can have similar manifestation as male neonates.

What happens in G6PD deficiency?

G6PD variants can be classified into three categories
Class I Mutations
severe deficiency with
no or
minimal detected
enzyme activity
often associated with
chronic non-
spherocytic anemia
(occurs even in
absence of oxidative
stress)
Class II Mutations
(G6PD Mediterranean)
severe deficiency
with 1% to 10%
residual enzyme actiity
G6PD enzyme shows
normal stability but,
very low activity in all
RBCs
Class III
(G6PD Group A-)
moderate deficiency
with 10% to 60%
residual enzyme
activity,
RBCs contain unstable
G6PD enzyme, but
normal activity in
younger RBCs and
reticulocytes
Class IV
Normal enzyme
activity at 60% to 150%
Class V
increased
enzyme activity at
>150%

of favismic patients
to
Malaria

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
results in erythrocytes that are more prone to suffering
damage.
• The invasion of malarial parasites exacerbates this
condition, making the cells highly susceptible to
phagocytosis.
• Infected G6PD-deficient erythrocytes are
morphologically different compared to non-infected
ones and are thus hyper susceptible to phagocytosis.

• Another enzymopathy involves pyruvate kinase
deficiency leading to altered membrane rigidity of
erythrocytes, thus preventing Plasmodium invasion.
• Moreover, pyruvate kinase deficiency significantly
reduces the intracellular concentration of glucose, a vital
source of energy for the intra-cellular life cycle of
Plasmodium.
• As such, both G6PD and pyruvate kinase have been
recognized as important drug targets against P.
falciparum.

DUFFY ANTIGEN SYSTEM
 Duffy antigen/chemokine receptor (DARC), also known as Fy glycoprotein (FY) or
CD234 (Cluster of Differentiation 234), is a protein that in humans is encoded by the
DARC gene.
 The Duffy antigen is located on the surface of red blood cells, and is named after the
patient in which it was discovered.
 The protein encoded by this gene is a glycosylated membrane protein and a non-
specific receptor for several chemokines.
 The protein is also the receptor for the human malarial parasites Plasmodium vivax
and Plasmodium knowlesi.
 Polymorphisms in this gene are the basis of the Duffy blood group system.

• Duffy-binding-like domains are so named because
of their similarity to the Duffy-binding proteins of
P. vivax and P. knowlesi.
• There are six variant types of DBL, named DBLα,
DBLβ, DBLγ, DBLδ, DBLε and DBLζ. CIDR is also
divided into three classes: CIDRα, CIDRβ and CIDRγ.
• Both DBL and CIDR have an additional type called
PAM, so named because of their specific
involvement in pregnancy-associated malaria
(PAM).

• In spite of the diverse DBL and CIDR proteins, the
extracellular amino terminal region is partly
conserved, consisting of about 60 amino acids of
NTS, one each of DBLα and CIDR1 proteins in
tandem.
• This semi-conserved DBLα-CIDR1 region is called
the head structure.
• The last CIDR region joins the TMD, which is
embedded in the cell membrane. The TMD and ATS
are highly conserved among different PfEMP1s.

 The Duffy antigen /chemokine receptor gene (gp-Fy;
CD234) is located on the long arm of chromosome 1
(1.q22-1.q23) and was cloned in 1993.
 The gene was first localised to chromosome 1 in 1968,
and was the first blood system antigen to be localised. It
is a single copy gene spanning over 1500 bases and is in
two exons.
 The gene encodes a 336 amino acid acidic glycoprotein.

It carries the antigenic determinants of the Duffy blood
group system which consist of four codominant alleles—
FY*A and FY*B—coding for the Fy-a and Fy-b antigens
respectively, FY*X and FY*Fy, five phenotypes (Fy-a, Fy-b,
Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b
where the Fy-b gene is poorly expressed.
Fy-x is also known as Fy-b weak or Fy-bWk.

to
Malaria

• In contrast to thalassemais and enzymopathies, the Duffy
antigen represents an extracellular-based resistance mechanism.
• The Duffy antigen, a receptor for chemokines, is present on the
surface of erythrocytes.
• This antigen is also an obligatory binding site for the malarial
toxin secreted by P. vivax.
• A point mutation in the Duffy gene leads to lack of expression of
the encoded receptor and thus negates P. vivax toxin
attachment.
• This innocuous polymorphism is the most common in Papua
New Guinea and Western Africa, which may explain why
infection of P.vivax is uncommon in these areas of the world.

