GENETIC DISORDERS C.

Complex multigenic disorders

Human Genetic Architecture  More common

 <2% of the human genome encodes
proteins
 >50% represents blocks of repetitive
DNA sequences whose functions remain
mysterious
 Genetics is the study of single or a few
genes and their phenotypic effects
 Genomics is the study of all the genes in
the genome and their interaction
 Any two individuals share >99.5% of
their DNA sequences
Genes and Human Diseases
 About 50% of spontaneous abortuses -
chromosomal abnormality
 1% of all newborn infants -gross
chromosomal abnormality
 About 5% of individuals < 25y/o
develop a serious disease with a
significant genetic component
Categories of Genetic Disorders
A. Disorders related to mutations in
single genes with large effects.
 Mendelian disorder
 High penetrance - mutation in single
genes with large effects
B. Chromosomal disorders
 Interactions between multiple genes
and environment
 Polymorphisms- variations in genes
 Small effect and is of low penetrance
 Multifactorial disorders
 atherosclerosis, diabetes
mellitus, hypertension, and
autoimmune diseases
Mutation
 Permanent change in the DNA
 Germ Cell Mutations
 transmitted to progeny
 inherited diseases
 Somatic Cell Mutation
 not inherited
A. Point mutations
 Change in a single nucleotide base
within a gene
 Three subtypes:
1. Silent Mutation - altered DNA, codes
for the same amino acid
2. Missense Mutation - altered DNA,
codes for different amino acid
a. Example: sickle cell anemia
b. GAG (glu) to GTG (val)
3. Nonsense Mutation – altered DNA,
codes for a stop codon (UAA,UAG,UGA)

 Structural or numerical alteration in the

autosomes and sex chromosomes
 Uncommon but associated with high
penetrance
B. Frameshift mutation

 Insertion or deletion of 1 or more

nucleotides, shift the reading frame of
the DNA strand
 If the number of base pairs involved is
three or multiples of three, frame shift
does not occur
C. Trinucleotide repeat mutation
 Amplification of a sequence of three
nucleotides
 Increasing severity of clinical disease in
each successive generation
(ANTICIPATION)
I. Disorders related to mutations in single
genes with large effects.
MENDELIAN DISORDERS
A. Autosomal Dominant Disorders
B. Autosomal Recessive Disorders
C. X-Linked Dominant Disorders
D. X-linked Recessive Disorders
Autosomal Dominant Disorders
 Two types of mutations:
1. Loss-of-function mutation
-mutations lead to the reduced
production of a gene product or
give rise to an inactive protein
2. Gain-of-function mutation
-the protein product of the
mutant allele acquires new
properties not normally
associated with the wild type
protein (e.g., activating
mutation in the erythropoetin
receptor associated with a
pathologic increase in red cell
production).
Examples of Autosomal Dominant Disorders
Autosomal Recessive Disorders
 Largest category
 Disease is expressed or as carriers
 Trait does not usually affect the
parents, but siblings may show the
disease which have ¼ chance of having
the trait
 Strong likelihood that affected
individual (proband) is the product of
consaguineous marriage
  Onset is frequently early in life X-Linked Disorders

 Many mutated genes encode enzymes  All sex-linked disorders are x-linked and
almost all are recessive
 Include almost all inborn errors of
metabolism X-Linked Recessive Disorders

 Affected males does not transmit the

disorder to his sons, but all daughters
are carriers

 Heterozygous female does not express

full phenotypic change because of
paired normal allele

 Sons of heterozygous women have 50%

of receiving the mutant gene

Examples of Autosomal Recessive Disorders

Examples of X-Linked Recessive Disorders Biochemical and Molecular Basis of Mendelian
Disorders

A. Enzyme Defects

B. Receptor Transport Defects

C. Non-Enzyme Protein Alteration

D. Genetically Determined Adverse Drug

Reaction

A. Enzyme Defects
X-Linked Dominant Disorders
1. Accumulation of Substrate
 Affected heterozygous female transmit - example: lysosomal and glycogen
to half her sons and half her daughters storage diseases

 Affected male parent transmit to all his
daughters but none of his sons IF
female parent is normal
 Examples:
1. Alports Syndrome
B. Receptor Transport Defects
2. Vitamin D resistant rickets
2. Metabolic Block ( amt of product)
- example: albinism, Lesch-Nyhan Syn.
3. Failure to inactivate a tissue-damaging
substrate
- example: α1- antitrypsin deficiency
 Defects in receptor-mediated
endocytosis or transport protein

