About pathology of Heredity and Congenital diseases

1. Etiology and
Pathogenesis of Heredity
and Congenital Diseases
NAME: MUHAMMAD FAISAL MUKHTAR
SUBJECT: PATHOLOGICAL PHYSIOLOGY

2. Hereditary Disorders and Congenital Diseases
Hereditary Disorder:
Hereditary disorders are derived from one’s parents, are transmitted in
the gametes through the Generations, and therefore are familial.
Congenital Diseases:
The term simply implies “present at birth”.
Of note, some congenital diseases are not genetic (e.g., congenital
syphilis). On the other hand not all genetic disorders are congenital; the
expression of Huntington disease, for example, begins only after the 3rd
or 4th decade of life.

3. Hereditary Disorders and Congenital
Diseases

4. Alterations in Protein-Coding Genes Other
than Mutation
Mendelian Disorders:
• Single-gene defects follow the well-known mendelian patterns of inheritance.
Although individually rare, together they account for approximately 1% of all
adult admissions to hospitals and about 6 to 8% of all pediatric hospital
admission.
• Mutations involving single genes follow one of three patterns of inheritance
Autosomal Dominant
Autosomal Recessive
X-linked

5. Disease Abnormal Protein Protein Type/ Function
Autosomal Dominant Inheritance
Familial Hypercholesterolemia LDL receptor Receptor Transport
Marfan Syndrome Fibrillin Structural Support, Extracellular Matrix
Ehler-Danlos Syndrome Collagen Structural Support, Extracellular Matrix
Hereditary Spherocytosis Spectrin, Ankyrin or Protein 4.1 Structural Support, Red Blood Cell Membrane
Neurofibromatosis, type 1 Neurofibromin-1 (NF-1) Growth Regulation
Adult Polycystic Kidney Disease Polycystin (PKD-1) Cell-Cell & Cell-Matrix Interactions
Autosomal Recessive Inheritance
Cystic Fibrosis Cystic Fibrosis Transmembrane Regulator Ion Channel
Phenylketonuria Phenylalanine Hydroxylase Enzyme
Tay-Sachs Disease Hexosaminidase Enzyme
Severe Combined Immunodeficiency Adenosine Deaminase Enzyme
α- and β-Thalassemias Hemoglobin Oxygen Transport
Sickle Cell Anemia Hemoglobin Oxygen Transport
X-Linked Recessive Inheritance
Hemophilia Factor VIII Coagulation
Duchenne/Becker Muscular Dystrophy Dystrophin Structural Support, Cell Membrane
Fragile X Syndrome FMRP RNA Translation

6. Transmission Patterns of Single-Gene
Disorders
DISORDERS OF AUTOSOMAL
DOMINANT INHERITANCE
 With any autosomal dominant disorder, some
patients do not have affected parents. Such
patients owe their disorder to new mutations
involving either the egg or sperm which they
were derived.
 Clinical features can be modified by reduced
penetrance and variable expressivity. Some
persons inherit the mutant gene but are
phenotypically normal, a phenomenon
referred to as reduced penetrance. In
contrast with penetrance, if a trait is
consistently associated with a mutant gene but
is expressed differently among persons
carrying the gene, the phenomenon is called
variable expressivity.
DISORDERS OF AUTOSOMAL
RECESSIVE INHERITANCE
 The trait does not usually affect the parents,
who are carriers of one diseased allele, but
multiple siblings may show the disease
 Siblings have one chance in four being
affected (i.e., the recurrence risk is 25% for
each birth); and
 If the mutant gene occurs with a low
frequency in the population, there is a strong
likelihood that the affected patient (the
proband) is the product of a consanguineous
marriage. They make up the largest group of
mendelian disorders.

7. Transmission Patterns of Single-Gene Disorders
• In contrast with the features of autosomal dominant diseases, the following features
generally apply to most autosomal recessive disorders:
The expression of the defect tends to be more uniform than in autosomal dominant
disorders.
Complete penetrance is common.
Onset is frequently early in life.
Although new mutations for recessive disorders do occur, they are rarely detected
clinically. Because the affected person is an asymptomatic heterozygote, several
generations may pass before the descendants of such a person mate with other
heterozygotes and produce affected offspring.
In many cases, enzymes are affected by the mutation. In heterozygotes, equal amounts of
normal and defective enzyme are synthesized. Usually the natural “margin of safety”
ensures that the cells with half of their complement of the enzyme functions normally.

8. Transmission Patterns of Single-Gene Disorders
• X-Linked Disorders:
The Y chromosome is home to the testes-determining gene SRY, which directs male
sexual differentiation, but apart from very rare instances of Y-linked familial deafness,
no Y chromosome-linked mendelian disorders have ever been reported. Thus, for most
part, sex-linked disorders are X-linked. Most X-linked disorders are X-linked
recessive and are characterized by
Heterozygous female carriers transmit them only to sons, who of course hemizygous
for the X chromosome.
Heterozygous females rarely express the full phenotypic change, because they have
the paired normal allele. Although one of the X chromosome in females is
inactivated, this process of inactivation is random, which typically allows sufficient
numbers of cells with the normal expressed allele to emerge.
An effected male doesn't transmit the disorder to sons, but all daughters are carriers.
Sons of heterozygous women have one chance in two of receiving the mutant gene.

