GENETIC

DISORDERS
 INTRODUCTION

Genetic disorders are far more common than

is widely appreciated
Overall frequency is approximately 670 per
1,000
Includes classic genetic disorders, cancer
and CV diseases
 INTRODUCTION

Genetics study single or a few genes

and their phenotypic effects
Genomics study of all genes in the
genome and their interactions
Proteomics measurement of all proteins
expressed in a cell or tissue
 DEFINITIONS

Hereditary
derived from ones parent and transmitted
through germ line
Familial
runs in the family
Congenital
present at time of birth
 MUTATIONS

a permanent change in DNA

germ cells -may give rise to inherited
diseases
somatic cells - important in the genesis of
cancers and some congenital malformations
 GENE MUTATION

Point mutation a single nucleotide base

is substituted by a different base
 GENE MUTATION

Point Mutation may be within

coding sequences
Missense mutation
alters genetic code
Nonsense mutation
production of stop codon
non coding sequences
Reduction or lack of transcription
 GENE MUTATION

Frameshift mutation one or two base

pairs may be inserted into or deleted from
the DNA alteration in the reading frame
of the DNA strand
 GENE MUTATION

Trinucleotide repeat
10-200 x amplification
C or G
Dynamic, continues to amplify thru generations
 GENETIC DISORDERS
1. Single Gene Mutation Disorders
Large effect
Mendelian
Submicroscopic
2. Chromosomal disorders
Structure or number alteration of chromosome
Visible with karyotyping
3. Complex Multigenic Disorders
Most common
Environmental interactions
4. Single-Gene Disorders with Non-Classic
Inheritance
 TERMS

Variable Expressivity trait seen in all

carriers but expressed differently
neurofibromatosis
Brown spots in some, tumors in others

Penetrance expressed in mathematical

terms (%)
50% penetrance = 50% of those who carry
the gene express the trait
 TERMS

Genetic Heterogeneity mutations at

different loci produce the same trait
Polymorphism implies presence of
multiple allelic forms of a single gene
Codominance both alleles of a gene pair
fully expressed in the heterozygote
Pleiotropism a single mutant gene
causing many end effects
 TERMS - GENES

Autosomal located on autosomes

Sexlinked located on X and Y
chromosome
Recessive expressed only when
homozygous on both chromosomes
Dominant expressed in homozygous or
heterozygous form
 MENDELIAN DISORDERS

Result of expressed mutations in single

genes of large effect
> 4500 Mendelian disorders
Every individual is carrier of 5 8
deleterious genes, mostly recessive
About 80 85% of these mutations are
familial; 15 20% are new mutations
acquired de novo by an affected
individual
 MENDELIAN DISORDERS

Transmission Patterns

Autosomal Dominant
Autosomal Recessive
X-linked
 MENDELIAN DISORDERS
Autosomal Dominant

Manifested even in the heterozygous state

Some patients do not have affected parents

and owe their disorders to new mutations
de novo
MENDELIAN DISORDERS Autosomal
Dominant
Both males and
females are affected
and can transmit the
disease
When an affected
person marries an
unaffected one, each
child has 1 chance in 2
(50%) of having the
disease
 MENDELIAN DISORDERS
Autosomal Dominant
Many new mutations seem to occur in germ cells of
older father
Clinical features can be modified by reduced
penetrance and variable expressivity
Onset may be delayed, S/S may not appear until
adulthood
 MENDELIAN DISORDERS
Autosomal Dominant
Usually involve non-enzyme proteins regulatory and
complex structural proteins
loss of function
dominant negative
gain of function
Autosomal Dominant Disorders