Resistance to
Cholera
Second: Genetic disease
Cystic fibrosis

NOTABLE HISTORY
1905
Austrian Karl Landsteiner
describes Meconium ileus
47
1938
Cystic fibrosis disease
identified by American
Dorothy H. Andersen
1838
Carl Von Rokitansky’s
autopsy of infant with
Meconium peritonitis

CYSTIC FIBROSIS TRANSMEMBRANE
CONDUCTANCE REGULATOR (CFTR) GENE
 The CFTR gene is located on the long arm of
chromosome 7.
 There are 1604 mutations in CFTR listed on
the CFTR mutation database
 The most common mutation is
Δ F508---70% CF alleles in caucasians.

PROTEIN FUNCTION AND BIOCHEMISTRY
CFTR controls chloride
ion movement in and
out of the cell.

WHAT IS CYSTIC FIBROSIS (CF)?
 A multisystem disease
 Autosomal recessive inheritance
 Cause: mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR)
gene
 chromosome 7
 codes for a c-AMP regulated chloride
channel
CysticFibrosis

PATHOGENESIS
 Defects in (CFTR), - encodes for a protein that functions as
chloride channel & regulated by (cAMP).
Abnormalities of cAMP-regulates chloride transport
 Defective CFTR - decreased secretion of chloride and
increased re-absorption of sodium and water
 Reduced height of epithelial lining fluid
 Decreased hydration of mucus - that is stickier to bacteria
Result in viscid secretions

PRESENTATION : CF PANCREAS
 C Chronic respiratory disease
 F Failure to thrive
 P Polyps
 A Alkalosis, metabolic
 N Neonatal intestinal obstruction
 C Clubbing of fingers
 R Rectal Prolapse
 E Electrolyte in sweat
 A Aspermia / absent vas deferens
 S Sputum – S.aureus/P.aeruginosa
CysticFibrosis

HALLMARKS OF CF
 Very salty-tasting skin
 Appetite, but poor growth & weight
gain
 Coughing, wheezing, at times with
phelgum & shortness of breath
 Lung infections, e.g.
pneumonia/bronchitis
greasy, bulky stools or difficulty in
bowel movements
53

to
Cholera

Resistance to
T.B
Third: Genetic disease
Tay-Sacchs Disease

GENETICS
 Tay–Sachs disease is inherited in the autosomal recessive pattern
 The HEXA gene is located on the long (q) arm of human chromosome 15, between positions 23
and 24.
 Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents
are carriers, there is a 25% risk of giving birth to an affected child with each pregnancy. The
affected child would have received a mutated copy of the gene from each parent.
 Tay–Sachs results from mutations in the HEXA gene on chromosome 15, which encodes the
alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100
different mutations had been identified in the human HEXA gene.
 These mutations have included single base insertions and deletions, splice phase mutations,
missense mutations, and other more complex patterns. Each of these mutations alters the
gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function.

THE HEXA GENE IS LOCATED ON THE LONG (Q) ARM OF
HUMAN CHROMOSOME 15, BETWEEN POSITIONS 23 AND 24

TAY–SACHS DISEASE IS INHERITED IN THE
AUTOSOMAL RECESSIVE PATTERN

CHERRY RED SPOT AS SEEN IN TAY SACHS DISEASE.
THE CENTER OF THE FOVEA APPEARS BRIGHT RED BECAUSE IT IS
SURROUNDED BY A MILKY HALO.

Without this enzyme, gangliosides, particularly
ganglioside GM2, increases and degenerates
central nervous system.

PATHOPHYSIOLOGY
 Tay–Sachs disease is caused by insufficient activity of the enzyme
hexosaminidase A.
 Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes,
that breaks down glycolipids.
 When hexosaminidase A is no longer functioning properly, the lipids
accumulate in the brain and interfere with normal biological processes.
Hexosaminidase A specifically breaks down fatty acid derivatives called
gangliosides; these are made and biodegraded rapidly in early life as the
brain develops.
 Patients with and carriers of Tay–Sachs can be identified by a simple
blood test that measures hexosaminidase A activity.