9. Diseases Caused by Mutations in Genes
Encoding Structural Protein
• Marfan Syndrome:
Marfan syndrome is an autosomal dominant disorder of connective tissues,
manifested principally by changes in the skeleton, eyes, and cardiovascular system. It
is caused by an inherited defect in an extracellular glycoprotein called fibrillin-1.
Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin, which
is required for structural integrity of connective tissues and activation of TGF-β.
Clinical features may include tall stature, long fingers, bilateral subluxation of lens,
mitral valve prolapse, aortic aneurysm, and aortic dissection.
Prevention of cardiovascular disease involves the use of drugs that lower blood
pressure and inhibit TGF-β signaling.
70-85% of cases are familial, and the rest are sporadic, arising from de novo FBN1
mutations in the germ cells of parents.

10. Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (EDSs) are a
group of diseases characterized by
defects in collagen synthesis or structure.
Clinical features may include fragile,
hyperextensible skin vulnerable to
trauma, hypermobile joints, and ruptures
involving colon, cornea, or large arteries.
Wound healing is poor.
There are six variants of EDS
Tissues rich in collagen, such as skin,
ligaments, and joints, frequently are
affected in most variants of EDS.
Skin fragility. The skin is extraordinarily
stretchable, extremely fragile, and
vulnerable to trauma.
Structural failure of organ or tissues. The
structural defect in connective tissue may
lead to serious internal complications,
including rupture of the colon etc.
Deficient synthesis of type III collagen
resulting from mutations affecting the
COL3A1.
Deficiency of the enzyme lysyl
hydroxylase.
Deficient synthesis of type V collagen
resulting from mutations in COL5A2 is
inherited as an autosomal dominant
disorder and results in classical EDS.

11. Diseases Caused by Mutations in Genes
Encoding Receptor Protein or Channels
• Familial Hypercholesterolemia:
Familial Hypercholesterolemia is a
“receptor disease” caused by loss-of-
function mutations in the gene encoding the
LDL receptor, which is involved in the
transport and metabolism of cholesterol.
As a consequence of receptor abnormalities
there is a loss of feedback control that
normally holds cholesterol synthesis in
check. Resulting elevated levels of
cholesterol induce premature
atherosclerosis and greatly increase the risk
of myocardial infraction. Familial
Hypercholesterolemia is among the most
common mendelian disorders.
• The amount of plasma cholesterol
(7% of total cholesterol) is
influenced by its synthesis and
catabolism, and the liver plays a
crucial role in both these process.

12. Familial Hypercholesterolemia
• Pathogenesis:
 In familial hypercholesterolemia, mutations in
the LDL receptor protein impair the
intracellular transport and catabolism of LDL,
resulting in accumulation of LDL cholesterol
in the plasma. In addition, the absence of LDL
receptors on liver cells impairs the transport
of IDL into the liver, so a greater proportion
of plasma IDL is converted into LDL.
 The patient of familial hypercholesterolemia
develop the excessive level of serum
cholesterol as a result of the combined effects
of reduced catabolism and excessive
biosynthesis.
 Analysis of cloned LDL receptor gene has
shown that more than 900 different mutations
can give rise to familial hypercholesterolemia.
 These can be divided into five categories.
1) Class 1 mutations are uncommon, and they
are associated with complete loss of
receptor synthesis.
2) With class 2 mutations, the most prevalent
type, the receptor protein is synthesized,
but its transport from the endoplasmic
reticulum to Golgi Apparatus is impaired
because of defects in protein folding.
3) Class 3 mutations produce receptors that
are transported to the cell surface but fail to
bind LDL normally.
4) Class 4 mutations give rise to receptors that
fail to internalize within clathrin pits after
binding to LDL.
5) Class 5 mutations encode receptors that can
bind LDL and are internalize but are
trapped in endosomes because dissociation
of receptor and bound LDL doesn’t occur.

13. Familial Hypercholesterolemia
• The discovery of the critical
role of LDL receptors in
cholesterol homeostasis has led
to the rational design of the
stain family of drugs that are
now widely used to lower
plasma cholesterol. They inhibit
the activity of HMG-CoA
reductase and thus promote
greater synthesis of LDL
receptors.

14. Cystic Fibrosis
• CF is an autosomal recessive disease caused by mutation in the CFTR gene encoding
the CF transmembrane regulator.
• The principal defect is chloride ion transport, resulting in high salt concentrations in
sweat and viscous luminal secretions in respiratory and gastrointestinal tract.
• CFTR mutations can be severe, resulting in multisystem diseases.
• Pancreatic insufficiency is extremely common; infertility caused by congenital
bilateral absence of vas deferens in characteristic finding in adult patients with CF.
• Liver disease, including cirrhosis is increasing in frequency as life expectancy
increases.
• Molecular therapies that enhance the transport or stability of mutant CFTR protein
are useful in patients who harbor certain CFTR alleles.

15. Cystic Fibrosis
PATHOGENESIS CLINICAL FEATURES

16. Diseases Caused by Mutations in Genes
Encoding Enzyme Proteins
Phenylketonuria:
• PKU is an autosomal recessive
disorder caused by a lack of the
enzyme phenylalanine hydroxylase and
a consequent inability to metabolize
phenylalanine.
• Clinical features include severe mental
retardation, seizures, and decreased
pigment of skin.
• Female patients with PKU who
discontinue dietary treatment can give
birth to children with malformations
and neurologic impairment resulting
from transplacental passage of
phenylalanine metabolites.