Nervous Huntington Disease, Neurofibromatosis

Urinary Polycystic Kidney Disease
GIT Familial Polyposis Coli
Hematopoletic Hereditary Spherocytosis,
Von Willebrand dse
Skeletal Marfan, Ehlers Danlos, Osteogenesis
Imperfecta
Metabolic Acute Intermittent Porphyria
Familial Hypercholesterolemia
 MENDELIAN DISORDERS
Autosomal Recessive
Single largest category of Mendelian disorders
Result only when both alleles at a given gene locus
are mutants
More uniform clinical expression of the defect
Complete penetrance is common
Onset is frequently early in life
Enzyme products are affected
De novo not detected
MENDELIAN DISORDERS Autosomal
Recessive
The trait does not
usually affect the
parents but siblings
may show the
disease
Siblings have
1chance in 4 (25%)
of being affected
 MENDELIAN DISORDERS
Autosomal Recessive Disorders
Metabolic Cystic fibrosis, Lysosomal
Glycogen Storage Disease
Hematopoietic Sickle cell anemia, Thalasemia
Endocrine Congenital Adrenal
Hyperplasia
Skeletal Ehlers - Danlos Syndrome;Alkaptonuria
Nervous Neurogenic Muscular
Atrophies, Friedreich Ataxia
 MENDELIAN DISORDERS
Sex-Linked Disorders
All sex - linked disorders are X linked, almost all X
- linked recessive
The only gene assigned with certainty to Y
chromosome is the determinant for testes
Male is hemizygous for X - linked mutant genes, so
these disorders are expressed in male
 MENDELIAN DISORDERS
Sex-Linked Disorders
An affected male does not
transmit the disease to his
sons, but all daughters are
carriers
Heterozygous females are
carriers
Sons of heterozygous
female have 1 chance in 2
(50%) of receiving the
mutant gene
 MENDELIAN DISORDERS
Sex-Linked Disorders
There are only few X - linked dominant
disorders
Transmitted by an affected heterozygous female
to half her sons and half her daughters
Transmitted by an affected male to all his
daughters but none of his sons, if the mother is
normal
Vitamin D resistant Rickets
 MENDELIAN DISORDERS
X - linked Recessive Disorders
Musculoskeletal Duchenne Muscular Dystrophy

Blood Hemophilia A and B,

Chronic Granulomatous Dse

Immune Wiskott-Aldrich Syndrome

Metabolic Diabetes Insipidus,

Lesch Nyhan
Nervous Fragile-X syndrome
 MENDELIAN DISORDERS
Biochemical and Molecular Basis
Enzyme defects
Membrane receptor defects
Non Enzyme (structural) protein defects
Unusual reaction to drugs**
 MENDELIAN DISORDERS
Enzyme defects and their consequences
Accumulation of substrate
May be toxic to tissues
Lysosomal Storage Diseases

Metabolic block with decrease in end product

May cause loss of function
Albinism, Lesch Nyhan

Failure to inactivate a tissue damaging substrate

Absence of regulatory component
1 Antitrypsin Deficiency
 MENDELIAN DISORDERS
Defects in membrane receptors and transport system
defective transport, accumulation in cell
Familial Hypercholesterolemia

Alteration in structure, function or quantity of non

enzyme protein
structural proteins
Sickle Cell Disease
Adverse reaction to drugs
only seen when certain drugs are introduced
G6PD
STRUCTURAL PROTEIN DEFECTS
Marfan Syndrome
Weakness in connective tissue particularly in
the skeleton, eyes and CVS
7085%, AD, dominant negative effect
Inherited defect in extracellular glycoprotein
fibrillin
Fibrillin 1 FBN1 (15q21) Marfan Syndrome
Fibrillin 2 FBN2 (5q23) Congenital Contractual
Arachnodactyly
STRUCTURAL PROTEIN DEFECTS
Marfan Syndrome
Tall, long lower
extremities
lax joint ligaments of
hands and feet
dolichocephalic with
frontal bossing
kyphosis and scoliosis
pectus excavatum
bilateral subluxation lens
MV prolapse and cystic
medial necrosis
STRUCTURAL PROTEIN DEFECTS
Ehlers Danlos Syndrome
heterogeneous group of disorder
defect of collagen synthesis and structure
encompasses all three Mendelian patterns
6 variants based on clinical manifestations
and inheritance