ISOZYMES AND GENES
 Lysosomal A, B, and S isozymes.
 Functional lysosomal β-hexosaminidase enzymes are dimeric in structure. Three
isozymes are produced through the combination of α and β subunits to form any
one of three active dimers:
hexosaminidase
isozyme
subunit composition function
A α/β heterodimer
only isozyme that can
hydrolyze GM2 ganglioside in
vivo
B β/β homodimer
exists in tissues but no known
physiological function
S α/α homodimer
exists in tissues but no known
physiological function

The α and β subunits are encoded by separate genes, HEXA
and HEXB respectively.
Beta-hexosaminidase and the cofactor GM2 activator
protein catalyze the degradation of the GM2 gangliosides
and other molecules containing terminal N-acetyl
hexosamines.
Gene mutations in HEXB often result in Sandhoff disease;
whereas, mutations in HEXA decrease the hydrolysis of
GM2 gangliosides, which is the main cause of Tay-Sachs

Signs or Symptoms
Tay–Sachs disease is classified in variant forms,
based on the time of onset of neurological
symptoms.
Infantile Juvenile Adult/Late Onset
3 to 10 months two and 10 years 20 and 30 years
Extremely rare usually non-fatal

Signs or Symptoms
-Loss of learned skills
-Loss of smile, crawl, grab.
-Blindness, Deafness, Paralysis.
-Dementia
-Unable to swallow
-Muscle atrophy
-Cherry-red spot in the back of their eyes

-Treatment
There is no treatment for Tay-Sachs
disease, nor there is any way to prevent
or reduce the progression of this
disorder.

Examination
Fund of eye: presence of bilateral pallor of papila
and cherry-red spot in the macula.
Biochemical profile:
Total Hexosaminidase 125.0 nM,
Hexosaminidase A: 0%.
Other blood tests without significant alterations.
The patient evolved with physical and
neurological progressive deterioration, being
diagnosed with TSD
Slide 39

to
T.B

• It is now known that carriers of the Tay-Sachs gene have
increased production of the b-subunit of hexosaminidase
and that the b-subunit is closely associated with increased
host defense against mycobacteria.
• Additionally, cell surface bactericidal activity declined in
the absence of b-hexosaminidase.

• It is therefore possible that b-hexosaminidase is cytotoxic
to Mycobacteria tuberculosis, making the organism more
susceptible to macrophage attack.
• In the advent of drug-resistant tuberculosis, developing
drugs that up-regulate or maintain b-hexosaminidase may
prove beneficial for the treatment of tuberculosis while
circumventing concerns of antibiotic resistance.

Resistance to
Mycotic abortion
Fourth: Genetic disease
Phenylketonuria

What is Phenylketonuria (PKU)?
an autosomal recessive metabolic genetic
disorder characterized by homozygous or compound
heterozygous mutations in the gene for the hepatic
enzyme phenylalanine hydroxylase (PAH), rendering it
nonfunctional.[ This enzyme is necessary to
metabolize the amino acid phenylalanine (Phe) to the
amino acid tyrosine (Tyr).

THE PAH GENE
The PAH gene is located on chromosome
12 in the bands 12q22-q24.1.
More than 400 disease-causing
mutations have been found in the PAH
gene.
 This is an example of allelic genetic
heterogeneity.

Dietary Proteins
PhenylalaninePhenylpyruvic
acid
Tyrosine
Phenylalanine
Hydroxylase
3, 4
dihydroxyphenyl
alanine (DOPA)
Melanin pigments

Phenylalanine
Tyrosine
p-hydroxyphenylpyruvic acid
Homogentisic acid
2,5 dihydroxyphenylacetic acid
Maleylacetoacetic acid
Triiothyronine (T3)
Thyroxine (T4)
Glutamine GABA
Pyruvate Oxaloacetate
Glutamate decarboxylase
Pyruvate carboxylase
Phenylpyruvic acid
Phenylalanine
hydrolase
Tyrosine
transaminase
p-hydroxyphenylpyruvic
acid oxidase
Homogentisic acid
oxidase
Fumanylacetoacetic acid
Fumaric acid Acetoacetic acid
Carbon dioxide + Water
Iodinase 3,4 dihydroxyphenylalanine (DOPA) Melanin
Pigments
(decrease
pigmentation,
Blue eyes)
(Cretinisim)
(increased mousy odor)
(seizure ,increase deep
tendon reflex)
(decrease ATP, mental retardation)
(-)BH4
X
X
X
X

