Neural Tube Defects

(NTD)

Cleft Lip + Cleft

Palate

Adult Onset Complex

Diseases

Disorder
Trisonomy 21

Disorder
Congenital birth
defects

Hirschsprung Disease
(HSCR)

the disease)
Abnormal/incomplete
closure of the neural
tube (3-4 of
gestation)
MTHFR gene =
genes in mother
Hemocysteine
metabolism
Mutation of:
TBX1 (gene
associated with
migration of facial
parts)
FGFR1

Abnormality
Meiotic Non
Disjunction
47,XX+21
47, XY +21

Abnormality

Defect of neural crest

migration to the
intestinal tract
(aganglionic plexus)
= no enervation
Associated gene:
many = primarily
RET (not everyone
that has RET
mutation will have

Anencephaly

Spina Bifida (normally at

lower back) = problem with
walking, evacuation, UTI

Affect respiration and

swallowing

Coronary artery Disease

Congestive heart failure
Hypertension
Stroke
Diabetes
Asthma
Cancer
Autoimmune
Psychiatric
Parkinson +
Alzheimer

Clinical
Down Syndrome

CHROMATIN + CHROMOSOME
Diagnosis
Karyotype

COMPLEX DISORDERS
Diagnosis

Clinical
Congenital Heart Disease
Neural Tube Defects: Spina
Bifida/ Anencephaly
Cleft lip / Cleft palate
Congenital intestinal
aganglionosis
Inability to defecate
Abdominal distention

Folic acid
supplementati
on =
decreases risk

Treatment

Treatment

2/3 F > M
Risk increases with
relatedness (degree)

Cigarette smoking during

pregnancy
2/3 M > F
Decreased risk as degree
increases
Recurrence risk in affected
families is almost twice as
that of the general population

Notes
Uneven number of
chromatids =
aneuploidy

Notes
First degree relative is
affected = risk = 3-5%
More first degree relatives are
affected = risk doubles
Both parents + a sibling = ~
40-45%

Diabetes Mellitus
Type 2

Alzheimer Disease

Cardiovascular
Disease

Hypercoagulability
Disorders

Diabetes Mellitus
Type 1

HLA-DQ6
Factors that affect
glucose metabolism =
glucose intolerance
(beta cell mass,
insulin secretion,
insulin action,
obesity, fat
distribution)
Association to genes
involved in glucose
and lipid metabolism
(GCK, HN4A, PPAR
gamma)
Mutations:
Amyloid Precursor
Protein (abnormal
protein aggregation in
neurons = amyloid
plaque) ! also
increased in Down
Syndrome (@
chromosome 21 =
abnl post translational
protein modification)
Prensilin 1/2 (PSEN

Multiple Genes
MTHFR
(coagulation)
LDL receptor

Missense mutation @
Factor V Leiden
clotting factor
Prothronbin clotting
factor (3 UTR
variant)
Tetrahydrofolate
reductase
Autoimmune
destruction of
pancreatic islets
(beta)
MHC
HLA-DQ2/DQ8
(HETS)

High Blood
Sugar

Insulin resistance at target cells

Higher environmental
conditions: health, obesity,
exercise

Weight loss = reduces the risk

Weakness and fatigue

F rarer to be affected = if
affected = offspring will have
higher risk
Environment: Oral
Contraceptives, surgery,
immobility, malignancy

M> F

Leading cause of death in US

Environmental factors: diet,

exercising, smoking

Progressive dementia

Risk associated with relative

degree

F>M

Sugar cannot get into the cell

Coronary Artery Disease

Cardiomyopathy
Conduction abnl
Hypertension
Stroke
Aneurysm
Peripheral vascular disease

Idiopathic Cerebral Vein

Thrombosis
Placental Artery Thrombosis
Deep Venous Thrombosis
(DVT)

Lack of insulin production

Genetical + environmental
influences
Most common among whites

Disorder
Phenylhenouria

Disorder
Osteogenesis
Imperfecta (OI)
Type 1: OI Tarda !
mild mutation
Type 2: OI
Congenita !
Perinatal = lethal
Type 3: Severe OI

pyrimidine dimers
@ 8 different genes

Abnormality
Defficiency of
Phenylalanine
Hydroxylase (PAH)

