GENETIC DISORDERS NOTES

TAY-SACHS DISEASE
● Also known as GM2 Gangliosidosis type 1
● Autosomal recessive disorder (meaning, affected person inherits one mutated HEX-A gene from each carrier
parent, so the chromosome pair both need to be mutated for this to happen)
● Mutation in Chromosome 15 codes for a lysosomal enzyme called beta-hexosaminidase A or HEX-A for short
○ HEX-A breaks down lipid called GM2 ganglioside
○ GM2 is found usually in neurons, so without the enzyme that breaks it, it ACCUMULATES inside
lysosomes (membrane-enclosed organelles that contain an array of enzymes capable of breaking
down all types of biological polymers—proteins, nucleic acids, carbohydrates, and lipids.)
● This disorder causes progressive symptoms in the central nervous system (CNS degeneration). Symptoms of
TSD start to appear at ages 3 - 6 months, and they usually end up dying when they turn 4 years old.
Symptoms include:
○ Decreased muscle tone
○ Increased reflexes
○ Visual difficulties
○ Seizures
● No cure.
● But symptoms appear in different stages of life
○ Infantile - 3 - 6 months
○ Juvenile - 2 - years
○ Chronic - 10 - 20 years
○ Late-onset - 20 - 30 years
■ Symptoms can be motor difficulties, bipolar-type psychological symptoms, “cherry red spot”
● TSD is either
○ Total deficiency - no synthesis of HEX-A enzyme
○ Varying degrees of enzyme activity - defective synthesis

SICKLE CELL ANEMIA

● A genetic disorder where the red blood cell is shaped like a crescent or a sickle, which causes the cell to be
easily destroyed and causes anemia.
● Mutation in the HBB gene causes the formation of abnormal hemoglobin (hemoglobin S)
● Sickle cell mutation is a non-conservative missense mutation - that occurs when the 6th amino acid of beta-
globin is val (hydrophobic) instead of glu (hydrophilic).
● Autosomal recessive disease
● Sickle Cell is caused by defective hemoglobin (the protein contained in red blood cells that is responsible for
the delivery of oxygen to the tissues and its color)
○ The type of hemoglobin that is usually affected in sickle cell is Hemoglobin A - two alpha globin and
beta globin, wherein the beta-globin chains end up misshapen.
○ If both alpha globin and beta globin are mutated is called Sickle Hemoglobin
■ This changes the shape of the hemoglobin when de-oxygenated and forms a polymer chain
with other hemoglobin that is called SICKLING
● Sickling causes acidosis (decrease of hemoglobin’s affinity for oxygen) and low-flow
vessels (where hemoglobin dumps lots of oxygen molecules)
● Sickle cell causes premature destruction of red blood cells which leads to anemia
● The crescent shape also can cause blocking in the blood vessels (vaso-occlusion)

PHENYLKETONURIA
● The autosomal recessive metabolic disorder is caused by a mutation in chromosome 12 that codes for the
protein phenylalanine hydroxylase. Without this protein, we cannot break down the phenylalanine into
tyrosine, and high levels of phenylalanine damage the brain. There is no cure but there are measures to take
to maintain a healthy condition
● Symptoms appear at an early age during infancy, this includes:
○ Facial distortion
○ Hypopigmentation
○ Intellectual disabilities
Hemophilia
Hemophilia A
● Decrease in the amount of function of clotting factors that causes blood loss which takes longer time to clot
up.
● Disorder of the secondary hemostasis due to Factor VIII deficiency.
○ Inability to form fibrin clot adequately.
● Males are predominantly affected
● Also called classic hemophilia, is the most common form of a genetic alteration in the f8 gene that causes an
underproduction of clotting factor viii an x-linked, recessive hemorrhagic trait or gene that induces Hemophilia
A.
Hemophilia B
● It is a rare genetic bleeding disorder in which affected individuals have insufficient levels of a blood protein
called factor ix they don't bleed faster, but bleed longer a genetic variation in the f9 gene results in low levels
of clotting factor IX

Cystic Fibrosis
● Autosomal recessive disorder
● A genetic disorder that results from the abnormal transport of chloride and sodium across an epithelium,
leading to thick, viscous secretions that clog the following organs:
○ Lungs
○ Pancreas
○ Liver
○ Intestine
○ sinuses
● Mutation in the cystic fibrosis transmembrane conductance regulatory gene (CFTR) in chromosome 7.
○ CFTR protein functions as a chloride channel that allows the passage of chloride ions across cell
membranes. CFTR regulates water and salt balance in mucus and sweat.
○ Mutated CFTR causes thicker mucus, causing obstruction and not allowing chloride ions to pass
○ The most common mutation that caused this is because of the deletion of the phenylalanine in the
CFTR gene in position 508
● Symptoms:
○ Persistent cough with phlegm
○ Chest and lung infections, weight loss
○ Difficulty in bowel movement, and unusually salty-tasting sweat
Cri-du-chat syndrome
● Caused by partial deletion of the short arm of Chromosome 5 (5p)
● The name comes from the high-pitched cry of affected infants because of the abnormal development of the
larynx or voice box, which makes them cry like a cat.
● Infants usually pass away by the age of 2
● Characterized by
○ Intellectual disability
○ Delayed development
○ Small head (microcephaly)
○ Distinctive facial distortions
■ Round face, low-set ears, hypoplastic nasal bridge
● Causes structural cardiac defects, difficulty swallowing
Duchenne Muscular Dystrophy
● Muscle is weak and unnourished because of degeneration.
● Recessive X-linked disease, so more common in boys
● Mutation in the dystrophin gene located in the X chromosome which codes for the dystrophin
○ In this disorder, there is NO dystrophin at all.
○ Dystrophin connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through
the cell membrane, in layman’s terms, Dystrophin stabilizes the muscle membrane and allows our
muscle to be weak,
● Gower’s sign - using arms to stand up because of weak muscles around the hips and upper legs. This is a
sign of DMD. Also Waddling gait during infancy.
● Causes: high creatine kinase, mutations in dystrophin, muscle biopsy.
● There is no proper treatment or cure.
● The disorder can be detected by the age of 5
● Loss of dystrophin causes myonecrosis or muscle necrosis (death of cells in muscle)