PHENYLALANINE HYDROXYLASE (PAH)
 Phenylalanine hydroxylase (PAH) is an enzyme that catalyzes the
hydroxylation of the aromatic side-chain of phenylalanine to generate
tyrosine.
 PAH is one of three members of the biopterin-dependent aromatic amino
acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin
(BH4, a pteridine cofactor) and a non-heme iron for catalysis.
 During the reaction, molecular oxygen is heterolytically cleaved with
sequential incorporation of one oxygen atom into BH4 and phenylalanine
substrate.

PHENYLALANINE HYDROXYLASE ACTION

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.

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.

What are the signs and symptoms of
phenylketonuria?
• A child with PKU may look normal and completely
healthy for the first few months of life.
• If left untreated, signs and symptoms may appear
between 3 to 6 months of age.
• Child may begin to be less active and do things
later than other children. He may lose interest or
not pay attention to things around him.

• Learning, speech, or behavior problems.
• More irritable, fussy, or restless than normal.
• Musty or mousy odor of his breath, hair, skin, or urine.
• Fair skin.
• Short stature (height) or small head.
• Skin may be dry or have rashes, such as eczema.
• Vomiting (throwing up), muscle stiffness, or seizures
(convulsions).

How is phenylketonuria diagnosed?
• Blood tests: A newborn
screening test is usually
done during your first days
of life. A sample of child's
blood is taken and sent to the
lab.

Guthrie test
• The Guthrie test, also known as the Guthrie bacterial
inhibition assay, is a medical test performed on newborn
infants to detect phenylketonuria, an inborn error of amino
acid metabolism.

• A drop of blood is usually obtained by pricking the heel of a
newborn infant in a hospital nursery on the sixth or seventh
day of life (end of the first week). The blood is collected on a
piece of filter paper and sent to a central laboratory.

• CT scan:. It may be used to look at child's bones,
muscles, brain, body organs, and blood vessels. child
may be given dye by mouth or in an IV before the
pictures are taken. The dye may help child's caregiver
see the pictures better. People who are allergic to
iodine or shellfish (lobster, crab, or shrimp) may be
allergic to some dyes. Tell the caregiver if child is
allergic to shellfish, or has other allergies or medical
conditions.

• Genetic tests: Genetic testing may be needed
to check child's genes. This test helps
caregivers learn how child's genes may affect
him. This may also help child's caregivers
decide on a treatment plan.

• Magnetic resonance imaging scan:
• Urine tests:

How is phenylketonuria treated?
• Diet: A special diet is needed to keep the amount
of phenylalanine in the body low.
This diet is different from one child
to another. It is started
as early as the first few days of life
or a few weeks after birth. This
special diet may need to be
followed for life.

• Medicines: child may be given medicines to
treat his symptoms. Medicines may be given to
treat his rash, vomiting, to control his seizures,
or to relax his muscles.
Special formulas or products: These are also
called protein substitutes that have little or no
phenylalanine. These formulas have the right
amino acids, calories, vitamins, and minerals
your child needs.

to
Mycotic Abortion

• Historically, physicians observed that women who were PKU carriers had a
much lower than average incidence of miscarriages.
• Woolf et al4 published data showing that women who were heterozygous
for the PKU disorder displayed a significantly reduced rate of spontaneous
abortions, when compared to wild-type homozygous individuals.
• This was the most prevalent in Scotland and Ireland, where the consistent
damp climate promotes the growth of mold and fungi on grains and beans.
• Aspergillus spp. produces a mycotoxin known as ochratoxin A which is
teratogenic at low doses and potentially lethal at high doses.

• In the case of pregnant women, ochratoxin A can cross the
placenta and cause spontaneous abortions.
• This toxin, being an N-acyl derivative of phenylalanine, is a
competitive inhibitor of phenylalanine in the phenylalanyl
tRNA synthetase-catalyzed reaction thus preventing protein
synthesis, which can be reversed by introducing phenylalanine
which is in excess in PKU individuals.
• The high frequency of the PKU gene present in women from
this particular section of Europe, as well as that observed in
Yemenite Jews, may help to protect against sudden
miscarriages, thus ensuring a normal pregnancy.

