DR MA OBIO
FMC path
GENETIC DISORDERS
CONTENTS
LEARNING OBJECTIVES
INTRODUCTION
INTRODUCTION
• Genetic disorders are conditions that occur as a result of changes to or
mutations in DNA within the body’s cells.
• There are several different genetic disorders due to DNA mutations
• Most cells within the body contain the molecule DNA which provides the
cell with instructions on how to function.
• A change or mutation within the DNA can cause the cell to function
abnormally & cause a genetic disorder.
• Each DNA strand is tightly coiled around a protein called a histone.
• This coiled structure is called a chromosome.
• Chromosomes contain small sections of DNA called genes which provide
the body with specific set of instructions.
• Each human cell normally contains 23 pairs of chromosomes with one of
each pair provided by each parent, thus a person has two copies of every
gene.
• Since genes pass from parent to child, these disorders may be heritable.
However not everyone with a genetic condition in their family will
experience symptoms of the disorder.
• Genetic conditions can affect any gene or chromosome implying that there
are a wide range of genetic disorders each causing various symptoms.
DEFINATION OF TERMS
Hereditary disorders
• Are derived from one’s parents
• Are transmitted in the gametes through the generations & thus familial.
Congenital disorders: Congenital simply means “present at birth.” Note
some congenital diseases are not genetic like in congenital syphilis.
• Also not all genetic diseases are congenital e.g. the expression of
Huntington disease begins only after the third or fourth decade of life.
• A karyotype is an individual’s complete set of chromosomes
HAPLOID: Presence of a single set of chromosomes
DIPLOID: Humans normal chromosome count is 46 (2n = 46). Containing two
complete sets of chromosomes(One from each parent)
EUPLOID: Any exact multiple of the haploid number (n) is called euploid (Having an
equal number of all the chromosomes of the haploid set
POLYPLOID: Presence of an extra set of chromosome in the cells due to abnormal
cell division & commonly occurs in plants
3n & 4n are called polyploid
Generally results in spontaneous abortion.
ANEUPLOID: Any number that is not an exact multiple of n is called aneuploid.
(One or more chromosomes added or deleted to the normal chromosome number)
Main cause of aneuploidy is nondisjunction of a homologous pair of chromosomes
at the first meiotic division
TRISOMIC: (2n + 1): Extra chromosome. Trisomies of certain autosomes
is compatible with life.
MONOSOMIC: (2n − 1): Monosomy involving an autosome is
incompatible with life while that involving sex chromosomes is
compatible with life.
MOSAICISM: Presence of 2 or more populations of cells with different
complements of chromosomes in the same individual.
Mosaicism affecting sex chromosomes is common while autosomal
mosaicism is not.
GENETIC ABNORMALITIES CONTRIBUTING TO HUMAN DISEASE
There are several types of genetic abnormalities that affect the structure &
function of proteins & disrupting cellular homeostasis contributing to disease.
1. Mutations in Protein-Coding Genes
Mutation: Refers to permanent changes in the DNA.
• Mutations affecting germ cells are transmitted to the progeny & may give rise to
inherited diseases.
• Mutations in somatic cells are not transmitted to the progeny but are important
in the causation of cancers & some congenital malformations.
A. 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. (Leading to alteration of the genetic code)
• The mutation in the β-globin chain of hemoglobin gives rise to sickle cell anemia
B. FRAMESHIFT MUTATIONS: Occur when the insertion or deletion of one or two
base pairs alters the reading frame of the DNA strand.
C. TRINUCLEOTIDE REPEAT MUTATIONS (TRM): Characterized by amplification of a
sequence of 3 nucleotides. Example is the Fragile X syndrome
2. Alterations in Protein-Coding Genes Other Than Mutations
In addition to alterations in DNA sequence, coding genes also can undergo
structural variations like copy number changes (Amplifications or deletions) or
translocations that result in aberrant gain or loss of protein function.
• Pathogenic germline alterations involve a contiguous portion of a chromosome
rather than a single gene (e.g. 22q microdeletion syndrome)
• The “Philadelphia chromosome” a translocation t (9; 22) between the BCR & ABL
genes in chronic myeloid leukemia is a classic example.
There are 3 major categories of genetic disorders
1. Mendelian disorders resulting from mutations in single genes.
• The genetic abnormalities show high penetrance, meaning that most individuals
who inherit the anomaly show phenotypic effects.
• These diseases are hereditary & familial.
• Examples: Storage diseases & inborn errors of metabolism.
2. Complex disorders involving multiple genes & environmental influences.
• These are called multifactorial diseases.
• Examples: Hypertension, Diabetes, Allergic & autoimmune diseases.