Abnormality
MUT @ Type 1
(Polypeptie problem
causes an effect in the
double helix)
Decrease synthesis +
Abnormal collagen
formation
Most = Di Novo
mutation @ pro alpha 1 /
2 chains

1 / PSEN 2) =
enzyme for APP
cleavage

Abnormality
Defective MMR +
Tumors with MSI

APOE = superficial
protein = move
cytochrome in plasma

Disorder
Lynch Syndrome
Families
Problem @ enzyme =
DNA repair

Defect of XP genes =
defects in the incision
step of NER of

Mutation @ XP-B,
XP-D, XP-G = code
for NER ! CSA +
CSB
Defect of XP-B +
XP-D = code for
NER

Werner Syndrome
Bloom Syndrome
Cockayne Syndrome
*
Trichothiodystrophy

Xeroderma
Pigmentosum

Diagnosis

Basal cell carcinomas

Eyes = irritated / cloudy
Hair growth = limited @ legs
Dry skin
Freckles
ENZYMES
Clinical
@ liver

Brittle Bone

Confused with child

abuse

Notes
AD

Notes

Children of the night

Treatment
Biophosphates
= prevents
osteoclast
reabsorb
(higher in OI)
= higher bone
mass and
strength

Treatment
Diet Modification
Tetrahydrobiopterin
Supplmentation
Enzyme replacement
therapy

Non Traumatic fractures

Detinogenesis Imperfecta
Hearing Loss
Asymptomatic
Prone = skin bruises

Notes
Hereditary

AR
Damage from UV (dimers)
= CT / CC

Surgery

Treatment

Clinical
Type 1 = Bowing + fractures of
LB

FIBROUS PROTEINS
Diagnosis
Family history
History of
fractures
X ray fractures
(vary ages +
stages)
Codfish
vertebrae

DNA REPAIR AND RECOMBINATION

Diagnosis

Clinical
Predisposed to early onset cacer
of the colon, endometrium, ovary
and other organs
Premature Aging
Retarded growth
Sunlight Hypersensitivity
Photosensitivity
Growth Defects
Mental Deficiency
Congenital hair shaft dysplasia
(deficiency of sulfur)
Photosensitivity
Short Stature
Intellectual impairment
Photosensitive
Highly susceptible to skin cancer
Neurological Problems

Collagen

Scurvy

NOT genetic

CANCER

Mut @ Type XXIX

Nonsense mediated decay

of mutant MRNA /
failure of collagen prochains to associate
Mut @ Type 4

EDS vascular = Type 3

! affect vessel elasticity

Substitution AA for GLY

or GLY by bulky AA @
carboxy end = cant form
3 helix
Diminished amount of
normal Type 5 (COL5A2
/ COL5A1)

Type 1 = Premature
termination codon
Collagen made @ low
amounts (still have one
normal collagen
chromosome)

COL1A1 and COL1A2

genes (Type 2 and 3)

MUT @ Fibrillin 1 =
FBN1 gene

Metalloproteinases =
disrupt ECM for
migration = Metastasis
Deletion of WBSCR =
contain elastin gene =
chromosome 7

Low Vitamin C
(hydroxylation) ! less
hydroxyproline =
decrease h bonds (lower
tensile strength) = weak
fibril
Endostatin forming
collagen = inhibit
angiogenesis for tumor

Collagen

Williams Syndrome
(WS)
Elastin
Marfan Syndrome
Elastin

Collagen

Ehlers Danlos
Syndrome (EDS)
Collagen

Alport Syndrome
Atopic Dermatitis
Collagen

Family History
Clinical
features @
multiple organ
systems

Weakness + malformations @
skin, bone, teeth
Blood vessel = weakened

Supravascular Aortic Stenosis

(SVAS)
Distinctive Facies
Mental Retardation
Connective tissue abnormalities
Growth anomalies
Eye: Ectopia lentis = lens
dislocation ! visual problems
Long extremities =
disproportionate bone
overgrowth
Heart: dilation of Aorta (prone

Skin hyperextensibility
Skin fragility
Abnormal wound healing
Joint dislocate easily