Resistance to
Some Viral Infections
Fifth: Genetic disease
Disorder Of Glycosylation IIb

Congenital Disorder
of glycosylation iib

CONGENITAL DISORDER OF GLYCOSYLATION
 A congenital disorder of glycosylation (previously called carbohydrate-deficient
glycoprotein syndrome) is one of several rare inborn errors of metabolism in
which glycosylation of a variety of tissue proteins and/or lipids is deficient or
defective.
 Congenital disorders of glycosylation are sometimes known as CDG syndromes.
They often cause serious, sometimes fatal, malfunction of several different
organ systems (especially the nervous system, muscles, and intestines) in
affected infants.
 The most common subtype is CDG-Ia (also referred to as PMM2-CDG) where
the genetic defect leads to the loss of phosphomannomutase 2, the enzyme
responsible for the conversion of mannose-6-phosphate into mannose-1-
phosphate.

CLASSIFICATION
 Historically, CDGs are classified as Types I and II (CDG-I
and CDG-II), depending on the nature and location of the
biochemical defect in the metabolic pathway relative to
the action of oligosaccharyltransferase.
 The most commonly used screening method for CDG,
analysis of transferrin glycosylation status by isoelectric
focusing, or other techniques, distinguish between these
subtypes in so called Type I and Type II patterns.

TYPE I
Type I disorders involve disrupted
synthesis of the lipid-linked
oligosaccharide precursor (LLO) or
its transfer to the protein.

TYPE II
Type II disorders involve malfunctioning
trimming/processing of the protein-bound
oligosaccharide chain.
There are many subtype including from a to l

to
Enveloped Viruses

• Resistance to glycosylation-dependent viral infections (e.g.,
HIV-1, dengue, herpes simplex 2, hepatitis C, and influenza)
has been linked to congenital disorder of CDGIIb.
• This condition is caused by defective
mannosyloligosaccaride
glucosidase (MOGS), which is the initial enzyme in the
processing phase of N-linked oligosaccharides.
• In this extremely rare condition, the process of attaching N-
glycans to proteins is disrupted, resulting in dysfunctional
glycoprotein synthesis.

• Due to the dependence of enveloped viruses on proper host cell
glycosylation for the assembly of their capsid proteins, it appears
that the defective glycosylation in patients with CDG-IIb hinders
cellular entry, cellular egress, and viral replication for
glycosylation-dependent enveloped viruses.
• Evidence to support the theory of lowered susceptibility in those
with defective glycosylation has been documented through a case
study of two siblings with CDGIIb.
• These individuals had appropriate immune responses to non-
replicating viruses, but failed to mount a humoral response to live
glycosylation-dependent virus vaccinesMMR and varicella.5

• Furthermore, the MOGS inhibitors castanospermine, N-
butyldeoxynojirimycin, and deoxynojirimycin have been shown to lower
replication in cells infected with enveloped viruses such as HIV, dengue,
hepatitis B and C, and herpes simplex virus.
• These findings are additionally supported by the antiviral use of 2-
deoxyglucose and tunicamycin, both of which truncate glycan polymers
and attenuates the replication of certain viruses.
In summary
The antiviral effects of defective glycosylation provide a strong basis for
continued researchon the next generation of MOGS inhibitors.

of thalassemic patients
to
Malaria

WHAT IS FAVISM?
Favism is formally defined as hemolytic response to the
consumption of broad beans
Favism is disorder characterized by hemolytic reaction to the
consumption of broad beans
• All individual with favism show
G6PD deficiency
• However not all individuals with
G6PD deficiency show favism

DECREASED AMOUNTS OF GLUTATHIONE
DUE TO DECREASED PRODUCTION OF NADPH
Reduction of amounts of NADPH in RBCs in G6PD deficiency causes
reduction of oxidized glutathione .
Role of reduced glutathione in RBCs:
Reduced glutathione gets rid of Reactive oxygen species including
hydrogen peroxide.
Reduced Glutathione helps to keep sulfhydryl groups of
haemoglobin protein in the reduced state.

