GENETIC

DISORDERS
 DISEASES
• GENETIC
• ENVIRONMENTAL
• BOTH
• The completion of the human genome project
has been a landmark event in the study of
human diseases
• We now know that humans have only about
30,000 genes
• The unraveling of our "genetic architecture"
promises to unlock secrets of inherited as well
as acquired human disease, since ultimately all
diseases involve changes in gene structure or
expression
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Human diseases- into three categories:
(1)Those that are genetically determined,
(2)Those that are almost entirely
environmentally determined, and
(3)Those to which both nature and nurture
contribute

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• Despite the complexities of this nature-
nurture interplay, there is little doubt that
nature (i.e., the genetic component) plays a
major, if not the determining, role in the
occurrence and severity of many human
diseases

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• Surveys indicate that as many as 20% of the
pediatric inpatients in university hospitals
suffer from disorders of genetic origin

• Chromosomal aberrations have been

identified in as many as 50% of spontaneous
abortuses during the first trimester, and many
more abortuses probably had gene mutations

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• Hereditary, familial, and congenital
• Hereditary disorders, by definition, are derived
from one's parents, are transmitted in the
gametes through the generations, and therefore
are familial.
• The term congenital simply implies "present at
birth."
• It should be noted that some congenital diseases
are not genetic
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Fundamental concepts
MUTATIONS :
 Mutation refers to permanent changes in the
DNA.
 Those that affect germ cells are transmitted to
the progeny and may give rise to inherited
diseases.
 Mutations in somatic cells are not transmitted
to the progeny but are important in the
causation of cancers and some congenital
malformations
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Nonsense mutation
Substitution of a single DNA base that results in
a stop codon, thereby leading to the truncation
of a protein.(too short and non functional)
Penetrance
• The likelihood that a person carrying a
particular mutant gene will have an altered
phenotype.

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Phenotype
• The clinical presentation or expression of a
specific gene or genes, environmental factors,
or both.
Silent mutation
Substitution of single DNA base that produces
no change in the amino acid sequence of the
encoded protein.
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Stop codon
• A codon that leads to the termination of a
protein rather than the addition of an amino
acid.
• The three stop codons are TGA, TAA, and TAG.

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 Classification
1) Genome mutation – loss or gain of whole
chromosome (monosomy , trisomy)
2) Chromosome mutation – rearrangement of
genetic material & give rise to visible
structural changes in chromosome
3) Gene mutation – majority of mutation with
hereditary disease
– Results in partial or complete deletion of gene,
more often affect single gene

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• Point mutations result from the substitution of a
single nucleotide base by a different base, resulting
in the replacement of one amino acid by another in
the protein product
– Missense mutations Vs nonsense mutations
• Frameshift mutations occur when the insertion or
deletion of one or two base pairs alters the reading
frame of the DNA strand
– If the number of base pairs involved in a deletion is three
or a multiple of three, frameshift does not occur

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• Trinucleotide repeat mutations - these
mutations are characterized by amplification
of a sequence of three nucleotides.
• All affected sequences share the nucleotides
guanine (G) and cytosine (C).
– Eg, in fragile X syndrome, there are 250 to 4000
tandem repeats of the sequence CGG within a
gene called FMR1. In normal populations, the
number of repeats is small, averaging 29
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Point mutation

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Frameshift mutation

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• Four categories of genetic disorders
1.Those related to mutant genes of large effect
(mendelian disorders)
2.Diseases with multifactorial (polygenic)
inheritance
3.Those arising from chromosomal aberrations
(cytogenetic disorders)
4.Single gene disorders with non classic
inheritance

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 MENDELIAN DISORDERS (DISEASES
CAUSED BY SINGLE-GENE DEFECTS)
• Single-gene defects (mutations) follow the
well-known mendelian patterns of inheritance
• Thus, the conditions they produce are often
called mendelian disorders
• Altogether they account for approximately 1%
of all adult admissions to hospitals and about
6% to 8% of all pediatric hospital admissions