17. Galactosemia
• Galactosemia is an autosomal
recessive disorder of galactose
metabolism resulting from a mutation
in the gene encoding the enzyme
galactose-1-phosphate
uridyltransferase (GALT).
• The liver, eyes and brain bear the brunt
of the damage. Nonspecific alterations
appear in the CNS, including loss of
nerve cells, gliosis, and edema. Almost
from the birth, affected infants fail to
thrive. Vomiting and diarrhea appear
within a few days of milk ingestion.
Jaundice and hepatomegaly usually
become evident during the 1st week of
life.
• Accumulation of galactose and
galactose-1-phosphate in the kidney
impairs amino acid transport, resulting
in aminoaciduria. Fulminant
Escherichia Coli septicemia occurs
with increased frequency.

18. Lysosomal Storage Disease
• Lysosomes, the digestive system of the
cells, contain a variety of hydrolytic
enzymes that are involved in breakdown
of complex substrates, such as
sphingolipids and mucopolysaccharides,
into soluble end products.
• These large molecules may be derived
from the turnover of intracellular
organelles that enter the lysosomes by
autophagy, or they may be acquired
from outside the cell by phagocytosis.
• With an inherited lack of lysosomal
enzyme, catabolism of its substrate
remains incomplete leading to
accumulation of partially degraded
insoluble , metabolites within lysosomes.
This is called primary storage.

19. Lysosomal Storage Disease
• Approximately 60 lysosomal storage diseases have been identified. These may result from
abnormalities of lysosomal enzymes or proteins involved in substrate degradation, endosomal
sorting, or lysosomal membrane integrity. Although the combined frequency of lysosomal storage
disorders (LSDs) is about 1 in 5000 live births, lysosomal dysfunction may be involved in the
etiology of several more-common diseases.
• Despite the complexity, certain features are common to most diseases in this group
 Autosomal recessive transmission
 Patient population consisting of infants and young children.
 Storage of insoluble intermediates in the mononuclear phagocyte system, giving rise to
hepatosplenomegaly.
 Frequent CNS involvement with associated neuronal damage.
 Cellular dysfunction caused out not only by storage of undigested material, but also a cascade of
secondary events, for example, macrophage activation and release of cytokines.

20. Classification of Lysosomal Storage Disease
Disease Enzyme Deficiency Major Accumulating Metabolites
Glycogenosis, type 2-Pompe Disease α-1,4-Glucosidase (lysosomal glucosidase) Glycogen
Sphingolipidoses
GM1 gangliosidosis
Type 1___ infantile, generalized
Type 2___ juvenile
GM1 ganglioside β-galactosidases GM1 ganglioside, galactose-
containing oligosaccharides
GM2 gangliosidosis
Tay-Sachs disease
Sandhoff disease
GM2 gangliosidosis variant AB
Hexosaminidase, α subunit
Hexosaminidase, β subunit
Ganglioside activator protein
GM2 ganglioside
GM2 ganglioside, globoside
GM2 ganglioside
Sulfatidoses
Metachromatic leukodystrophy Arylsulfatase A Sulfatide
Multiple Sulfatase deficiency Arylsulfatase A, B,C; steroid sulfatase;
iduronate sulfatase, hepran, N-sulfatase
Sulfatide, steroid sulfate, dermatan
sulfate
Krabbe disease Galactosylceramidase Galactocerebroside
Fabry disease α-Galactosidase A Ceramide trihexoside
Gaucher disease Glucocerebrosidase Glucocerebroside
Niemann-Pick disease, types A&B Sphingomyelinase Sphingomyelin

21. Classification of Lysosomal Storage Disease
Disease Enzyme Deficiency Major Accumulating Metabolites
Mucopolysaccharidoses(MPSs)
MPS 1 H (Hurler) α-L-Iduronidase Dermatan sulfate, Heparan Sulfate
MPS 2 (Hunter) I-Iduronosulfate sulfatase Dermatan sulfate, Heparan Sulfate
Mucolipidoses (MLs)
I-cell disease (ML2) and
pseudo-Hurler
polydystrophy
Deficiency of phosphorylating enzymes essential for the
formation of mannose-6-phosphate recognition marker;
acid hydrolases lacking the recognition marker can't be
targeted to the lysosomes but are secreted extracellularly
Mucopolysaccharide, glycolipid
Other diseases of complex carbohydrates
Fucosidosis α-Fucosidase Fucose-containing sphingolipids and
glycoprotein fragements
Mannosidosis α-Mannosidase Mannose-containing oligosaccharides
Aspartyglycosaminuria Aspartylglycosamine amide hydrolase Aspartyl-2-deoxy-2-acetamido-
glycosylamine
Other lysosomal storage diseases
Wolman disease Acid lipase Cholesterol esters, triglycerides
Acid phosphate deficiency Lysosomal acid phosphatase Phosphate esters

22. Lysosomal Storage Disease

23. Glycogen Storage Diseases (Glycogenoses)
• An inherited deficiency of anyone of the enzymes involved in glycogen synthesis or degradation can
result in excessive accumulation of glycogen or some abnormal form of glycogen, predominantly in
liver or muscles or in all tissues.
• In the hepatic form (von Gierke disease), liver cells store glycogen because of a lack of hepatic,
glucose-6-phosphatase.
• There are several myopathic, forms, including McArdle disease, in which lack of muscle
phosphorylase gives rise to storage in skeletal muscles and cramps after exercise.
• In pompe disease there is lack of lysosomal acid maltase, and all organs are effected but heart
involvement in predominant.
• Subgroups of glycogenosis
 Hepatic Type
 Myopathic Type
 Miscellaneous Type