Reduced production of reduced glutathione results in:
1- A decrease in detoxication of peroxides. This causes damage to
RBCs membrane and hemolysis (ending in hemolytic anemia).
2- Hemoglobin protein is denatured forming insoluble masses (Heinz
bodies). Heinz bodies attach to red cell membranes.
Membrane proteins are also oxidized.
Accordingly, red cells become rigid and removed from the
circulation by macrophages in the spleen and liver ending in
anemia

Although Deficiency of G6PD occurs in all cells of affected individual. It is severe in RBCs
because the only pathway to form NADPH in RBCs is pentose phosphate pathway (using
G6PD).
Individuals who have inherited one of the many G6PD mutations do not show clinical
manifestation.
Some of patients with G6PD develop hemolytic anemia if they are exposed or ingest any
oxidizing drugs

G6PD VARIANTS
Most G6PD variants are caused by point mutations in the G6PD
gene.
Some of these point mutations do not disturb the structure of the
enzyme's active site and hence, do not affect enzyme activity.
Other point mutations may lead to production of mutant enzymes
with one or more of the following:
altered catalytic activity
decrease stability
an alteration of binding affinity for NADP+ or Glucose 6-phosphate.

Both G6PD Mediterranean and G6PD A- represent mutant enzymes that differ
from the normal variants by a single amino acid.
This change is due to DNA changes in the form of point mutations or missense
mutations.
Frame shift mutations or large deletions have not been identified indicating
that the complete absence of G6PD is lethal.
Mutation causing non spherocytic hemolytic anemia are clustered near the
carboxyl end of the enzyme, whereas mutations causing milder forms of the
disease tend to be located at the amino end of the enzyme.

CARE OF G6PD PATIENTS
The most important measure is prevention – avoidance of the drugs and foods that
cause hemolysis.
Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may
prevent infection-induced attacks.
In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis
in acute renal failure.
Blood transfusion is an important symptomatic measure, as the transfused red cells are
generally not G6PD deficient and will live a normal lifespan in the recipient's circulation.

Some patients may benefit from splenectomy as this is an important site of
red cell destruction.
Folic acid should be used in any disorder featuring a high red cell turnover.
Although vitamin E and selenium have antioxidant properties, their use does
not decrease the severity of G6PD deficiency.

HEMOLYTIC ANEMIA
 G6PD deficiency cause impraired red blood cells’ transport of oxygen
effectively throughout the body resulting in stress conditions and hence
leading to hemolysis.
 There are other conditions that also caused by G6PD deficiency- neonatal
jaundice, abdominal back pain, dizziness, headache, irregular breathing,
and palpitations.

ASSOCIATED CONDITIONS OF
G6PD DEFICIENCY

NEONATAL HYPERBILIRUBINEMIA IN G6PD
Newborns with G6PD deficiency have a 9% incidence of hyperbilirubinemias.
Estimated at 3.4% incidence, the condition ranges by infant race/ethnicity
(12.2% in African American male infants to nearly 0% in white female infants).
Oxidant stressors, sepsis, and delay in bilirubin elimination (such as co-
inheritance with Gilbert’s disease or persistent enterohepatic recirculation)
add to total plasma or serum bilirubin (TSB) rise, need for phototherapy, and
risk for exchange transfusion.
Vinod K. Bhutani, MD,jaundice due to glucose-6-phosphate dehydrogenase deifciency, NeoReviews Vol.13
No.3 March 2012

CLINICAL PATTERNS OF HYPERBILIRUBINEMIA IN G6PD DEFICIENT
NEONATES
Early-onset hyperbilirubinemia (ie, TSB >75th percentile and increased bilirubin production)
Pre-discharge TSB <75th percentile track exacerbated by starvation, unrecognized sepsis or
late prematurity;
Slow postnatal rise with natural decline
Slow postnatal rise with persistent prolonged unconjugated hyperbilirubinemia, >2 weeks age
Complicated by acute-onset, dramatic hyperbilirubinemia with TSB rise >1 mg/dL per hour
(“favism”).
No.3 March 2012

ELEVATION OF COHB IN G6PD DEFICIENT NEONATES
Within the reticuloendothelial system, hemoglobin releases globin and heme,
which in turn undergo further degradation to release equimolar amounts of
bilirubin and CO.
The CO released then binds strongly to hemoglobin, forming
carboxyhemoglobin (COHb).
Cathy Hammerman, MD and Michael Kaplan, MB, ChB; Recent Developments in the
Management of Neonatal Hyperbilirubinemia.