3. Diseases arising from chromosomal abnormalities
• Changes in the number or structure of chromosomes.
4. Other genetic diseases which involve single gene mutations but do
not follow simple Mendelian rules of inheritance.
These single-gene disorders with non-classic inheritance patterns
include:
1. Those resulting from triplet repeat mutations
2. From mutations in mitochondrial DNA
3. Those in which the transmission is influenced by an epigenetic
phenomenon called genomic imprinting.
MENDELIAN DISORDERS
DISEASES CAUSED BY SINGLE-GENE DEFECTS
• Single-gene defects (Mutations) follow the Mendelian patterns of inheritance
• Mutations involving single genes follow one of 3 patterns of inheritance
1. Autosomal dominant
2. Autosomal recessive
3. X-linked.
AUTOSOMAL DOMINANT INHERITANCE
• Are manifested in the heterozygous state thus at least one parent in an index case usually is
affected.
• Affect males & females equally
• Both sexes can transmit the disorder.
• Involves dysfunctional receptors & structural proteins
Examples
Familial hypercholesterolemia
Hereditary spherocytosis
Huntington disease
Polycystic kidney disease
Marfan syndrome
AUTOSOMAL RECESSIVE INHERITANCE
• Are manifested in the homozygous state.
• Occur when both copies of a gene are mutated i.e. both alleles at a given gene
locus are mutants.
• Frequently involve enzymes.
• Males & females are affected equally
Sickle cell anemia
Phenylketonuria
Galactosemia
Cystic fibrosis
Tay-Sachs disease
Glycogen storage diseases
Mucopolysaccharidosis (MPSs)
X-LINKED INHERITANCE
• Are transmitted by heterozygous females to their sons who manifest the
disease.
• Female carriers usually are unaffected because of random inactivation of
one X-chromosome.
Examples
Duchenne muscular dystrophy
Hemophilia
BIOCHEMICAL BASIS & INHERITANCE PATTERN FOR SOME
MENDELIAN DISORDERS
DISEASES CAUSED BY MUTATIONS IN GENES ENCODING STRUCTURAL
PROTEINS
• Marfan syndrome: Autosomal dominant disorder of connective
tissues manifested principally by changes in the skeleton, eyes &
cardiovascular system
• It is caused by an inherited defect in an extracellular glycoprotein
called fibrillin-1 secreted by fibroblasts (Major component of
microfibrils found in the extracellular matrix)
• Fibrillin is encoded by the FBN1 gene, which maps to chromosomal
locus 15q21
DISEASES CAUSED BY MUTATIONS IN GENES ENCODING RECEPTOR
PROTEINS OR CHANNELS
1. Familial Hypercholesterolemia (FH)
2. Cystic fibrosis (CF)
DISEASES CAUSED BY MUTATIONS IN GENES ENCODING ENZYME PROTEINS
1. Phenylketonuria (PKU)
2. Galactosemia
DISEASES CAUSED BY MUTATIONS IN GENES ENCODING PROTEINS THAT
REGULATE CELL GROWTH
1. Oncogenes
2. Tumor suppressor genes (TSGs)
COMPLEX MULTIGENIC DISORDERS (Multifactorial or polygenic
disorders) --- CMDs
CYTOGENETIC DISORDERS
CYSTIC FIBROSIS (CF)
• CF follows a simple autosomal recessive transmission
• Is a disorder of epithelial ion transport affecting fluid secretion in exocrine
glands & the epithelial linings of the respiratory, GIT & reproductive tracts.
• The ion transport defects lead to abnormally viscid mucous secretions that
block the airways & pancreatic ducts leading to recurrent & chronic
pulmonary infections & pancreatic insufficiency.
• Increased sodium chloride in the sweat: The exocrine sweat glands are
structurally normal (Remain so throughout the course of this disease), a
high level of sodium chloride in the sweat is a consistent & characteristic
biochemical abnormality
Familial Hypercholesterolemia (FH)
• Is a “Receptor disease” caused by loss-of-function mutations in the gene
encoding the LDL receptor involved in transport & metabolism of
cholesterol
• FH is one of the most common Mendelian disorders
• About 7% of the body’s cholesterol circulates in the plasma predominantly
as LDL.
• Mutations in the LDL receptor protein impair the intracellular transport &
catabolism of LDL resulting in accumulation of LDL cholesterol in the
plasma. (Reduced catabolism & excessive biosynthesis)
• This leads to skin xanthomas & premature atherosclerosis increasing the
risk of myocardial infarction.
PHENYLKETONURIA (PKU)
• Results from mutations that cause severe lack of the enzyme phenylalanine hydroxylase
(PAH).