Hematuria
Hearing loss = collagen @ ear
Highly allergic
Chronic inflammatory skin

Eye =
corrective lens
Skeletal =
surgery
Cardio:
Preventative

Elastin insufficiency
@ vessels ! smooth
muscle hypertrophy

AD

AD or AR

Elastin
Homocystinuria
Elastin
Stickler Syndrome
Elastin
Junctional
Epidermolysis
Bullosa
Laminin (basal
membrane protein)
Congenital Muscular
Dystrophy
Laminin

Mucopolysaccharides
Proteoglycan
Leukocyte Adhesion
Defficiency

TGFBR2
MUT @ CBS
MUT @ COL2A1 /
COL11A1 / COL11A2
Defect @ Laminin 6 & 7
= inhibits cohesion of
epidermis + dermis
(Epidermis > Basal
Lamina > Dermis)
Defect @ Laminin 2 =
links muscle cell
cytoskeleton + ECM

Deficiencies of lysosomal
glycosidase =
accumulation of carbs @
lysosomes
Leukocytes cant activate
integrins ! leukocytes

Blue sclerae
Easy bruising
Arterial Tortuosity + Aneurism
Intellectual Disability
Intravascular thrombosis
Hearing loss
Spontaneous blistering of skin +
mucous membrane
Dehydration = loss of fluid
Lack of Laminin 2 =
Apoptosis
Muscle Dystrophy
Scoliosis
Feeding + Respiratory
difficulties
Motor Delay
IQ = normal
Hepato + Splenomegalia
Loss of function

to aneurism) + mitral valve

Mass Phenotype: weak mitral

valves + skin + skeletal findings

Dural Ecstasia = membrane that

supports spinal cord

Other FBN1
syndromes

Integrin
blocking

AR
AD

Disorder =
proteoglycan
degradation

Marfan Like

Beta-blockers
(inhibit
growth of
aneurism) +
antiotensin
converting
enzyme
inhibitors =
decrease
hemodynamic
stress @
aortic wall

Progressive = from
early infancy

Craniosynostosis
Developmental delay

Marfan Like

Marfan like

Cleft Palate

Muscular Hypoplasia

Ectopia Lentis
Long/slender fingers + toes

Elasin

Hetero MUT @ FBN2

AA MUT @ TGFBR1 /

Mitral Valve Prolapse Syndrome

= >20 yrs + valve prolapse +
subtle skeletal features

Congenital
Contractural
Arachnodactylyl
(CCA)
Elastin
Shprintzen-Golberg
Syndrome (SGS)
Elastin
Loeys Dietz (LDS)

Transcription
inhibitor
Rifampicin

Cockayne Syndrome
*

Beta (+) Thalassemia

*
Beta Thalassemia
*
B0 Thalassemia
*

Integrin

CANCER
Adhesion Proteins
Systemic Lupus
Erythematous
Proteoglycan +
Collagen

Disorder
Alpha Amanitin
Sensitivity
Transcription
Inhibitor
Actinomysin D,
Acridine

movement
Inhibit transcriptional
elongation
Binds @ beta subunit
of bacterial POL
Blocks promoter
clearance =
elongation
MUT @ CSB protein
= subunit of EUK
POL 2
Increase rate of
elongation by POL 2
(CSB)
MUT @ promoter
region of B globin
gene = decrease
production
Point mutation @
POLY A signal =
decreases B globin
Mutation @ 5 or 3
intron site = incorrect
splicing = premature
codification

are required for adhesion

to vascular endothelial
cells (@ infection)
MUT @ Beta 2 integrin
Fibronectin = defective
@ Tumor cells =
abnormal movement @
ECM
Autoimmune disorder =
cartilage degradation
(composed of collagen
and proteoglycans)

Abnormality
Forms tight complex
with POL 2 = inhibits
mRNA + Protein
Synthesis
Weak inhibitor of
POL 3
Intercalates between
GC pairs @ DNA =
interferes with POL