Because endogenous CO production in the newborn occurs almost exclusively
by this pathway, hemolysis can be quantitated by determining blood COHb
levels.
Elevated COHb levels have been correlated with increased hemolysis in
fetuses and neonates suffering from immune hemolytic disease and even
with kernicterus and death in G6PD-deficient infants.
Cathy Hammerman, MD and Michael Kaplan, MB, ChB; Recent Developments in the
Management of Neonatal Hyperbilirubinemia.

RISK OF SEPSIS
Increased risk of sepsis has also been reported among preterm infants with
G6PD deficiency.
The prevalence of G6PD deficiency among 170 infants with birthweight <2.0
kg admitted to a neonatal intensive care nursery was 5.3%.
Stage 2 necrotizing enterocolitis was 6.9-fold higher (95% CI: 2–23.5)
compared with matched cohort.
Schutzman DL, Porat R. Glucose-6-phosphate dehydrogenase deficiency: another risk factor for necrotizing
enterocolitis? J Pediatr. 2007;151(4):435–437

NEONATAL SCREENING FOR G6PD DEFICIENCY
Newborn screening relies on the accurate (phenotypic) identification of deficient enzyme
activity.
However, variations due to partial genotypic manifestations, postnatal age, and population
of younger, high enzyme activity RBCs are significant confounding factors.
No.3 March 2012

The definitive biochemical test is the spectrophotometric quantitative
enzyme assay based on rate of NADPH formation (mmoles/min/gHb) with
absorbance at 340 nm wavelength and expressed as IU/ gHb.
A useful semi-quantitative screening test, Fluorescent spot test (FST) relies on
the ability of NADPH to fluoresce intensely with exposure to long wave
ultraviolet light.
It lacks the sensitivity to diagnose infants with partial enzyme activity (20%–
60%) including female heterozygotes.

Other tests that detect NADPH such as methylene blue reduction, cresyl blue
dye decolorization, cytochemical staining are also available.
Identification of specific mutations by DNA/polymerase chain reaction (PCR)
screening, ideal for identification of female heterozygotes, is limited by the
diversity of known mutations, time-intensive process and occasional
mismatch with phenotype expression of enzyme activity.

In patients with acute hemolysis, testing for G6PD deficiency may be falsely
negative because older erythrocytes with a higher enzyme deficiency have
been hemolyzed.
Female heterozygotes may be hard to diagnose because of X-chromosome
mosaicism leading to a partial deficiency that will not be detected reliably
with screening tests.

Thus, a two-step approach to measure enzyme functional assay with
concomitant DNA verification seems to be the most accurate and practical
approach to screen, monitor and diagnose neonatal G6PD deficiency.

DRUGS TO
AVOID IN
G6PD
DEFICIENCY

FOOD TO AVOID IN G6PD DEFICIENCY

• One proposed mechanism for an evolutionary advantage afforded by CFTR mutations relates to the virulence of
cholera in affected individuals.
• The etiologic agent, Vibrio cholerae, produces a toxin that constitutively activates guanine nucleotide-binding
proteins that in turn hyperactivate the same chloride channels affected by mutations in the CFTR gene.
• This hyperactivation causes a profound secretory diarrhea.
• In murine model studies, heterozygous mice were less susceptible to the cholera toxin and consequently did not
suffer from symptoms as severe as seen in mice with normal CFTR function.
• It is postulated that this result was due to heterozygous mice having only 50% of the functioning chloride channels
compared with a wild-type mouse.
• The decrease in functioning chloride channel is reduced the mass influx of ions, thus ameliorating diarrhea.
• Research concerning the CFTR chloride channel and its role in intestinal secretions resulted in potentially novel
therapies for cholera.
• The volume of fluid losses seen in cholera cases could be reduced by pharmacologic inhibition of CFTR and
chloride secretions.

Genetic Diseases: Is it sometimes benefits?

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