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Human inherited diseases
• A genetic disorder that is caused by
abnormality in an individual's DNA.
Abnormalities can range from small mutation
in a single gene to the addition or subtraction
of a whole chromosome or set of
chromosomes.
• Incidence: • Nearly 3-5 % of all diseases in general
populations have genetic causes.
Classification
Inherited diseases can be classified into 4 main
groups:
I. Chromosomal disorders
II. Monogenic disorders
III. Multigenic ( multifactorial) disorders
IV. Mitochondrial disorders
1. Chromosomal disorders
Abnormalities in chromosomal numbers or structure
(cytogenetics). Also it is called
chromosome aberrations, which are two types:
Numerical and Structural.
Numerical changes are either polyploidy when the
changes involves a set number of chromosomes or
aneuploidy in which the changes is limited to the
number of individual chromosomes.
The incidence of aneuploidy is usually more common
than polyploidy.
• Polyploidy occurs in humans as triploidy, with
69 chromosomes (sometimes called 69,XXX), or
tetraploidy with 92 chromosomes (sometimes
called 92,XXXX).
• Triploidy, is usually responsible for 17 % of
spontaneous abortions. The main causes
include fertilization with diploid spermatocyte
or the fertilization with a single normal egg by
two sperms.
• In aneuploidy, an extra or missing chromosome
is a common cause of genetic disorders (birth
defects). Some cancer cells also have abnormal
numbers of chromosomes. Aneuploidy occurs
during cell division in the form of monosomies or
trisomies (disomies is normal), when the
chromosomes do not separate properly between
the two cells. This generally happens when the
cytokinesis occurring properly while the
karyokinesis occurring incompletely.
• Usually aneuploidy causes the termination of
developing fetus, but there can be cases of
live birth incidences. The most frequently
extra chromosomes among live births
occurring in numbers 13, 18 and 21.
• An example of a chromosomal aneuploidy is
Down syndrome, or trisomy 21, which is
associated with mental retardation and other
birth defects, such as heart problems.
• Another example is Turner syndrome, which is
caused by the absence of one sex chromosome
(monosomy).
• Although most Turner patients are infertile, there
have been few cases of fertility but these women
have increased risk of chromosomal errors and
high incidence of fetal miscarriage (premature
termination of fetus).
1. Chromosome structural changes involve the loss
or gain of portions in chromosomes, due to :
deletion,
inversion,
duplication and
translocation
2. Monogenic disorders
A genetic mutation that involves single allele on
nuclear chromosome and follows classical Mendelian
inheritance.
The primary genetic defect is usually a point or frame
shift mutations. Such genetic changes may affect the
synthesis of structural or transport protein, receptor,
coagulation factor, immunoglobulin, peptide hormone,
natural inhibitor, or an enzyme. Also called In born
errors of metabolism which means inherited defect
involving one of the steps in certain metabolic pathway.
• The severity of mutation depends on the function
of protein being affected :
• Some mutations can be harmless like pentosuria
& fructosuria (Appearance of pentose and
fructose sugars in urine due to defect in their
metabolisms).
• Others can be harmful due to decreased
formation of an important structural protein like
collagen or receptor protein like LDL receptor or
regulatory natural inhibitor like α1-antitrypsin or
some enzymatic defect in metabolism that causes
one of the following metabolic changes:
1. Decrease in the rate of product
formation
Deficiency of glucose 6-phosphatase. A
liver enzyme in glycogen catabolic pathway
leads to reduced formation of glucose from
glucose-6-phosphate. The genetic disease
is called Von Gierke’s glycogen storage
disease in which liver abnormally
accumulates glycogen without being able
to degrade glycogen into glucose.
2. Decrease in the rate of substrate removal
• The deficiency of phenyl alanine hydroxylase
enzyme leads to accumulation of phenyl alanine
substrate as well as its chemically deaminated
products phenylketones, which appears in urine due
to their excessive formation (Phenylketonuria
disease or PKU). Normally this enzyme converts the
amino acid phenylalanine to the amino acid tyrosine,
therefore patients with PKU have low levels of
tyrosine. The high levels of phenylalanine
metabolites affect neuronal development, which
leads to mental retardation.
• The symptoms associated with this
disease can be prevented by proper
nutrition. Phenylalanine is an amino acid
found in many proteins; therefore,
patients affected with PKU can escape
the disease by strictly limiting themselves
to low protein diets. Providing that PKU
be detected early, a proper nutrition
lacking phenylalanine will prevent the
disease development.
3. Altered feedback control
• Cortisol hormone is synthesized in the adrenal
gland from cholesterol in a pathway requires the
enzyme 21-hydroxylase.Excessive formation of
cortisol can inhibit this pathway by feedback
inhibition.
• Deficiency of 21-hydroxylase enzyme causes
reduced formation of cortisol which stops the
feedback control mechanism and leads to
increase secretion of adrenocorticotrophic
hormone (ACTH) in a disease called Congenital
adrenal hyperplasia.
21-Hydroxylase
Cholesterol  Cortisol
CRH=Corticotropin releasing hormone
Pedigree
It is a family of genetic tree which describes
the interrelationship between parents &
children for a particular trait.
The pedigree not only gives genetic
information about the history of the family for
certain trait, but also can predict to some
extent the segregation of this trait in future
generations.
