● Autosomal dominant disorders cause less severe manifestation than autosomal recessive

disorders
 ● Mitochondrial disorders include Leber hereditary optic neuropathy.
● Pleiotropy is when single gene mutation have many phenotypic effects
● Genetic heterogeneity: mutations at several genetic loci may produce the same trait.
● Genetic anticipation: A phenomenon in which a genetic disease has an earlier appearance
or has higher severity than the preceding generation.
● Hermaphrodite: having both ovarian and testicular tissue
● Pseudohermaphrodite represent a disagreement between the phenotypic and gonadal sex.
● In female pseudohermaphroditism, there is normal gonads and internal genital but the
external genitalia is ambiguous
● Female pseudohermaphroditism has ambiguous or completely female external genitalia
Disorders with defects in structural proteins:
Marfan syndrome:
● It is an autosomal dominant disorder where we have a mutation in fibrillin 1 which is a
component of CT and is associated with elastin which functions to support CT.
● There is increased transforming growth factor signaling activation which is responsible
for defective formation of fibrillin 1. The transforming growth factor plays an important
role in wound healing, angiogenesis, immunoregulation and cancer.
● Symptoms: Tall, long extremities, long fingers, flat feet, over flexible joints, scoliosis.
● Fibrillin 1 is also one of the things that compose the zonule (holds the lens) of the eye.
This is why the lens in marfan syndrome is up and to the right. This is why they have
vision problems and why they wear glasses.
● Cardiovascular involvement: mitral valve prolapse because of the poor support to the
valve. Aortic aneurysm because there is weakness in the wall of the blood vessels.
Dissection of the aorta; when there is a tear in the intima of the blood vessel, the blood
spills out into these tears and the chance of rupture is high.
EDS:
● It is an autosomal dominant disorder where we have defective collagen. It could be
abnormal structure of collagen or deficiency in collagen fibrils.
● Collagen is responsible for the strength of CT.
● We can also have it as an autosomal recessive disorder.

● Patients have normal height, the skin is very stretchy, hypermobility of joints, rupture of
organs.
● Because blood also contains collagen (type III), we have easy bruising.
● There is also aneurysm of the aorta and aortic dissection like marfan.
● There is kyphosis and lordosis like marfan.
Familial hypercholesterolemia:
● Chylomicrons enter the lymphatics and move to the blood vessels where they have
different ways they can go. They can go to the liver where the liver uses cholesterol to
synthesize bile, sex hormones, etc. The extra cholesterol is released from the liver as
 VLDL (contains more triglycerides) which circulates in the blood. We have lipoprotein
lipase in the blood which breaks down fatty acids which turns VLDL into IDL and then
LDL (contains more cholesterol).
● LDL receptor defect causes familial hypercholesterolemia. This can cause atherosclerosis
because the defect will lead to the oxidation of the LDL which becomes engulfed by
macrophages. This leads to foam cells and inflammation which leads to plaque.
● It is an autosomal dominant disease that leads to premature changes of atherosclerotic
changes in the blood vessel.
● Young patients with myocardial infarction can be a sign of familial hypercholesterolemia.
● Patients present with Xanthelasma and xanthomas which cause lipid accumulation around
the eye.
Lysosomal storage disease:
Tay-Sachs disease:
● It's a lysosomal storage disease most common in Ashkenazi jews.
● It is an autosomal recessive disorder characterized by the absence of beta hexosaminidase
A which breaks down fatty substances like GM2 gangliosides. The gangliosides
accumulate mostly in the brain and cause neuronal damage.
○ Gangliosides are glycosphingolipids which are in the plasma membrane.
● It is a neurodegenerative disorder which affects CNS.
● Symptoms: flappy (muscles relaxed) baby, ataxia (can not walk by themselves), seizures
(due to increased discharge from the brain), mental retardation, and cherry red spot in the
macula of the eye,
○ When seizure continues for more than 5 minutes, it causes permanent brain
damage
● There is low life expectancy (2-4 years) and patients end up in a vegetative state.
Niemann-Pick disease:
● It is an autosomal recessive disorder caused by deficiency in sphingomyelinase.
Sphingomyelin accumulation leads to damage of cells in the CNS or other systems.
We have three types:
● Type 1: Neurodegeneration: Symptoms are similar to tay sach: incoordination, ataxia, and
severe mental retardation. Symptoms start by 6 months of age. Life expectancy 3-5 years
● Type 2: The brain is not affected. It causes organomegaly like liver and spleen. These
symptoms occur in the pre-teen years. Patients can survive until adulthood. It leads to
splenomegaly, hepatomegaly, abdomen enlargement, lymph node enlargement, and
cherry red spots on the macula.
● Type 3: It is mixed between 1 and 2. Patients may start presenting symptoms early in life
or in adult years. Patients have moderate enlargement of spleen and liver, and there is
brain damage.
Gaucher disease:
 ● It is an autosomal recessive disorder characterized by glucocerebrosidase deficiency. The
glucocerebrosides accumulate in macrophages and other cells.
● Type 1: No neurological symptoms, symptoms appear at any age, the disease is
progressive. It causes organomegaly. It can accumulate in the bones and cause increased
risk of fractures.
● Type 2: severe neurological symptoms, symptoms appear in the first year, and is rapidly
progressive
● Type 3: moderate to severe neurological symptoms, symptoms appear during childhood,
and it is progressive.
Mucopolysaccharidosis: defects in the breakdown of mucopolysaccharides
MPS I: Hurler:
● It is an autosomal dominant disorder characterized by deficiency of alpha L-iduronidase.
● It presents with corneal clouding, hepatosplenomegaly, coarse facial features, mental
retardation, dysostosis (abnormal development) of bone, cardiac involvement.
● Usually dies in childhood
MPS II: Hunter:
● It is an X-linked recessive disease characterized by deficiency of iduronate 2 sulfatase
which degrades dermatan and heparan sulfate.
● It presents with hepatosplenomegaly, dysostosis of bones, coarse facial feature, no
corneal clouding, cardiac involvement, and later developmental regression.
● Usually dies earlier than 15 years.