 Examples:

1. LDL receptor in familial

hypercholesterolemia

2. CFTR in cystic fibrosis

C. Non-Enzyme Protein Alteration

 Globin in Sickle Cell Anemia

 Collagen in Osteogenesis
Imperfecta
 Spectrin in Hereditary
Spherocytosis
 Dystrophin in Duchenne Muscular
Dystrophy
D. Genetically Determined Adverse Drug
Reaction
 hemolytic anemia with sulfonamide use
in patients with G6PD Deficiency
B. Ehler-Danlos Syndrome
 Clinically and genetically heterogenous
group of disorders that result from
some defect in the synthesis or
structure of Fibrillar collagen

 Skin is extraordinarily stretchable,

Disorders Associated with Defect in
extremely fragile and vulnerable to
“Structural” Proteins
trauma
A. Marfan Syndrome

 CT disorder

 Defect in extracellular glycoprotein -

Fibrillin 1

 Changes in skeleton, eyes and CVS

 -tall w/ long extremities, lax

joint ligaments
 -frontal bossing
 -kyphoscoliosis, pectus
excavatum or carinatum
 -ectopia lentis
 -MVP, cystic medial necrosis of
ascending aorta
Disorders Associated with Defect in “Receptor”
Proteins
 Familial hypercholesterolemia
- Mutation in gene encoding LDL
receptor which is involve in the
transport and metabolism of
cholesterol
- Loss of feedback control and
elevated levels of cholesterol
that induce premature
atherosclerosis, leading to
greatly increased risk of
myocardial infarction
Disorders Associated with Defect in Enzyme
A. Lysosomal Storage Diseases
B. Glycogen Storage Diseases
C. Alkaptonuria
Disorders Associated with Defect in Enzyme
A. Lysosomal Storage Diseases
1. Tay- Sachs Disease
- Hexosaminidase α- Subunit Deficiency
- GM2 ganglioside accumulates
(heart,liver,spleen)
- Cherry-red spot in macula-
accentuation of macular choroid
contrasted with pale retina
- Predominant CNS &retinal involvement
- Neurons ballooned with cytoplasmic
vacuoles (lysosomes filled with
gangliosides)
- Relentless motor and mental
deterioration
Cherry-red spot in macula- accentuation of
macular choroid contrasted with pale retina
Ganglion cells in Tay-Sachs disease. A, Under
the light microscope a large neuron has obvious
lipid vacuolation. B, A portion of a neuron under Zebra Bodies- membranous cytoplasmic bodies
the electron microscope shows prominent concentric lamellated myelin figures
lysosomes with whorled configurations. Part of
3. Gaucher Disease
the nucleus is shown above.
- MC lysosomal storage dse
2. Niemann-Pick Disease Type A and B
- Cluster of AR d/o from mutations in the
- Sphingomyelinase deficiency gene encoding Glucocerebrosidase
- Sphingomyelin accumulates - CLINICAL SUBTYPES:
- Zebra Bodies -membranous a) TYPE 1- Chronic non- neuronopathic -is
cytoplasmic bodies, concentric the most common (99% of cases);
lamellated myelin figures predominant splenic and skeletal; NO
- Lipid laden phagocytic foam cells brain involvement
- Vacuolation of neurons b) TYPE 2- Acute Neuronopathic -
- TYPE A -severe infantile form with progressive CNS involvement
extensive neurologic involvement and c) TYPE 3- intermediate bet. 1 and 2
organomegaly
- TYPE B -organomegaly w/o CNS
involvement
- Massive splenomegaly and
hepatomegaly
- Cherry red spot in macula
 - Clinical Features:
 Coarse facial features
 Clouding of cornea
 Joint stiffness
 Mental retardation
 Increase urine metabolites

Mucopolysaccharidoses Types

Gaucher disease involving the bone marrow.

Gaucher cells (A, H&E; B, Wright stain) are
plump macrophages that characteristically have
the appearance in the cytoplasm of crumpled
tissue paper (B), due to accumulation of
glucocerebroside.