24. Principal Subgroups of Glycogenoses
Clinicopat
hologic
Category
Specific
Type
Enzyme
Deficiency
Morphologic Changes Clinical Features
Hepatic
Type
Hepatore
nal (von
Gierke
disease,
type1)
Glucose-6-
phosphatase
Hepatomegaly: intracytoplasmic
accumulations of glycogen and small
amounts of lipid; intranuclear glycogen
Renomegaly: intracytoplasmic
accumulations of glycogen in cortical tubular
epithelial cells
In untreated patients, failure to thrive, shunted growth,
hepatomegaly and renomegaly
Hypoglycemia resulting from failure of glucose
mobilization, often leading to convulsions
Hyperlipidemia and hyperuricemia resulting from
deranged glucose metabolism; many patients develop
gout and skin xanthomas
Bleeding tendency caused by platelet dysfunction
Myopathic
Type
McArdile
disease
(type 5)
Muscle
phosphorylase
Skeletal muscle only: accumulations of
glycogen predominant in subsarcolemmal
location
Painful cramps associated with strenuous exercise
Myoglobinuria occurs in 50% of cases
Compatible with normal longevity
Miscellane
ous Type
Generaliz
ed
glycogen
osis
(pompe
disease,
type 2)
Lysosomal
glucosidase
(acid maltase)
Mild hepatomegaly: ballooning of lysosomes
with glycogen creating lacy cytoplasmic
pattern
Cardiomegaly: glycogen within sarcoplasm
as well as membrane-bound
Skeletal muscle: similar to heart
Massive cardiomegaly, muscle hypotonia, and
cardiorespiratory failure before age 2
Milder adult form with only skeletal muscle
involvement manifests with chronic myopathy

25. Diseases Caused by Mutations in Gene Encoding
Proteins That Regulate Cell Growth
• There are two classes of genes:
Protoonco-genes
Tumor Suppressor Genes
• Mutations affecting theses genes, most often in somatic cells, are
involved in the pathogenesis of tumors. In approximately 5 to 10% of
all cancers, however, mutations affecting certain tumor suppressor
genes are present in all cells of the body, including germ cells, and
hence can be transmitted to the offspring.
• These mutant genes pre-dispose the offspring to hereditary tumors.

26. Complex Multigenic Disorders
• Complex multigenic disorders- so called “multifactorial or polygenic disorders”- are
caused by interactions between genetic variants and environmental factors. A genetic
variant that occurs in at least 1% of the population is called a polymorphism. According to
common disease-common variant hypothesis, complex multigenic disorders occur
when many polymorphisms, each with a modest effect and low penetrance, are
coinherited
• Two additional important facts have emerged from studies of common complex disorders
such as type 1 diabetes
• Although complex disorders result from the collective inheritance of many
polymorphisms, different polymorphisms vary in significance. For example, of the 20 to
30 genes implicated in type 1 diabetes, 6 or 7 are most important and a few HLA alleles
contribute more than 50% of the risk.
• Some polymorphisms are common to multiple-diseases of the same type, whereas others
are disease specific.
• Many of disease-associated polymorphisms are in noncoding regions.

27. Cytogenetic Disorders
• It is estimated that approximately 1 in 200
newborn infants has some form of chromosomal
abnormalities. Cytogenetic disorders result from
alterations in the number or structure of
chromosomes and may affect autosomes and sex
chromosomes. Karyotype is a basic tool of
cytogeneticist.
• A karyotype is a photographic representation of
a stained metaphase spread in which the
chromosomes are arranged in order of increasing
length.
• A variety of techniques for staining
chromosomes has been developed. With the
widely used Giemse stain (G banding)
technique, each chromosome set can be seen to
be possess a distinctive pattern of alternating
light and dark bands of variable widths.
• The use of banding techniques allow
identification of each chromosome, and can
detect and localize structural abnormalities large
enough to produce changes in banding pattern.

28. Cytogenetic Disorders
CHROMOSOME STRUCTURE,
STAINING AND NAMING
G-BANDED KARYOTYPE
FROM NORMAL
MALE(46,XY)

29. Numeric Abnormalities
• In humans, the normal chromosomes 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. Polyploid generally results in a
spontaneous abortion. Any number that is not multiple of n is called
aneuploid. The chief cause of aneuploid is nondisjunction of a homologous
pair of chromosomes at the first meiotic division or a failure of sister
chromatids to separate during the second meiotic division.
• When non disjunction occurs at the time of meiosis, the gametes formed have
either an extra chromosome (n+1) or one less chromosome (n-1). Fertilization
of such gametes by normal gametes would result in two types of zygotes:
trisomic, with an extra chromosome (2n+1) or monosomic chromosome (2n-
1).
• Mosaicism is a term used to describe the presence of two or more populations
of cells with different complements of chromosomes in the same individual.

30. Structural Abnormalities
• Translocation implies transfer of a part of
one chromosome to another chromosome.
This process is usually reciprocal (i.e.,
fragments are exchanged between two
chromosomes.)
• Isochromosomes result when the centromere
divides horizontally rather than vertically.
• Deletion involves loss of a portion of a
chromosome. A single break may delete a
terminal segment.
• Inversion occurs when there are two
interstitial breaks in a chromosomes, and the
segment reunites after a complete turnaround.
• A ring chromosome is a variant of deletion.
After loss of segments from each end of the
chromosome, the arms unite to form a ring.