Classical I, II AD Kyphoscoliosis VI AR
Hypermobility III AD Arthrochalasia VII a,b AD
Vascular IV- AD Dermatosparaxis VIIc- AR
 STRUCTURAL PROTEIN DEFECTS
Ehlers Danlos Syndrome
Skin, joints and
internal
complications
Skin is hyper
extensible
Joints hypermobile
Rupture of colon,
arteries, eyes
 DEFECTS IN RECEPTOR PROTEINS
Familial Hypercholesterolemia
Mutation in the gene on
chromosome 19
encoding the LDL
receptor
Most frequent
Mendelian disorder
Heterozygotes (50% LDL
receptors)
5 groups based on LDL
receptor defect
DEFECTS IN RECEPTOR PROTEINS
Familial Hypercholesterolemia
Xanthomas
Atherosclerosis
Ischemic heart disease
often before the age
of 20
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
Defect in enzymes
Lysosomes are part of
intracellular digestive
tract (hydrolytic
enzymes)
Catalyze complex
macromolecules
autophagy /
heterophagy
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
Causes:
missing enzyme
lack of enzyme activator or
protein protector
lack of substrate activator
protein
lack of transport protein

Defects result in
accumulation of partially
degraded insoluble
metabolite
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
TAY SACHS DISEASE

GM2 gangliosidosis accumulates

Hexosaminidase A deficiency ( sub-u, chromosome 15)
1 in 30 Ashkenazic Jews
CNS component prominent
s/s appear at 6 months
Motor and mental retardation
Blindness
Vegetative at 12 years
Death at 23 years cherry red spot
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
TAY SACHS DISEASE
neurons have large
cytoplasmic lipid
vacuole
whorled
configurations on EM
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
NIEMANN-PICK DISEASE

Accumulation of sphingomyelin
Deficiency in sphingomyelinase
Common in Jews
Type A: 75 80% of cases severe infantile
form (extensive neurologic involvement,
marked visceral accumulation)
Type B: organomegaly only
Type C: most common/different biochemical
defect
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
NIEMANN-PICK DISEASE
Fine vacuolation of
phagocytic cells
Zebra bodies (EM)
Cherry red spot seen in 1/3
of cases
Evident at 6 months
Hepatosplenomegaly, failure
to thrive, fever,
vomiting,lymphadenopathya
nd psychomotor dysfunction
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
Most common GAUCHER DISEASE
lysosomal storage
disease
Deficiency in
glucocerebrosidase,
AR
Accumulation in
phagocytes and CNS
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
GAUCHER DISEASE
Type I chronic nonneuropathic form
Adults, 99% of cases
Massive splenomegaly, skeletal involvement
Type II acute neuropathic form
Infantile
hepatosplenomegaly, convulsions, mental deterioration
early death
Type III
Combination of I and II
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
GAUCHER DISEASE
Gaucher - distended
phagocytic cells,
crumpled paper
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
MUCOPOLYSACCHARIDOSES (MPS)

Enzymes involved in the degradation of

mucopolysaccharide
Severe somatic and neurologic changes occurs
(retardation)
Most are AR
MPS I (Hurler syndrome) most severe form,
normal at birth, L iduronidase deficiency
MPS II ( Hunter syndrome) - x-linked,
L iduronosulfate sulfatase deficiency
 DEFECTS IN ENZYMES
Lysosomal Storage Diseases
MUCOPOLYSACCHARIDOSES (MPS)
Coarse facial features
Clouding of cornea
Joint stiffness
Organomegaly
Subendothelial deposits

Zebra bodies Balloon cells

 DEFECTS IN ENZYMES
Glycogen Storage Diseases
AR, defects in the synthesis or catabolism of glycogen
Hepatic Form von Gierke,
Glucose 6 phosphatase deficiency
hepatomegaly and hypoglycemia
Myopathic Form McArdle,
muscle phosphorylase deficiency
muscles, muscle cramps after exercise, and failure
of lactate to rise after exercise, muscle weakness
Miscellaneous Type Pompe,
deficiency of acid maltase ( glucosidase)
storage in heart, prominent cardiomegaly
Von Gierke