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 Terminology
• Genetic heterogeneity – mutations at several
genetic loci may produce the same trait

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• Mutations involving single genes follow one of
three patterns of inheritance:
1.Autosomal dominant
2.Autosomal recessive
3. X-linked

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 1.Autosomal dominant disorders
• The mutated gene is dominant to its allele, so the
presence of the abnormal gene inevitably causes
disease
• Mutations affect either structural proteins such
as collagen or receptor protein
• Eg. neurofibromatosis, polyposis coli, adult
polycystic kidney
• Clinical features can be modified by reduced
penetrance & variable expressivity
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 AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES
• NEITHER parent may have the disease (NEW mut.)
• REDUCED PENETRANCE (environment?, other
genes?)
• VARIABLE EXPRESSIVITY (environment?, other
genes?)
• May have a DELAYED ONSET
• Usually result in a REDUCED PRODUCTION or
INACTIVE protein
• Some generations NOT skipped
AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

 2. Autosomal recessive disorders
• The mutated gene is recessive to its allele
• Occur only when both alleles are abnormal
• Heterozygous carriers are usually normal (no
clinical problems)
E.g. Recessive mental retardation, congenital
deafness, cystic fibrosis, sickle cell anemia,
glycogen storage diseases

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 Characterstics
• The trait does not affect the parents, but siblings
may show the disease
• Siblings have one chance in 4 of being affected
• Expression of the defect tends to be more uniform
than ADD
• Complete penetrance is common
• Onset is frequently seen early in life
• ARD includes almost all inborn errors of metabolism

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 AUTOSOMAL RECESSIVE
• Disease is in HOMOZYGOTES
• More UNIFORM expression than AD
• Often COMPLETE PENETRANCE
• Onset usually EARLY in life
• NEW mutations rarely detected clinically
• Proteins show LOSS of FUNCTION
• Include ALL inborn errors of metabolism
• MUCH more common that autosomal dominant
• Some generations are SKIPPED
AUTOSOMAL RECESSIVE PEDIGREE

1) BOTH SEXES
INVOLVED

2) GENERATIONS
SKIPPED
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3. X-linked disorders:
Mutated gene is located on X chromosome
a) X-linked recessive disorders: recessive gene
on X-chromosome will manifest in male but
not in female
• The female is protected by the normal allele
on the second X chromosome, only acts as a
carrier
E.g. Red-green color blindness, hemophilia,
Duchene muscular dystrophy

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 SEX LINKED PEDIGREE

1) MALES ONLY, sons of affected males are OK

2) GENERATION SKIPPING DOESN’T MATTER
b) X-linked dominant disorders: both males and
females have the disease and transmit the
gene, and it appears in any generation
Eg. vitamin D resistant rickets

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 Biochemical & molecular basis of
single gene disorder
Classification
1) Enzyme defects & their consequence
2) Defects in membrane receptors & transport
system
3) Alterations in structure, function or quality
of non enzyme protein
4) Mutations resulting in unusual reaction to
drug
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1. Enzyme defects & their consequence
• Reduced activity Vs reduced amount of enzyme
• Three major consequences
A. Accumulations of substrate
- Excessive accumulation of complex substrates with
lysosome as a result of deficiency of degradative enzyme
is called lysosomal storage disease
B. Decreased amount of end product e.g. Albinism
C. Failure to inactivate a tissue damaging substrate
e.g. α1 antitrypsin unable to inactivate neutrophil
elastase ---- pulmonary emphysema

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 Disorders associated with defects in
enzyme
Lysosomal storage disease
• Lysosome – intracellular digestive tract
contains hydrolytic enzyme (in acidic meliew)
• Deficiency of function of lysosomal enzyme
lead to partially degraded insoluble
metabolite with in lysosome so this organelle
become large & numerous enough to
interfere with normal cell function →
lysosomal storage disease

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 Classification
• Based on the biochemical nature of
accumulated metabolite
– Glycogenoses
– Lipidoses (sphingolipidoses)
– Mucopolysaccharidoses
– Mucolipidoses
* Read on lysosomal storage diseases!!