31. General Features of Chromosomal Disorders
Chromosomal disorders may be associated with absence (deletion,
monosomy), excess (trisomy), or abnormal rearrangements (translocation) of
chromosomes.
In general, a loss of chromosomal material produces more severe defects than
does a gain of chromosomal material.
Excess chromosomal material may result from a complete chromosome (as in
trisomy) or from part of a chromosome (as in Robertsonian translocation).
Imbalance of sex chromosomes (excess or loss) are tolerated much better
than are similar imbalance of autosomes.
Sex chromosome disorders often produce subtle abnormalities, sometimes
not detected at birth. Infertility, a common manifestation, can’t be diagnosed
until adolescence.

32. Cytogenetic Disorders Involving Autosomes
Trisomy 21 (down syndrome):
Down syndrome is characterized by
extra copy of genes on chromosome
21, is the most common of the
chromosomal disorders. About 95% of
affected persons have trisomy 21, so
their chromosome count is 47.
The parents of such children are
normal in all respects. The correlation
with maternal age suggests that in most
cases the meiotic nondisjunction of
chromosome 21 occurs in the ovum.
Indeed, in 95% of cases the extra
chromosome is of maternal origin.

33. 22q11.2 Deletion Syndrome
• The 22q11.2 deletion syndrome encompasses a
spectrum of disorders that result from a small
interstitial deletion of band 11 on the long arm of
chromosome 22.
• The clinical features of this syndrome include
congenital heart disease affecting the outflow tracts,
abnormalities of the palate, facial dysmorphism,
development delay, thymic hypoplasia with
impaired T cell immunity, and parathyroid
hypoplasia resulting in hypocalcemia.
• Previously these clinical features were believed to
represent two different disorders: DiGeorge
Syndrome & Velocardiofacial Syndrome.
However, it is now known that both are caused by
22q11.2 deletion.
• In fact, it is estimated that schizophrenia develops in
approximately 25% of adults with this syndrome.
Conversely, deletions of the region can be found in
2 to 3% of the individuals with childhood-onset
schizophrenia.

34. Cytogenetic Disorders Involving Sex
Chromosomes
• A number of abnormal karyotypes involving the sex chromosomes, ranging from 45,
X to 49, XXXXY, are compatible with life. Indeed, phenotypically normal males with
two and even three Y chromosomes have been identified. Such extreme karyotypic
deviations are not encountered with the autosomes. In large part, this latitude relates
to two factors.
1) Lyonization of X chromosomes and
2) The small amount of genetic information carried by the Y chromosome.
• The Lyon hypothesis explain that why normal females are in reality mosaics,
containing two cell populations: one with an active maternal X, the other with an
active paternal X. The molecular basis of X inactivation involves a long non-coding
RNA that is encoded by XIST gene.
• Most important the initial presumption that all of the genes on the inactive X are
“switched off” has been revised, as roughly 21% of gene on Xp, and a smaller
number (3%) on Xq, escape X inactivation.

35. Turner Syndrome and Klinefelter Syndrome

36. Single-Gene Disorders with Atypical Patterns
of Inheritance

37. Triplet Repeat Mutation
• Fragile X Syndrome:
 Fragile X syndrome is the phenotype of
diseases in which the causative mutation
occurs in a long repeating sequence of three
nucleotides. Other examples of diseases
associated with trinucleotides repeat
mutations are Huntington disease and
myotonic dystrophy.
 Fragile X syndrome results from a mutation in
the FMR1 gene, which maps to Xq27.3 and
the second most common genetic cause of
mental retardation, after Down syndrome.
 Analysis of several pedigrees, however,
shows some patterns of transmission not
typically associated with other X-linked
recessive disorders.
• These include the following
 Carrier males, approximately 20% of males
who, by pedigree analysis, are known to carry
a fragile X mutation do not manifest the
typical neurological symptoms or physical
characteristics of fragile X during childhood.
 Affected females, from 30 to 50% of carrier
women with the fragile X mutation on one
chromosome might show features of mild
cognitive impairment or other behavioral
disturbances.
 Anticipation, this term refers to phenomenon
whereby clinical features of fragile X
syndrome worsen with each successive
generation.

38. Fragile X Syndrome
• Pathogenesis:
• The molecular basis for fragile X
syndrome is beginning to be
understood and relates to silencing of
the production of FMR1 gene, familial
mental retardation protein (FMRP).
• The normal FMR1 gene contains CGG
repeats in its 5’ untranslated region.
• The resulting absence of FMRP is
believed to cause the phenotypic
changes. FMRP is widely expressed in
normal tissues, but higher levels are
found in the brain and testis.

39. Fragile X Tremor/Ataxia
• Although initially assumed to be innocuous, CGG premutation in the FMR1
gene can cause a disease that is phenotypically different from fragile X
syndrome through a distinct mechanism involving a toxic “gain-of-function”.
This disease was discovered when it was noted that approximately 20% of
females carrying the premutation(carrier females) have mild cognitive
impairment and premature ovarian failure and more than 50% of
premutation-carrying males exhibit a progressive neurodegenerative
syndrome starting in their sixth decade.
• In these patients, the FMR1 gene instead of being methylated and silenced
continues to be transcribed. CCG-containing FMR1 mRNAs so formed are
“toxic”. They accumulate in the nucleus and form intranuclear inclusions.
• In this process the aggregated mRNA recruits RNA-binding proteins. Perhaps
sequestration of these proteins at abnormal location leads to toxic event for
cell.