Diagnose

Cannot form 1st

phospho NTD bond

Affect many body

cells
Microcephaly
Mental Retardation
Horse Riding Stance
Anemia

Joint Pain
Swelling
Warmth to the touch

RNA
Clinical
Irreversible
hepatocellular + renal
dysfunction
Gastro intestinal
disturbance

drugs =
designed to
treat
autoimmune
disorders +
inflammation

Steroids
Antiinflammatory
medications
Immune
modulators
Treatment

ANTIBIOTIC
Specific inhibitor
Antibiotic (within
bacteria)
Tuberculosis
treatment
Multi-systemic
disorders

ALL Hb have 3
introns + 2 exons

Notes
Toxin produced by
mushroom
Fungal enzymes =
similar to ours
@ Cancer Chemo
Phenyl intercalation

Fragile X syndrome

Achnodroplasia
+
Thanatophoric
Dysplasia
De novo mutations

Beckwith

disorder

Expansion of CGG on
X chromosome
Failure to express the
protein code by
FMR1 gene = DNA
methylation (silencing
for normal neural
development)
G380R missense
mutation
Gain of function =
activation of FGFR3
in chondrocytes =
inhibit growth
Mutation @ FGFR3
= also cause
thanatophoric
dysplasia
Maternal copy is

Abnormality
MUT @ NF1 gene

Amplification of
unstable repeated
regions (CTG repeat
@ DM1 in DMPK
gene)
in DM2 =
tetranucleotide repeat
(CCTG = ZNF9 gene)
CAG repeat @ 4p16
Polyglutamine

Gene that increase

repeat expansion

Handshake test

Affects: muscle
coordination
Cognitive decline
dementia
Retardation
Normal structure
Hand calluses (self abuse)
Pectus excavatum
(identation of chest)
Mitral valve prolapse
Hypotonia (low muscle
tone)
A = midget
TD = formation of ribs and
respiratory tract

Increased risk of childhood

Progressive
neurodegenerative disorder

MENDELIAN INHERITANCE
Diagnosis
Clinical
@ tissue of many
Caf ole spots = simpler
organs
mutation
Polyp @ skin
Tumors (benign) + brain
tumor
eye

* MUTATIONS @ RNA SYNTHESIS

exons / introns = splicing
5UTR = proper translation / stability
3 UTR = stabilization
TATA Box = efficiency of transcription (Beta plus)
POLY A = stabilization
Regulatory Areas = synthesis
5/3 intron = spliceosome (Beta0)
Poly A signal = decreased stability / translation
Disorder
Neurofibromatosis
Type 1

Myotonic Dystrophy

Huntingtons Disease

Treatment

severity of disease

MOST COMMON
FORM OF
INHERITED
MENTAL
RETARDATION

Clinical heterogeneity
= different mutation
at same gene

IGF2 = insulin

Notes
AD disorder with
complete penetrance
and variable
expressivity

Number of CAG
repeats = affect the

cancer
Overgrowth disorder

Predictors of
severity:
High HBF (mild)

replaced with an extra

parental copy
Extra IGF2
expression

Neuro genetic disorder

Developmental Delay
Sleep disturbance
Seizures
Jerky movements

Chronic Hemolysis:
Anemia
Gallstones
Jaundice (bilirubin from broken
RBC)
Vaso Occlusion:
Pain
Stroke
Leg ulcers

Sickle Cell Trait:

Carrier (do not have the severe
symptoms)
Pain with less O2 than usual
Kidney problems = impaired
urine-concentration ability
Pregnant = UTI
Splenic infarcts

Penicillin

Removal of
spleen (too
much shocks)

O2 injected in

IV = provoke
volume of
vessels

Preventative
transfusions

Intravenous
medications =
alleviate acute
pain

PROTEIN FUNCTION
Abnormality
Diagnosis
Clinical
Treatment
Point mutation that
Newborns are
Pain
Hydroxyurea
changes the
screen by IEF
Ischemia
= stimulates
conformation of HB
Organ Damage
the production
Chronic
Spleen damage during childhood
of fetal HB
Glu-6-Val @ two
Low Hb, Low Hct,
Chronic hemolytic anemia
beta subunits =
high Retic, high
contact alpha subunits
bili

o Dominant modifier = DFNM1 = suppress deafness ! protects

Each conception is an independent event = probabilities can be repeated with each pregnancy
Disorder
Sickle Cell Anemia