• Affected infants are normal at birth but within a few weeks exhibit a rising plasma
phenylalanine level which impairs brain development with evident severe mental
retardation (Usually by 6 months of life).
Biochemical abnormality in PKU: Inability to convert phenylalanine into tyrosine.
1. In normal children < 50% of dietary intake of phenylalanine is necessary for protein
synthesis.
2. The rest is converted to tyrosine by the phenylalanine hydroxylase system
3. Blockage of phenylalanine metabolism from lack of PAH enzyme leads to shunt pathways
yielding several intermediates excreted in large amounts in the urine & sweat.
• These impart a strong musty or mousy odor to affected infants.
• The concomitant lack of tyrosine (Precursor of melanin) is responsible for
the light color of hair & skin.
GALACTOSEMIA
• Autosomal recessive disorder of galactose metabolism resulting from a
mutation in the gene encoding the enzyme galactose-1-phosphate
uridyltransferase (GALT).
• It affects 1 in 60,000 live-born infants.
• Due to the transferase deficiency, galactose-1-phosphate & other
metabolites like galactitol accumulate in many tissues (Liver, spleen, lens of
the eye, kidney & cerebral cortex).
• Two classes of genes proto-oncogenes & tumour suppressor genes,
regulate normal cell growth.
• Oncogenes
• Are genes that induce a transformed phenotype when expressed in cells by
promoting increased cell growth
• Oncogenes are mutated or overexpressed versions of normal cellular genes
called proto-oncogenes.
• Most oncogenes encode transcription factors that participate in progrowth signaling pathways or factors that enhance cell survival.
• They are considered dominant genes because a mutation involving a single
allele is sufficient to produce a pro-oncogenic effect.
Tumour suppressor genes (TSGs)
• Are genes that normally prevent uncontrolled growth & when mutated or
lost from a cell allow the transformed phenotype to develop
• Often both normal alleles of TSGs must be damaged for transformation to
occur.
• TSGs
• “Governors”: Act as important brakes on cellular proliferation
• “Guardians”: Responsible for sensing genomic damage. May initiate
“Damage control response” that leads to the cessation of proliferation or if
the damage is too great to be repaired induce apoptosis.
COMPLEX MULTIGENIC DISORDERS (Multifactorial or polygenic disorders) --CMDs
• Are caused by interactions between genetic variants & environmental factors.
• Environmental influences significantly modify the phenotypic expression of
complex traits
CYTOGENETIC DISORDERS
• Cytogenetic deals with the study of chromosomes in a cell
• In humans the chromosome is located within the nucleus
• A karyotype is an individual’s complete set of chromosomes
• It is a photographic representation of a stained metaphase spread in which the
chromosomes are arranged in order of decreasing length in the laboratory.
Numeric Abnormalities
• In humans each cell normally contains 23 pairs of chromosomes
(Diploid) making a total of 46
• Twenty two of these pairs (44) are called autosomes & looks the same
in both males & females
• The 23rd pair (2) are called the sex chromosomes.
• Females have two copies of the X chromosome
• Males have one X & one Y chromosome
Structural Abnormalities
Typically result from chromosomal breakage followed by loss or rearrangement of material.
Types of chromosomal rearrangements.
The patterns of chromosomal rearrangement after breakage are as follows:
1. Translocation: Transfer of part of one chromosome to another chromosome
2. Isochromosomes: Result when the centromere divides horizontally rather than vertically.
3. Deletion: Involves loss of a portion of a chromosome.
4. Inversions: Occur when there are 2 interstitial breaks in a chromosome & the segment reunites
after a complete turnaround.
5. Ring chromosome
• Is a variant of a deletion
• After loss of segments from each end of the chromosome, the arms unite to form a ring.
CYTOGENETIC DISORDERS INVOLVING AUTOSOMES
• Three autosomal Trisomies (21, 18 & 13) & one deletion syndrome (Cri- du-chat
syndrome) resulting from partial deletion of the short arm of chromosome 5
• Other additional trisomies & deletion syndromes like trisomy 21 & 22q11.2
deletions occur
TRISOMY 21 (DOWN SYNDROME)
1. Characterized by extra copy of genes on chromosome 21 is the most common
chromosomal disorders.
2. About 95% of affected persons have trisomy 21 (Chromosome count of 47)
3. The most common cause of trisomy & Down syndrome is meiotic
nondisjunction.
4. The parents are normal but maternal age has a strong influence on the
incidence of Down syndrome.
5. It occurs in 1 in 1550 live births in women younger than 20 years
compared to 1 in 25 live births in women older than 45 years.