40. Fragile X Tremor/Ataxia
• Many neurodegenerative diseases related
to trinucleotide repeat expansions are
recognized. Some general principles are:
In all cases, gene functions are altered by
an expansion of the repeats, but the
precise threshold at which premutations
are converted to full mutations differs
with each disorder.
Expansion in Fragile X syndrome occurs
in oogenesis.
The expansion may involve any part of
gene, and range of possibilities can be
divided into two categories, those that
affect untranslated regions and those who
affect coding regions.

41. Diseases Caused by Mutations in
Mitochondrial Genes
• Mitochondria contain several genes that encode enzymes involved in
oxidative phosphorylation. Inheritance of mitochondrial DNA differs
from that of nuclear DNA in that the former is associated with maternal
inheritance.
• Reason for this peculiarity is that ova contain the normal complement
of mitochondria within their abundant cytoplasm, whereas spermatozoa
contain few, if any, mitochondria.
• Diseases caused by mutations in mitochondrial genes are rare, because
mitochondrial DNA encodes enzymes involved in oxidative
phosphorylation, diseases caused by mutations in such genes affect
organs most dependent on oxidative phosphorylation (CNS, skeletal
muscle, cardiac muscle, liver and kidney).

42. Prader-Wili
Syndromes
All humans inherit two copies of
each gene (except, the sex
chromosome genes in male), carried
on homologous maternal and
paternal chromosomes. It has been
established, however, the functional
differences exist between the
paternal and maternal copies of
some genes.
Mental retardations, short stature,
hypotonia, obesity, small hands and
feet, and hypogonadism characterize
Prader-Willi syndrome.

43. Angelman Syndromes
• The differences arise from an
epigenetic process called genomic
imprinting, whereby certain
homologous genes are
differentially “inactivated” during
paternal and maternal
gametogenesis.
• Patients with Angelman syndrome
also are mentally retarded, but in
addition they present with ataxic
gait, seizures, and inappropriate
laughter.

44. Congenital Anomalies
• Congenital anomalies are structural defects that are present at birth, such as
cardiac defects and renal anomalies.
• Malformations are primary errors of morphogenesis.
• Disruptions result from secondary destruction of an organ or body region that
was previously normal in development.
• Deformations like disruptions, also represent an extrinsic disturbance of
development rather than intrinsic error of morphogenesis.
• Sequence refers to multiple congenital anomalies that result from secondary
effects of single localized aberration in organogenesis.
• Malformation syndrome refers to presence of several defects that can’t be
explained on basis of single localizing initiating error in morphogenesis.

45. Congenital Anomalies
ETIOLOGY
• Known causes of errors in human malformations
can be grouped into:
 Genetic causes of malformations include Down
syndrome, Turner syndrome and Klinefelter
syndrome.
 Environmental influences, such as viral
infections, drugs and radiation to which the
mother was exposed during pregnancy, e.g.,
Syphilis
 Multifactorial inheritance, which implies the
interaction of environmental influences with two
or more genes of small effect, is most common
cause of congenital malformations.
PATHOGENESIS
• The pathogenesis of congenital anomalies is complex
and still poorly understood, but two general principles
are relevant to etiologic agent
1) The timing of paternal teratogenic insult has an
important impact on occurrence and type of
anomalies produced.
 In early embryonic period, an injurious agent damages
either enough cells to cause death or only a few cells.
 The fetal period that follows organogenesis is marked
chiefly by further growth and maturation of organs.
2) The complex interplay between environmental
teratogens and intrinsic genetic defects are
exemplified by the facts.
 Cyclopamine is a plant teratogens.
 Valporic acid is an anti-epileptic and teratogens.

46. Perinatal Infections
TRANSCERVICAL
• Transcervical, or ascending,
infections are caused by spread of
microbes from the cervicovaginal
canal and may be acquired in utero
or during birth.
• For Example:
α-hemolytic streptococcal infection
Herpes simplex
TRANSPLACENTAL
• Transplacental infections gain
access to the fetal blood stream by
crossing the placenta via the
chorionic villi and may occur at
any time during gestation.
• For Example:
• Toxoplasma
• Listeria

47. Prematurity and Fetal Growth Restriction
• Prematurity is defined by a gestational age than 37 weeks and is the 2nd most
common cause of neonatal mortality. The major risk factors for prematurity
include preterm premature rupture of membranes, multiple gestation,
intrauterine infection leading to inflammation of placental membranes,
structural abnormalities of uterus and cervix etc.
• The immaturity of organ systems in preterm infants makes them especially
vulnerable to several important complications
Respiratory distress syndrome
Necrotizing enterocolitis
Sepsis
Intraventricular and germinal matrix hemorrhage

48. Prematurity and Fetal Growth Restriction
• Fetal growth restriction may result from
Fetal Abnormalities: This category consists of conditions that
intrinsically reduce growth potential of the fetus despite an adequate
supply for nutrients from mother.
Placental Abnormalities: Placenta causes include any factor that
compromises the uteroplacental blood supply. Examples include
placental previa, placental abruption or placental infraction.
Maternal Factors: This category comprises by far the most common
causes of the growth deficit in SGA infants, such as, Eclampsia.