4. Mucopolysaccharidoses

- Deficiency in lysosomal enzymes

involved in the degradat’n of
mucopolysaccharides (GAG)
- All are Autosomal Recessive except
Hunter Syndrome (X-Linked Recessive)

Morphology:

- Balloon Cells- distended cells with

apparent clearing of the cytoplasm
- Hepatosplenomegaly, skeletal
deformities, valvular lesion &
subendothelial arterial deposits (esp
coronary arteries, & brain lesions.
B. Glycogen Storage Diseases

- hereditary deficiency of one of the

enzymes in the synthesis or sequential
degradation of glycogen
- glycogen storage in these disorders may
be limited to a few tissues, may be
more widespread while not affecting all
tissues, or may be systemic in
distribution Pompe disease (glycogen storage disease type
II). A, Normal myocardium with abundant
eosinophilic cytoplasm. B, Patient with Pompe
disease (same magnification) showing the
myocardial fibers full of glycogen seen as clear
spaces.

C. Alkaptonuria (Ochronosis)

- First human inborn error of metabolism

to be discovered
- Autosomal Recessive
- lack of Homogentisic oxidase- an
enzyme that converts homogentisic
acid to methylacetoacetic acid
- black urine if allowed to stand
- blue-black pigmentation (homogentisic
acid) evident in the ears, sclera, nose,
mand cheeks
- deposits of pigments in articular
cartilages of the joints
- calcification and bluish-black
discoloration of the tricuspid and aortic
valve
-
Disorders Assoc. w/ Defects in Proteins that
Regulate Cell Growth

 Normal growth and differentiation of

cells are regulated by two classes of
genes

1. Proto-oncogenes -products
promote cell growth
B. DELETION
2. Tumor suppressor genes -
products restrain cell growth  Loss of a portion of a
chromosome

 Cri du chat Syndrome -short
 Mutations in these two classes of genes arm of chromosome 5
are important in the pathogenesis of
tumors

 Mutations in somatic cells  not

inherited

 Mutations transmitted through the

germ line  familial cancers are
inherited (mc AD, few AR)

II. Chromosomal Disorders

C. INVERSION
 Most human cell: diploid (46
chromosomes)  Rearrangements that involves two
breaks within a single chromosome
 Autosomes: 22 pairs with reincorporation of the inverted
 Sex Chromosomes: XX/XY

 Gametes are haploid (23 chromosomes)

Structural Disorders of Chromosomes

A. NONDISJUNCTION

 Unequal separation of
chromosomes in meiosis I

- Turners Syndrome: 22+23 = 45

- Down’s Syndrome: 24+23= 47
F. ISOCHROMOSOME FORMATION - Causes:
a) Nondisjunction : 95%
 One arm of the chromosome is lost b) Robertsonian translocation: 4:
and the remaining arm is c) Mosaicism: 1%
duplicated, resulting in a
chromosome consisting of 2 short Clinical Findings:
arms only or of two long arms
 mental retardation
 epicanthal folds, flat facial
profile,
 macroglossia
 Simian crease
G. TRANSLOCATION  sterility in all males
 Transfer of chromosome parts
between non homologous
chromosomes

Cytogenetic Disorders Involving Autosomes

A. TRISOMY 21 – DOWN SYNDROME

B. TRISOMY 18 – EDWARD SYNDROME

C. TRISOMY 13 – PATAU SYNDROME

D. Chromosome 22q11.2 Deletion

a. Di George Syndrome

b. Velocardiofacial syndrome

A. TRISOMY 21 – DOWN SYNDROME

Associations:
- mc of the chromosomal disorders
- major cause of mental retardation  endocardial cushion defects
- parents of such children have a normal  Hirschprung’s disease
karyotype are normal in all respects  duodenal atresia
- Maternal age has a strong influence  inc. risk of leukemia: AML-
 1 in 25 live births for <3yo ALL- >3yo
mother > age 45  Alzeimers disease
-
B. TRISOMY 18 – EDWARD SYNDROME D. Chromosome 22q11.2 Deletion

Clinical Findings: a. Di George Syndrome

 mental retardation - small deletion of band q11.2 on the

 clenched hands w/ overlapping fingers long arm of chromosome 22
 VSD - thymic hypoplasia, T-cell immunodef.,
 early death parathyroid hypoplasia, hypocalcemia,
cardiac malformation

b. Velocardiofacial Syndrome

- facial dysmorphism (prominentnose,

retrognathia) cleft palate, CV, learning
disabilities

Cytogenetics Disorders Involving Sex

Chromosomes

A. KLEINFELTER SYNDROME (46 XXY)

B. TURNER SYNDROME (45 X)

C. TRISOMY 13 – PATAU SYNDROME
C. HERMAPHRODISM AND
Clinical Findings: PSEUDOHERMAPHRODISM

 mental retardation A. KLEINFELTER SYNDROME (46 XXY)