Mc Ardle
 DEFECTS IN ENZYMES
Alkaptonuria (Ochronosis)
AR
Deficiency of homogentisic
oxidase
Black color urine upon standing
(alkaptonuria)
Blue black discoloration of
collagen (Ochronosis)
Arthropathy due to deposition in
the articular cartilage, vertebral
column, knees, hips
COMPLEX MULTIGENIC DISORDERS

result from combined actions of

environmental influences and a mutant gene
having two or more alleles (polymorphism)
having additive effects
the genetic component exerts a dosage effect
- the greater the number of inherited
deleterious genes, the more severe the
expression of the disease
MULTIFACTORIAL DISORDERS

Cleft lip or cleft palate (or both)

Congenital heart disease
Coronary heart disease
Hypertension
Gout
Diabetes mellitus
Pyloric stenosis
CHROMOSOMAL DISORDERS

somatic cells contains 46 chromosomes

(22 homologous pairs of autosomes and 2
sex chromosomes, XX or XY)

Alteration of number or structure of

chromosomes
 KARYOTYPING
study of chromosomes
Arrangement of a
photographed or
imaged stained
metaphase spread in
which the chromosome
pair are arranged in
order of decreasing
length
 KARYOTYPE
Total number of chromosomes +
sex chromosome complement +
description of abnormality
e.g., 47, XY, + 21
p = petit; short arm
q = long arm
each arm is divided into regions,
regions into bands and sub - bands
e.g., Xp21.2
 CHROMOSOMAL DISORDERS

NUMBER
Euploidy exact multiple of a haploid
Aneuploidy- not an exact multiple of 23
Monosomy- 2n-1 (autosomal not viable)
Trisomy 2n+1

STRUCTURE
 CAUSES OF ANEUPLOIDY

Nondisjunction - occurs when a homologous

pair of chromosome fails to disjoin or separate
during cell division
when it occurs during gametogenesis gametes
either with extra (n + 1) or one less (n - 1)
chromosome
with fertilization by normal gametes trisomic (2n +
1) or monosomic (2n - 1) zygotes is produced
 CAUSES OF ANEUPLOIDY

Anaphase lag - one homologous

chromosome in meiosis or one
chromatid in mitosis lags behind
cell one normal cell + one with
monosomy
 STRUCTURAL ABERRATIONS
Inversion two breaks
inverted
reincorporation

Isochromosome
formation lost of one
arm followed by
duplication of remaining
arm 2 short arms or
2 long arms
STRUCTURAL ABERRATIONS

Translocation a segment of one

chromosome transferred to
another
Robertsonian fusion- long arm of
one transferred to short arm,
results in one very long arm and
one very short arm
STRUCTURAL ABERRATIONS

Deletion lost of a portion of chromosome

Ring chromosome deletion of ends

followed by fusion
CYTOGENETIC DISORDERS Involving
Autosomes
Trisomy 21 - Down Syndrome
Trisomy 18 - Edwards Syndrome
Trisomy 13 - Patau Syndrome
Chromosome 22q11.2 Deletion
Syndrome
TRISOMY 21 (Down Syndrome)
Most common chromosomal
disorder
Major cause of mental
retardation
Meiotic nondisjunction
Strongly influenced by
maternal age
INCREASED RISK
Congenital heart disease (40%)
acute leukemia
Alzheimers dse
abnormal immunity
TRISOMY 18 (Edward Syndrome)

More severe malformation

meiotic nondisjunction
prominent occiput, MR,
micrognathia, low set ears,
short neck, overlapping fingers,
heart defect, renal
malformation, hip abduction,
rockerbottom feet
Rarely survive beyond one year
TRISOMY 13 (Patau Syndrome)

meiotic
nondisjunction
microcephaly and MR,
cleft lip and cleft
palate, polydactyly,
cardiac defect, rocker-
bottom feet
Polydactyly

Syndactyly
CHROMOSOME 22q11.2 DELETION
SYNDROME
Spectrum of disorders,
congenital heart defects,
facial dysmorphism,
developmental delay, and
variable T-cell deficiency
with hypocalcemia
Di George syndrome
Velocardiofacial syndrome
Fluorescence In Situ Hybridization