49. Respiratory Distress Syndrome of the
Newborn
• The most common cause of respiratory distress in newborn is
respiratory distress syndrome(RDS), also known as Hyaline
membrane disease because of formation of “membranes” in the
peripheral air spaces observed in infants who succumb to this
condition.
Pathogenesis:
• The fundamental defect in RDS is the inability of the immature lung to
synthesize sufficient surfactant. Surfactant is complex of surface-active
phospholipids, principally dipalmitoyl phosphatidylcholine(lecithin).
• Hormones regulate surfactant synthesis. Corticosteroids stimulate the
formation of surfactant lipids and associated proteins.

50. Respiratory Distress Syndrome of the
Newborn
Clinical Features:
• The control of RDS vary, depending on the
maturity and birth weight of the infants and
the promptness of therapy. The control of
RDS focuses on prevention, either by
delaying labor until the fetal lung reaches
maturity or by inducing maturation of the
lung in the at-risk fetus.
• Retinopathy of prematurity has two phase
pathogenesis.
i. Expression of the proangiogenic vascular
endothelial growth factor
ii. The major abnormality in
bronchopulmonary dysplasia is a striking
decrease in alveolar septation.

51. Necrotizing Enterocolitis
• Necrotizing enterocolitis (NEC) most
commonly occurs in premature infants, with
the incidence of the disease being inversely
proportional to the gestation age. In addition
to prematurity, most cases are associated with
eternal feeding, suggesting that some
postnatal insult sets in motion the cascade
culminating in tissue destruction.
• NEC typically involves the terminal ileum,
cecum and right colon, although any part of
small or large intestine may be involved.
• The clinical course is fairly typical, with the
onset of bloody stools, abdominal distention,
and development of circulatory collapse.
When detected early, NEC often can be
managed conservatively, but many cases (20
to 60%) require operative intervention
including resection of necrotic segments of
bowel.

52. Sudden Infant Death Syndrome (SIDS)
• SIDS is defined as the sudden death of an
infant under 1 year of age which remains
unexplained after a thorough case
investigation, including performance of a
complete autopsy, examination of the death
scene, and review of clinical history.
 Pathogenesis:
• SIDS is multifactorial condition, with a
mixture of contributing causes in a given
case. Three interacting variables have been
proposed:
a) A vulnerable infant
b) A critical development period in
homeostatic control
c) One or more exogenous stressors

53. Fetal Hydrops
• Fetal hydrops refers to the accumulation of
edema fluid in the fetus during intrauterine
growth.
• The degree of fluid accumulation is variable,
from generalized hydrops fetalis to localized
cystic hygromas.
• The most common causes of fetal hydrops are
nonimmune (chromosomal abnormalities,
cardiovascular defects and fetal anemia),
whereas immune hydrops has become less
frequent as a result of Rh antibody
prophylaxis.
• Erythroblastosis fetalis (circulating immature
erythroid precursors) is characterized finding
of fetal anemia-associated hydrops.
• Hemolysis-induced hyperbilirubinemia can
result in bilirubin toxicity.

54. Tumors and Tumor like Lesions of Infancy
and Childhood
• Malignant neoplasms constitute the second most common cause of
death in children between the age of 4 to 14 years.
• Two special categories of tumor like lesions should be recognized:
Heterotopia or Choristoma refers to microscopically normal cells or
tissues that are present in abnormal locations. Examples are a
pancreatic tissue “rest” found in wall of stomach, small intestine etc.
Hamartoma refers to an excessive but focal overgrowth of cells and
tissues native to the organ in which it occurs. The line of demarcation
between a hamartoma and a benign neoplasm frequently is tenuous and
is variously interpreted.

55. Benign Neoplasm
• There are three main types of benign neoplasm
Hemangiomas are the most common neoplasms of infancy. In
children, most hemangiomas are located in skin, particularly on face
and scalp, where they produce flat to elevated, irregular, red-blue
masses; the flat, larger lesions are referred to as part-time stains.
Lymphangiomas represent the lymphatic counterpart of hemangiomas.
Microscopic examination shows cystic and cavernous spaces lined by
endothelial cells and surrounded by lymphoid aggregates.
Teratomas may occur as benign, well-differentiated cystic lesions
(mature teratomas), as lesions of indeterminate potential, or as
unequivocally malignant teratomas.

56. Malignant Neoplasms
• The organ systems involved most commonly by malignant neoplasms in
infancy and childhood are the hematopoietic system, neural tissue, and soft
tissues.
• Malignant neoplasms of infancy and childhood differs from those in adults.
The main differences are as follows:
Relatively frequent demonstration of a close relationship between abnormal
development and tumor induction.
Prevalence of genetic abnormalities or familial syndromes that predispose to
cancer.
Tendency of fetal and neonatal malignancies to regress spontaneously or to
undergo “differentiation” into mature elements.

57. Neuroblastoma
• Neuroblastomas and related tumors arise from
neural crest derived cells in the sympathetic
ganglia and adrenal medulla.
• Neuroblastomas are undifferentiated, whereas
ganglion neuroblastomas and
ganglioneuromas demonstrates evidence of
differentiation.
• Age, stage, and MYCN amplification and
ploidy are most important prognostic features;
children younger than 18 months usually have
a better prognosis than older children,
whereas children with higher-stage tumors or
MYCN amplification fare worse. A high
frequency of relapsed neuroblastomas have
mutations in RAS-MAP kinase pathway.
• Neuroblastomas secrete catecholamine, whose
metabolites (VMA/HVA) can be used for
screening patients.