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 2. Defects in membrane receptors &
transport system
• Many biologically active substances have to
be actively transported across the cell
membrane which is achieved by either
receptor mediated endocytosis or by
transport protein
• Eg. Reduced synthesis of LDL receptors

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 Disorders associated with defects in
receptor proteins
Familial hypercholesterolemia

• Is a "receptor disease" that is the consequence of a mutation

in the gene encoding the receptor for low density lipoprotein
(LDL), which is involved in the transport and metabolism of
cholesterol.

• Heterozygous mutant gene (1:1500) individuals have 2-3 fold

elevation of cholesterol lead to tendinous xantomas &
atherosclerosis
• Homozygous mutant- 5-6 fold plasma cholesterol elevation
– Develops skin xantomas, coronary, cerebral & peripheral vascular
atherosclerosis, MI before age 20.

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 3. Alterations in structure, function or
quality of non enzyme protein
• Genetic defects resulting in alteration of non
enzyme protein often have wide spread
secondary effects
• eg. Sickle cell disease ( defect in structure of
globulin molecule)

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 4.Disorders associated with defects in
structural proteins
Marfan syndrome
• Disorder of connective tissue of the body,
manifested principally by changes in skeleton,
eye & CVS
• Prevalence- 1:1500, 70-80% familial ADD
• Pathogenesis – defects in an extracellular
glycoprotein called fibrillin 1
• Fibrillin is particularly abundant in the aorta,
ligaments, and ciliary zonules of the lens
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 Morphology
• Skeletal abnormality
– Tall exceptionally long extremities & long tapering fingers
& toes
– Ratio upper segment to lower segment is lower
– Long head (dolichocephalic)
– Spinal deformities (kyphosis, scoliosis…)
– Chest (pectus excavatum or pigeon chest)
• Ocular changes –bilateral subluxation or dislocation
of the lens ( ectopia lentis ) out ward & upward lens
• CVS – mitral valve prolapse & dilation of ascending
aorta
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• In addition to these features, Marfan patients
have defects in the skin, skeletal muscles, and
lungs.
• "Stretch marks" occur in areas of flexural
stress; muscle appears myopathic with loss of
bulk and hypotonia; damage to the connective
tissue in lungs may manifest as spontaneous
pneumothorax

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• Although the lesions just described typify
Marfan syndrome, it must be emphasized that
there is great variation in the clinical
expression.
• Clinical diagnosis is based on major
involvement of two of the four organ systems
(skeletal, cardiovascular, ocular, and skin) and
minor involvement of another organ

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 CYTOGENETIC DISORDERS
• It is estimated that approximately one of 200
newborn infants has some form of chromosomal
abnormality
• It is estimated that in 50% of first-trimester
abortions, the fetus has a chromosomal
abnormality
• Cytogenetic disorders may result from alterations
in the number or structure of chromosomes and
may affect autosomes or sex chromosomes
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• In humans, the normal chromosome count is
46 (i.e., 2n = 46)
• Any exact multiple of the haploid number (n)
is called euploid
• Chromosome numbers such as 3n and 4n are
called polyploid. Polyploidy generally results
in a spontaneous abortion
• Any number that is not an exact multiple of n
is called aneuploid

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• karyotyping is the basic tool of the
cytogeneticist
• A karyotype is a photographic representation
of a stained metaphase spread in which the
chromosomes are arranged in order of
decreasing length.