TRISOMY DELETION
 CYTOGENETIC DISORDERS
Involving Sex Chromosomes
More common than autosomal abnormalities
Better tolerated
Not usually recognized until puberty
Increased # of X is associated with mental
retardation
Lyon hypothesis
Only one X is functional
Inactive x is seen as Barr body

Regardless of the # of x chromosomes, the

presence of a Y chromosome determines male sex
 KLINEFELTER SYNDROME
Most common
sex chromosomal disorders
cause of hypogonadism in
male
47, XXY
Lower IQ
Infertility
FSH & estradiol
testosterone
Meiotic nondisjunction
(maternal)
Klinefelter syndrome
 TURNER SYNDROME
Most common sex
chromosomal abnormality
in females
45 xo
edema, congenital heart
disease, absent 2o sex
characteristics, normal IQ,
amenorrhea
autoantibody to thyroid
(50%), glucose intolerance,
and obesity
 HERMAPHRODITISM

Both ovaries and

testes, extremely
rare, 46, XX (50%)
PSEUDOHERMAPHRODITISM

Disagreement of gonadal and phenotypic sex

Male - mutations in the gene for androgen

receptor
normal testes, ducts and external ambiguous
Female 46, XX; excessive and inappropriate
exposure to androgenic steroids during early
gestation
normal internal, virilized external genitalia
SINGLE - GENE DISORDER NONCLASSIC
INHERITANCE
Four categories
1. Trinucleotide repeat mutations
2. Mutations in mitochondrial genes
3. Genomic imprinting
4. Gonadal mosaicism
 TRINUCLEOTIDE-REPEAT
MUTATIONS
long repeating sequences of 3 nucleotides
involving G and C, DNA becomes unstable
Depends on sex of transmitting parent
Oogenesis Fragile X
Spermatogenesis Huntington
May occur in various areas
Non coding Fragile X
Coding Huntington
 FRAGILE X SYNDROME

seen as a discontinuity of
staining or as a
constriction in the long
arm of X - chromosome
and is liable to chromatid
breaks
 FRAGILE X SYNDROME
one of the most
common causes of
familial mental
retardation MALES
Reduction in FMRP
long face, large
mandible, large everted
ears and macro -
orchidism
Fragile X syndrome
 FRAGILE X SYNDROME

Atypical patterns of transmission:

* carrier males transmit to daughters
grandchildren affected
* affected females
30-50% carriers are affected
* risk of phenotypic effects
9% brothers MR
40% grandsons MR
* anticipation worsens w/ each generation
LEBER HEREDITARY
OPTIC NEUROPATHY
Mutations in Mitochondrial Genes
a feature unique to mtDNA is maternal
inheritance because the ova contain mitochondria
within their abundant cytoplasm whereas the
sperm, few, if any
mothers transmit mtDNA to all their offspring but
only daughters transmit the DNA further to their
progeny
 LEBER HEREDITARY OPTIC
NEUROPATHY
mtDNA encodes enzymes involved in oxidative
phosphorylation, thus mutations affect primarily
the CNS, skeletal and cardiac muscles, liver and
kidneys
Maternally inherited, ova with more mitochondria
progressive bilateral loss of central vision
First noted between 15 and 35 yrs and leads to
blindness; cardiac conduction defects and minor
neurologic manifestations may be seen
 GENOMIC IMPRINTING

Imprinting selectively inactivates either the

maternal or paternal allele
Occurs in the ovum, sperm before fertilization
Maternal imprinting- maternal alleles silenced
Paternal imprinting paternal alleles silenced
PRADER - WILLI SYNDROME

Retardation, short
stature, hypotonia,
obesity, small hands
and feet, and
hypogonadism
Deletion affects the
paternally derived
chromosome 15
 ANGELMAN SYNDROME

mentally retarded,
with ataxic gait,
seizures and
inappropriate laughter
(happy puppets)
deletion affects the
maternally derived
chromosome 15
 GONADAL MOSAICISM

Mutation occurs during early embryronic

development
Parents are phenotypically normal but disease
seen in multiple children