In a pedigree, the following symbols are used:
Squares(□)→ Males
Circles (○) → Females .
Horizontal lines connect male and female→
mating.
Vertical lines extending downward from a
couple→ their children.
Dark color → individuals affected by the disease
White color→ healthy individuals.
Mode of inheritance for monogenic disorders:
• The mode of inheritance for monogenic disorders
can be either autosomal dominant or autosomal
recessive or sex linked.
1-Autosomal dominant disorder
Autosomal ( defective gene is present on one of the
22 somatic( non-sex ) chromosome pairs).The
phenotypic properties of the dominant disorder
(symptoms) will appear even when the individual
has mutation in only one copy of the two gene
alleles ( heterozygous) .In fact the homozygous state
of this dominant mutation is usually lethal causing
spontaneous abortion in pregnant women.
• Males and females are affected with
equal frequency, which can occur in each
generation. The child of an affected
individual has a 50 % risk of inheriting
the mutated gene.
• The trait does not skip a generation.
• Where one parent is affected, about half
of the progeny will be affected.
Selected examples
• Familial hyperlipidemia: Abnormal increase
of all lipid fractions in plasma.
• Familial hypercholesterolemia: Abnormal
increase of cholesterol in plasma
• Spherocytosis: Hemolytic type of anemia
due to the formation of abnormal spherical
RBC shape instead of the normal disc shape.
Pedigree of autosomal dominant trait
• Example. Wooly hair results from a dominant
allele; therefore, individuals who are
homozygous dominant (WW) or heterozygous
(Ww) have this trait. Individuals who are
homozygous recessive (ww) for this gene have
normal hair. The man at the top of the pedigree
has normal hair, so his genotype is ww. His wife
has wooly hair, but must be heterozygous (Ww)
since three of their six children have normal hair.
Wooly hair
2-Autosomal recessive disorders
• These disorders range in severity from traits
that are mild such as Albinism to those very
severe like Cystic fibrosis.The heterozygous
individual of this mutation is a normal carrier
or some times shows mild clinical symptoms
(e.g.Thalasemia).Thus recessively autosomal
disorder shows up a disease symptoms only in
the homozygous individuals who inherit one
recessive allele from each parent.
• The majority of individuals affected with
recessive disorders are born to normal parents
who are both carriers. These individuals carry
25 % risk of disease incidence compared with
25 % chance of normal genotype and 50 %
probability of a heterozygous carriers. If one
of the parent is a carrier and the other is
homozygous for the recessive defect then the
probability of disease is increased to 50 % for
each child.
• The clinical expression of autosomal recessive
disorders is usually more predictable than in
autosomal dominant disorders. That is most
recessively mutated alleles lead to a complete
or partial loss of protein functions. In addition,
lethal alleles are more common in recessive
than in autosomal dominant inheritance
because the effects of lethal allele are masked
in the heterozygous state.
Selected examples
• Phenylketonuria
• Thalasemia = Defective hemoglobin due to the
formation of short α or β chains resulted from
frame shift mutation.
• Sickle cell disease= Abnormal precipitation of
hemoglobin due to substitution mutation in βchains of hemoglobin that change the shape of
hemoglobin to curved shape instead of disk
shape.
Pedigree for autosomal recessive disorder
• This figure shows the pattern of albinism
inheritance that can be observed for a
recessive trait. The half-filled symbols
indicate carriers (heterozygotes). An
individual expressing a recessive trait
(homozygous recessive) may not appear in
every generation.
3. Sex –linked disorders
• Genes carried either on the y or x sex
chromosomes are said to be sex linked.
Disorders, which are transmitted as y- linked,
are very rare. In contrast, the x-linked
defective alleles can be inherited as x- linked
either recessive or dominant disorders
similar to that of the autosomal genetic
transmittance.
• As females have two x-chromosomes
they will be unaffected carriers of xlinked recessive disease, unless they are
homozygous for the mutated allele(very
rare).However males who have only one
copy of the x chromosome will develop
the clinical symptoms of the disease from
the mutated allele.
Selected examples
• Hemophilia: defect in one of the clotting
factors in blood
• Duchenne muscular dystrophy: defect in
membrane protein called dystrophine,
which is present in muscle cells. The
defect leads to muscle weakening.
X-Linked Recessive Pedigree
• Completely affected mother can pass the
disease to their sons, but the daughters will
remain carriers.
X-Linked dominant
• The x-linked dominant disorder is rare, which
shows the clinical symptoms in the heterozygous
female or in a male with single copy of the
mutated allele.
• Both Males and Females carrying a single copy
of the allele are affected. Females will pass the
disease to half of their children in a sexunspecific manner. Males will pass the disease to
all their daughters but none to their sons.
• An X-linked dominant form of the
disease hypophosphatemia (a form of
rickets) exists. This disease occurs due
to an excess excretion of phosphates
from the body, which results in bones
being unable to properly calcified and
having short stature.
• Y-Linked dominant
• Males always affected by the disease
because they carry a copy of the
mutated allele. All sons inherited the
disease from their fathers while
daughters are free of the disease.
• Y-linked diseases are generally rare because
there are very few genes present on this
relatively small chromosome. Only those genes
important to spermatogenesis are mainly found
on this chromosome, and therefore their defect
is linked to male infertility.
• One such condition, Sertoli syndrome, results in
the complete absence of the germ cells in the
male testis.
END