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Numeric Abnormalities :Alteration in the
number of chromosomes
1. Aneuploidy: trisomy(2n+1),monosomy(2n-1)
2. Polyploidy
3. Mosaicism: presence of more than one
population of cells, one with normal
chromosomes the other with extra or missing
chromosomes

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Structural Abnormalities (aberrations of
chromosomes)
 Deletion: loss of a terminal or insertional
segment of chromosome.
 Translocation: transfer of a segment of one
chromosome to another
 Isochromosome: one arm, short or long, is lost
and the remaining arm is duplicated resulting in a
chromosome of two short arms only or of two
long arms
 Inversions: arise from 2 chromosomal breaks
with inversion through 180 degree of the
segment between breaks

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• Pericentric inversions result from breaks on
opposite sides of the centromere; whereas
• paracentric inversions involve breaks on the
same arm of the chromosome

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A. Syndromes associated with sex
chromosomes abnormalities:
1)klinefelter’s syndrome:
 Male with karyotype(47,xxy):the syndrome is
characterized by infertility, atrophic testis,
gynecomastia.
 Male hypogonadism /hypo function of testis

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 KLINEFELTER (XXY, XXXY, etc.)

• Hypogonadism found at puberty

• #1 cause of male infertility
• NO retardation unless more X’s
• 47, XXY 82% of the time
• L----O----N----G legs, atrophic testes,
small penis
 2)Turner’s syndrome:
 Female with karyotype(45,x),the syndrome is
characterized by atrophic ovaries, infantile
external genitalia, lack of secondary sexual
characteristics
 Female hypogonadism/ hypo function of
ovary

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 TURNER (XO)
• 45, X is the “proper” designation
• Mosaics common
• Often, the WHOLE chromosome is not
missing, but just part
• NECK “WEBBING”
• EDEMA of HAND DORSUM
• CONGENITAL HEART DEFECTS most
FEARED
3)47,xxx syndrome: Female showing normal
physical and reproductive development, there
may be difficulty in auditory perception and
receptive and expressive language skills
4)47,xyy syndrome: Tall male with no apparent
abnormality in physical and reproductive
development, there may be a risk of criminal
behavior

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 B. Syndromes associated with
Autosome abnormalities:
Trisomy 21 (Down syndrome)
• Most common & major cause of mental
retardation
• Chromosome count is 47, most other has
normal chromosome with translocation
• Maternal age influence in the incidence of
Down’s
• 1% cases, mosaics – no maternal age influence
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• Nondisjunction is a failure of paired
chromosomes or chromatids to separate and
move to opposite poles of the spindle at
anaphase, during mitosis or meiosis.
• Numerical chromosomal abnormalities arise
primarily from nondisjunction.

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 Diagnosis
• Flat facial profile, oblique palpebral fissures &
epicantal fold
• Mental retardation
• Congenital heart disease --- endocardial cushion
• GI atresia
• ALL --- 20 fold ↑
• Infection
*READ -- Other trisomies – Trisomy 18 (Edward syndrome)
- Trisomy 13 (patau syndrome)
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 DISORDERS WITH MULTIFACTORIAL INHERITANCE

• A multifactorial physiologic or pathologic trait may be defined

as one governed by the additive effect of two or more genes
of small effect, conditioned by environmental, nongenetic
influences
• The genetic component exerts a dosage effect
• Environmental influences, however, significantly modify the
phenotypic expression of multifactorial traits
• The following features characterize multifactorial inheritance
 The risk of expressing a multifactorial disorder is conditioned
by the number of mutant genes inherited.
 The rate of recurrence of the disorder (in the range of 2% to
7%) is the same for all first-degree relatives (i.e., parents,
siblings, and offspring) of the affected individual.
 The likelihood that both identical twins will be affected is
significantly less than 100% but is much greater than the
chance that both nonidentical twins will be affected.
 The risk of recurrence of the phenotypic abnormality in
subsequent pregnancies depends on the outcome in previous
pregnancies.
 Disorders
 Cleft lip or cleft palate (or both)
 Congenital heart diseases
 Coronary heart diseases
 Hypertension
 Gout
 Diabetic mellitus
 Pyloric stenosis
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