Wiedemann
Syndrome
Paternal Uniparental
Disonomy
Angelman Syndrome
Deletion or
inactivation/imprinting
of maternally inherited
= UBE3A Paternal
gene
UBE3A = not
expressed only those
who inherit the
deletion from mom =
are affected
MODIFIER GENES = ASSOCIATED DISORDERS
Cystic Fibrosis
o Classic gene = F508
o Pulmonary problems
Melanoma
o CDKN2A = Cycle arrest @ G1
o MC1R = melanin binds to this receptor = protects from UV
Retinis Pigmentosa
o Needs to be HET for both
" Peliphirin + ROM 1 mutations
Deafness
o HOMO DFNB26 = deaf

Notes
Homozygous
Inherited
Crystal formation =
cause the formation
of the sickle cell =
change the shape of
the RBC
@ Africa, Middle
East/Asia, USA
Heterozygote benefit
= malaria resistance
Typically appear @
infants first years
(first symptom =
dactylitis + fever =
6mo-2yrs)
Stimulate
deformation of
nearby RBC

growth factor

Happy Puppet
UBE3A = normally
expressed in the brain
only when inherited
from mom

Hemoglobin C S
Disease
Alpha Thalassemia

Substitution of
GLU6LYS
Deletion of the alpha
gene
-1 = Silent Carrier

Diagnosed
immediately at
birth

Accute Chest syndrome

(pulmonary collapse)

Produce shortened digits

Painful swelling (hand/foot)

Liver microinfarcts
Loss of kidney ability to
concentrate urine
Intellectual loss
Stroke (block blood flow)

Ulcer

Damaged Retina

Papillary necrosis
Chronic nephropathy
Retinopathy (blind)
Hypoxia lack of O2 @
muscles

(combat
infections =
more
susceptible
with SS)

Priapism
Forms Hb crystals
Cause hemolytic anemia
Less severe vaso-occlusive
crises

Can result in death

Equal amounts of
HbS and HbC =
present n the RBC
Four genetic loci
Alpha Thalassemia
Trait = can be

Hemolytic anemia =
deformed (fragile
+rigid) sickle cell =
destroyed @ spleen
and bone marrow

When occluded = the

sinuses will exude =
pain

Severity depends on
modifier genes
Accumulation
of iron from
transfusions =
use chelate

Clump and block

blood flow
Proportion of sickling
falls as Hb =
saturated by O2

Pneumococcal
vaccination

Variability in
HbF levels
Bone Marrow expansion =
anemia stimulates RBC
production = bone swelling
Microinfarction
Complications arise from!
Red Cell Loss
Red Cell Clumping
Splenic uptake (of RBC)
Hyposplenism = Howell Jolly
bodes @ RBC
Splenic crisis ! takes in and
sequesters RBC ! shock
(hemorrhage like without
bleeding)
Bone infarctions = affect bone
growth

Beta Thalassemia
Major

Beta Thalassemia

Beta Thalassemia
Minor

-2 = Major

-2 = Alpha
Thalassemia Trait
-3 = HbH disease !
too high affinity for
O2
-4 = Barts Hb =
Hydrops fetalis
Decrease the rate of
synthesis
Lead to hemolysis
precipitation of the
excessive chain
Ineffective
erythropoesis

-1 = Minor

Anisocytosis
(RBC of unequal
size)
High HbF /
Variable HbA2 /
no HbA

Presence of HbA2
Microcytosis
Usually Asymptomatic =
symptoms occur under stressful
conditions (pregnancy)
Alpha Hb tetramers = unstable
and precipitate
Splenomegaly

B(+) partial block in beta chain

synthesis
B0 = complete absence of B
chain production
Marked expansion of the
marrow (increased
erythropoiesis)
Splenomegaly
Microcytic anemia
Chronic hemolysis = increased
bilirubin and gallstones
Minor:
Mostly undetected
Slightly decreases fraction of
HbA

Bone Marrow
Transplant

Transfusion +
iron chelators

AR (both parents are

carriers)

confused with iron

deficiency anemia
(treated erroneously
with iron
microcytosis)
High among asians
Several months after
birth (gamma is
changed)
Die from heart
failures