Glycogen storage disorders:

● Only know I,II, and IV.

Chromosomal disorders: trisomies could be due to robertsonian translocation, mosaicism, and
nondisjunction. The triple test for trisomies is AFP (alpha fetoprotein) in fetus (low), HCG
(Human chorionic gonadotropin) in the placenta (high), and estriol in the fetus and placenta
(low).
Trisomy 21: down syndrome:
● Symptoms increase with increasing age of the mother.
● Symptoms include: flat and small noses, smooth philtrum (skin between mouth and
nose), Almond shaped eyes with oblique palpebral fissure, low set ears, mouth is open
because of mental retardation, brushfield spots in the eye, simian crease on hand (single
transverse line), large gap between 1st and 2nd toes.
● They can have duodenal atresia, acute lymphoblastic leukemia, alzheimer, congenital
heart anomalies, hirschsprung disease (absence of nerve cells (ganglions) in a segment of
the bowel in an infant which causes the muscles in the bowels to lose their ability to
move stool through the intestine (peristalsis)).
● AFP is low, estriol is low, and HCG is high
Trisomy 18: Edwards syndrome:
● Patients present with micrognathia (undersized lower jaw), low set ears, clubfeet (rocker
bottom) (feet rotated externally), clenched fists, high chance of ventricular septal defects,
and mental retardation.
Trisomy 13: Patau’s syndrome:
● It causes microphthalmia (small eyes), microcephaly (small head), cleft lip, cleft palate,
rocker bottom feet, low set ears, increased risk of congenital heart defects
Klinefelter Syndrome:
● Patients have XXY chromosomes which means that they have nondisjunction of the sex
chromosomes.
● Patients are tall, have low testosterone levels, hypogonadism, testicles are atrophied,
testicles have a higher chance of having cryptorchidism which means that the testicles
have not descended yet, gynecomastia (enlarged breast in men), female voice, lower IQ
than usual but not too low, FSH and LH levels are high.
● We can inject testosterone.
● They look more male than female.
Turner syndrome:
● It is an X0 syndrome, they have a missing X chromosome on the 23rd pair. Patients look
like females but have low height, short necks. Patients have a higher chance of having
edema and molar rash. They have atrophied ovaries which means they have a small
chance of becoming pregnant so they are infertile. They have a bicuspid aortic valve (two
cusps instead of three) and aortic coarctation (narrowing of the aorta). They also have
cystic hygroma (a group of cysts, found mostly in the neck). They have widely spaced
nipples.
DiGeorge Syndrome:
 ● A disease characterized by developmental anomalies of the third and 4th pharyngeal
pouches due to a deficiency on the 22nd chromosome. It is characterized by thymic
hypoplasia, hypoparathyroidism, and heart anomalies.
○ The low calcium levels cause increased neuromuscular excitability by decreasing
the threshold needed for the activation of neurons.
● There is also congenital heart disorder where the aorta and pulmonary artery are
connected to each other. There is only 1 truncus and it is called truncus arteriosus. There
is also an interrupted aortic arch.
● For tests, B cells are normal but in reality, there is secondary B cell deficiency because
we need T cells to activate B cells.
● To test for hypocalcemia, we have chvostek and trousseau signs. If you lightly tap on the
cheek, it will cause contraction of the facial muscles, this is the Chvostek test. When you
are measuring the BP and inflating the balloon, the pressure causes tetanic contractions of
the digits and causes them to flex inward, this is the trousseau sign. There is no mental
retardation.
● The treatment is thymus transplant.
● There is more frequent cleft lip/palate, small jaw, small upper lip/mouth, eyes slanted
upward or downward, low-set ears, short stature, mild to moderate learning difficulties,
and cardiac malformations.
Fragile X syndrome:
● There are too many repeated sequences on the X chromosome which makes it look
fragile.
● Patients present with elongated face, and broad forehead, large and prominent ears,
prominent lower jaw, macroorchidism (very large testicles) post puberty, strabismus (eyes
do not look in the same place), heart anomalies like mitral valve prolapse, scoliosis.
● It is the second most common cause of retardation after down syndrome.
Prader-Willi/ Angelman syndrome:
● It is an example of genetic imprinting disease, meaning genes are expressed in a
parent-of-origin-specific manner.
● Prader Willi syndrome is due to deletion of paternal copy of UPD of chromosome
15q11-q13. There is language, motor, and developmental delays along with excessive
weight gain. Patients are short, obese (high appetite), hypogonadism, hypotonia, mildly
retarded.
● Angelman syndrome is due to deletion of maternal copy of UBE3A gene or UPD of
chromosome 15q11-q13. There is severe mental retardation and a happy demeanor.
Patients have spontaneous laughter, jerky movements, severe retardation, and other
motor and mental symptoms.