 cleft lip and palate
- Male hypogonadism (only consistent
 polydactyly
finding)
 VSD
- One of the most common causes of
 polycystic kidneys
hypogonadism in the male.
 early death
- 1 in 660 live male births
- Rarely be diagnosed before puberty
- Eunuchoid body habitus with long legs
- Small atrophic testes assoc. w/ small
penis
- Lack of secondary male chars.
- Gynecomastia
- Lower IQ than normal, MR- uncommon
- Increased incidence of type 2 DM &
metabolic syn.
- MVP is seen in about 50% of adults
 - Increased risk for breast cancer,
extragonadal germ cell tumors, and
autoimmune dses. such as SLE
- FSH – elevated
- Testosterone - variably reduced
- Plasma estradiol - elevated (unknown
mech.)
- E:T determines the degree of
feminization
- as infants develop  bilateral neck
webbing
- CHD - 25% to 50% - most impt. cause of
increased mortality (preductal
coarctation of the aorta and bicuspid
aortic valve)
- Failure to develop normal secondary
sex char.
- Infantile genitalia, streak ovaries
- Mental status - usually normal,
- Shortness of stature (mc)
- Single most important cause of primary
amenorrhea
- Hypothyroidism
- Horseshoe kidney

B. TURNER SYNDROME (45 X)

- complete or partial monosomy of X

chrom
- hypogonadism in phenotypic females
- mc sex chromosome abnormality in
females
- 1 in 2000 live-born females.
- during infancy
o edema of the dorsum of the
hand and foot
o swelling of the nape of the
neck- related to distended
lymph channels - cystic
hygroma
C. TRUE HERMAPHRODISM
- extremely rare
- both male & female gonads
- karyotype usually 46 XX (50%)
- ovotestes -combined ovarian and
testicular tissue
PSEUDOHERMAPHRODISM
 phenotype & genotype do not match
a. Female pseudohermaphroditism
- Less complex
- Genetic sex in all cases is XX
- Female genotype, male phenotype
 Ovaries and internal genitalia –
normal
 Ext. genitalia - ambiguous or
virilized
- BASIS: excessive and inapprop.
exposure to androgenic steroids during
the early part of gestation
- Adrenogenital syndrome
b. Male pseudohermaphroditism
- Possess a Y chromosome
- Male genotype, female phenotype
 Gonads are exclusively testes
 Ext. genitalia - ambiguous or
completely female
- Defective virilization of the male
embryo
- Complete androgen insensitivity
syndrome (testicular feminization)
Single-Gene Disorders with Nonclassic
Inheritance
A. TRINUCLEOTIDE – REPEAT MUTATIONS
B. MITOCHONDRIAL GENE MUTATION
C. GENOMIC IMPRINTING
A. TRINUCLEOTIDE – REPEAT MUTATIONS
 Fragile X Syndrome
- Prototype
- nucleotides G and C (CGG
repeats)
- 2nd mc genetic cause of MR
- Long face with large mandible,
large everted ears and macro-
orchidism
OTHER TRINUCLEOTIDE REPEAT MUTATIONS
1. EXPANSIONS AFFECTING NONCODING
REGIONS
a. Friedreich ataxia (GAA)
b. Myotonic dystrophy(CTG)
2. EXPANSIONS AFFECTING CODING REGIONS
a. Spinobulbar muscular atrophy (CAG)
b. Huntington disease (CAG)
c. Dentatorubral-pallidoluysian atrophy
(CAG)
d. Spinocerebellar ataxia (CAG)
B. MITOCHONDRIAL GENE MUTATION
 Leber Hereditary Optic neuropathy
- Prototype
- neurodegenerative disease
- bilateral loss of central vision
 2. Angelman Syndrome

- Microdeletion of the entire gene site on

maternal chromosome 15
- MR, ataxic gait, seizures, inaprop.
Laughter
- “happy puppets syndrome”

C. GENOMIC IMPRINTING DISORDERS

1. Prader-Willi Syndrome

- Microdeletion of the entire gene site on

paternal chrom. 15
- MR, short stature, hypotonia, obesity,
hypogonadism, small hands and feet
- Elongated face, thin upper lip, and a
prominent nose

III. Complex Multigenic Disorders

 Interactions between variant forms of

genes and environmental
factors

 Environmental influences can

significantly modify the phenotypic
expression of complex traits.

a. type II diabetes mellitus

b. nutritional influences