6. The correlation with maternal age suggests that in most cases the meiotic
nondisjunction of chromosome 21 occurs in the ovum (In 95% of cases the
extra chromosome is of maternal origin).
7. No effect of paternal age has been found in those cases in which the extra
chromosome is derived from the father.
8. In about 4% the extra chromosomal material is present as a translocation
of the long arm of chromosome 21 to chromosome 22 or 14.
9. 1% are mosaics usually with a mixture of 46 & 47-chromosome cells
resulting from mitotic nondisjunction of chromosome 21 during an
early stage of embryogenesis.
DIAGNOSTIC CLINICAL FEATURES
1. Flat facial profile
2. Oblique palpebral fissures
3. Epicanthic folds usually evident at birth.
Other clinical features
• Severe mental retardation
• Congenital heart disease (40%): Defects of the endocardial cushion (Atrial septal
defects, atrioventricular valve malformations & ventricular septal defects
• Cardiac problems are responsible for most deaths in infancy & early childhood.
• Others are atresia’s of the esophagus & small bowel
• 10-20 fold increased risk of developing acute leukemia.
• Virtually all patients older than 40 years develop neuropathologic changes
characteristic of Alzheimer disease (Degenerative disorder of the brain)
• Abnormal immune responses that predisposes to serious infections particularly
of the lungs & to thyroid autoimmunity
DIAGNOSIS
1. Molecular diagnosis prenatally using polymorphic genetic markers.
2. Next-generation sequencing (Fetal DNA) is a sensitive & specific
noninvasive method (“Liquid biopsy”) for prenatal diagnosis of trisomy
21 & other trisomies.
3. Confirmatory diagnosis is by conventional cytogenetics on fetal cells
(Amniocentesis)
CYTOGENETIC DISORDERS INVOLVING SEX CHROMOSOMES
• Some abnormal karyotypes involving the sex chromosomes are compatible with life (45,X to
49,XXXXY)
• Extreme karyotypic deviations seen with sex chromosomes are not encountered with the
autosomes.
• This is due to 2 factors
1. Lyonization of X-chromosomes
2. Small amount of genetic information carried by the Y- chromosome.
TURNER SYNDROME
a. Characterized by primary hypogonadism in phenotypic females from partial or complete
monosomy of the short arm of the X-chromosome.
b. In 57% cases the entire X-chromosome is missing (45,X karyotype)
c. Diagnosis (Cytogenetic) at birth or early childhood.
CLINICAL FEATURES
• Short stature: Growth retardation below the third percentile
• Swelling of the nape of the neck in infancy (Distended lymphatic channels or
webbing of the neck in older children
• Low posterior hairline
• Cubitus valgus (Increase in the carrying angle of the arms)
• Shield like chest with widely spaced nipples
• High arched palate
• Lymphedema of the hands & feet
• Congenital malformations (Horseshoe kidney, bicuspid aortic valve & coarctation
of the aorta
• Cardiovascular abnormalities are the most common cause of death in childhood
Adolescence girls fail to develop normal secondary sex characteristics:
a. Infantile genitalia
b. Minimal breast development
c. Little pubic hair appears.
4. Most have primary amenorrhea
5. Transformation of the ovaries into white streaks of fibrous stroma
devoid of follicles.
• Normal mental status
• Hypothyroidism from autoantibodies
ASSIGNMENT
READ THE FOLLOWING
1. THE HUMAN GENOME
2. LYON HYPOTHESIS
DIAGNOSIS & TESTS
1. Family history of a genetic disorder: Consider genetic counseling
2. If there’s a family history:DNA testing for genetic disorders can be an important part of
starting a family like:
• Carrier testing: This blood test shows whether you or your partner carry a mutation
linked to genetic disorders. Recommended for everyone considering pregnancy even if
there is no family history.
• Prenatal screening: This testing usually involves blood testing from a pregnant person on
the likelihood that a fetus could have a common chromosome condition.
• Prenatal diagnostic testing (Amniocentesis): To find out whether the developing fetus
faces a higher risk for certain genetic disorders.
• Newborn screening: Using sample of the newborn baby’s blood. Detecting genetic
disorders early in life can help the newborn receive timely care if needed.
MANAGEMENT AND TREATMENT
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Most genetic disorders do not have a cure.
Treatments to slow disease progression or lessen their impact
Treatment depends on the type & severity of the disease
Treatment mainly supportive
Chemotherapy to slow abnormal cell growth.
Nutrition counseling or dietary supplements
Physical, occupational or speech therapy.
Blood transfusion
Surgery to repair abnormal structures or treat complications.
Specialized treatments like radiation therapy for cancer.
Organ transplant