58. Retinoblastoma
• Retinoblastoma is the most common primary
intraocular malignancy of children.
Approximately 40% of tumors are associated
with germline mutation in RB gene and are
therefore heritable. The remaining 60% of the
tumors develop sporadically, and these have
somatic RB gene mutations.
 Clinical Features:
• The presenting findings include poor vision,
strabismus, a whitish hue to the pupil, pain,
and tenderness in the eye.
• The median age at presentation in 2 years,
although the tumor may be present at birth.
Untreated, the tumors usually are fatal, but
when treated with chemotherapy, radiotherapy
and enucleation, survival is rule.

59. Wilms Tumor
• Wilms tumor is the most common renal
neoplasm of childhood.
• Patients with three syndromes are at increased
risk for Wilms tumor: Denys-Drash,
Beckwith-Wiedemann, and Wilms tumor,
aniridia, genital abnormalities, and mental
retardation (WGAR) syndrome.
• WAGR syndrome and DDS are associated
with WT1 inactivation, whereas Beckwith-
Wiedemann arises through imprinting
abnormalities at the WT2 locus, principally
involving the IGF2 gene.
• The morphologic components of Wilms tumor
include blastema (small, round blue cells) and
epithelial and stromal elements.
• Nephrogenic rests are precursor lesions of
Wilms tumors.

60. Molecular Diagnosis of Mendelian and
Complex Disorders
• Several factors have since enable the rapid expansion of molecular
diagnostics from the realm of research to an almost ubiquitous presence in
both academic and commercial pathological laboratories, these include
The sequencing of the human genome and deposition of these data in publicly
available databases.
The availability of numerous “off-the-shelf” polymerase chain reaction kits
tailor-made for identification of specific genetic diseases.
The availability of high-resolution microarrays that can interrogate both DNA
and RNA on a genomewide scale using a single platform.
The emergence of automated, high throughput, next generation sequencing
technologies.

61. Indications for Genetic Analysis
PRENATAL GENETIC
ANALYSIS
• Advanced maternal age (beyond 34 years), which is
associated with greater risk of trisomies.
• Confirmed carrier status for a balanced reciprocal
translocation, Robertsonian translocation or
inversion.
• Fetal abnormalities observed on ultrasound, or an
abnormal result on routine maternal blood
screening.
• A chromosomal abnormality or mendelian disorders
affecting a previous child.
• Determination of fetal sex when the patient or
partner is a confirmed carrier of an X-linked genetic
disorder.
POSTNATAL GENETIC
ANALYSIS
• Multiple congenital anomalies
• Suspicion of a metabolic syndrome
• Unexplained mental retardation
and/or developmental delay
• Suspected aneuploidy or syndromic
chromosomal abnormality
• Suspected monogenic disease,
whether previously described or
unknown.

62. Molecular Diagnosis of Copy Number
Abnormalities
Fluorescence in Situ Hybridization:
• FISH uses DNA probes that recognize
sequences specific to chromosomal
regions of greater than 100 kilobases in
size, which defines the limit of resolution
with this technique for identifying
chromosomal changes. Such probes are
labeled with fluorescent dyes and are
applied to metaphase spreads or
interphase nuclei.
• The ability of FISH to circumvent the
need for driving cells is invaluable when
a rapid diagnosis is warranted. Such
analysis can be performed on paternal
samples, peripheral blood lymphocytes,
and even archival tissue sections.

63. Array-Based Genomic Hybridization
• In array comparative genomic
hybridization (aCGH), the test
DNA and a reference DNA are
labeled with two different
fluorescent dyes that fluoresce red
and green respectively.
• The differentially labeled samples
are then cohybridized to an array
spotted with DNA probes that span
the human genome at regularly
spaced intervals, and usually cover
all 22 autosomes and sex
chromosomes.

64. Direct Detection of DNA Mutations by
Polymerase Chain Reaction(PCR) Analysis
• PCR analysis, which involves
exponential amplification of DNA, is
now widely used in molecular
diagnosis.
• The DNA sequence of the PCR
product can be analyzed by
Sanger sequencing, has for many years
been the “workhorse” of genome
sequencing, including the origin of
Human Genome Project.
Another approach for identifying
mutations at specific nucleotide
position would be add fluorescently
labeled nucleotides C and T to PCR
mixture.

65. Linkage Analysis and Genomewide
Association
LINKAGE ANALYSIS
• Linkage analysis deals with
assessing shared marked loci (i.e.,
SNPs) in family members
exhibiting the disease or trait of
interest, with the assumption that
SNPs in linkage disequilibrium
with the disease allele are
transmitted through pedigrees.
• Linkage analysis is most useful in
mendelian disorders that are related
to one gene with profound effects
and high penetrance.
GENOMEWIDE
ASSOCIATION
• In GWASs large cohorts of patients
with and without a disease are
examined across the entire genome
for variants SNPs that are
overrepresented in persons with the
disease.
• This identifies regions of genome
that contain a variant gene or genes
that confer disease susceptibility.
The causal variant within the
region is then provisionally,
identifying using a “candidate
gene” approach.

66. Thank You