14-02-13

Keys to success in Gene9cs

GENETICS

Important terminology in Gene9cs

#1

#2

#3

#4

#5 -

PEDIGREE INTRODUCTION

Heteroplasmy:

Variable expression:

Incomplete penetrance:

Loss of heterozygosity:

Imprin9ng:

Pleiotropy:

An9cipa9on:

Mosaicism:

14-02-13

Autosomal Dominant Disorders

Autosomal Dominant Inheritance

Defect of a single gene leads to the disease

50% chance of inheritance of AD disorder

Tuberous Sclerosis
Mul9 organ disorder
Non-malignant tumors grow abundantly

Hamar9a Malformed 9ssues
Hamartomas Benign growths

Muta9on of 2 genes: ________ & ________
Codes for proteins called: ___________
&______________

14-02-13

Tuberous Sclerosis
Follows the 2-hit hypothesis

Brain tumor associated with TS = ____________

Dermatological ndings include:
- Ash-leaf spots [fair skinned pt use Woods lamp]

Renal angiomyolipoma

Marfan Syndrome
Findings:
Above average height
Arachnodactyly
Spinal abnormali9es
Lens disloca9on (upper por9on: pa9ent has
trouble seeing above eye level)
Aor9c aneurysm OR dilated aorta
Dural ectasia

Marfan Syndrome
Muta9on of _________ gene on Chrom ____.

Encodes for the Fibrillin-1 protein.
Fibrillin-1 is a component of the ECM

These situa9ons look like Marfans syndrome:
- Homocys9nuria
- Congenital contractural arachnodactyly
- Ehlers-Danlos syndrome
- S9ckler syndrome
- MEN 2B

Neurobromatosis
Type 1 Von Recklinghausen disease
- Muta9on of _______________ 1 gene, which is
found on Chrom _______.
- Tumor suppressor gene ________________
works to inhibit the p21 ras oncoprotein.

Type 2 Central neurobromatosis
- Muta9on of the ___________ protein found on
Chrom ______.

14-02-13

Neurobromatosis Type 1
Diagnosed by nding:

Caf-au-lait spots
Neurobromas
Lisch nodules

Hun9ngtons Disease
Trinucleo9de repeat disorder (CAG)
Demonstrates gene9c an9cipa9on
CAG encodes for the AA _______________
Aected gene = _______________, and is located
on Chrom _____.

Aected gene encodes for the __________ protein.

Neurobromatosis Type 2
Diagnosed by nding:

Bilateral acous9c neuromas (CN 8 aka
Schwannoma)

Tumors can cause:
- HA
- Balance problems
- Facial weakness/paralysis (CN7 compression)

Hun9ngtons Disease
Hypermethyla9on of AA residues leads to the
respression of transcrip9on
Gene9c muta9on leads to atrophy of the
______________ nucleus, which causes loss of
GABAergic neurons.

Diagnosis made by:

14-02-13

Hun9ngtons Disease
2 forms of the disease:
1. Adult onset
2. Early onset
Findings:
- Personality changes
- Chorea
- Muscle rigidity
- Writhing
- Psychomotor func9on worsens
- Impaired execu9ve planning
- Short & long-term decits

Re9noblastoma
Re9nal cancer caused by muta9on of the
_______ gene on Chrom _____.

Re9noblastoma protein a regulator of the
G1S phase transi9on

Hun9ngtons Disease
Neuropsychiatric Manifesta9ons include:
- Anxiety
- Depression
- Blunted aect
- Aggression
- Compulsive behaviors
Management: No cure
Can regulate with CNS depressants

Re9noblastoma
Screening part of well baby screening
Looking for the:
1. Red reex (red/orange re9nal reec9on)
2. Corneal light reex (symmetrical reec9on)

Hyperphosphorylated protein = ____________

Hypophosphorylated protein = _____________

14-02-13

Re9noblastoma
Findings:
- Leukocoria
- Deteriora9ng vision
- Irrita9on of the eye
- Concurrent glaucoma
- Enlargement of the eye

Myotonic Dystrophy
Chronic, slowly progressing mul9systemic
disease characterized by:
Was9ng of the muscles
Cardio disturbances
Endocrine disorders
Visual disturbances
2 types: Type 1 (Steinert diz) Type 2 (PROMM)

Myotonic Dystrophy

Familial Hypercholesterolemia

Type 1: DMPK gene

On long arm of chromosome _____
Encodes _________________ protein kinase
Is a trinucleo9de repeat disorder (CTG)

Muta9on of _____ gene that encodes the LDL

receptor protein
Gene located on chromosome _____ located
on the short arm of the chromosome.

Type 2: ZNF9 gene

Found on chromosome _____
Tetranucleo9de repeat disorder (CCTG)

Main ndings: Xanthelasma, tendon xanthomas

High risk of __________________, which may
lead to CAD

14-02-13

Adult Polycys9c Kidney Disease

Adult Polycys9c Kidney Disease

Both AR and AD versions

Findings in the kidney:

- Mul9ple cysts on both kidneys

AD version: 3 muta9ons in PKD-1, PKD-2, PKD-3

PKD-1 gene located on Chrom _____ and codes
for a protein that regulates the cell cycle &
intracellular transport of _______________ in
epithelial cells.

Extrarenal ndings:
- Cerebral aneurysms
- Pancrea9c & hepa9c cysts
- Mitral valve prolapse
- Aor9c root dilata9on
- Colonic diver9cula

Von Hippel Lindau

Caused by muta9on of the ______ tumor
suppressor gene located on Chrom ____.
Pa9ents develop:
- Benign & malignant tumors (MC In CNS)
- Capillary hemangioblastomas in re9na
- Clear cell renal carcinoma
- Pheocromocytoma
- Pancrea9c neuroendocrine tumors

Von Hippel Lindau

Diagnosis: Family hx + sx men9oned above

Management: No cure
Rou9ne screenings important
Early recogni9on + symptoma9c tx can
improve quality of life

14-02-13

Achondroplasia
MCC of dwarsm
Fibroblast growth factor receptor 3 (FGFR3)
muta9on (at the epiphyseal growth plate)
Results in abnormal car9lage forma9on
* No eect on intelligence

Acute Intermitent Porphyria

Heme produc9on disturbed
Porphobilinogen deaminase deciency
2nd MC porphyria (auer Cutanea Tarda)
Findings:
- Severe abdominal pain
- Peripheral neuropathy
- CNS signs
** NO RASH

Achondroplasia
Findings:
- Short stature
- Large head-to-body size dierence
- Prominent forehead
- Decreased muscle tone
- Bowed legs
- Spinal stenosis
- Kyphosis and lordosis

Von Willebrand Disease

Type 1 & 2 = AD Type 3 = AR
vWF deciency
vWF required for platelet adhesion
vWF gene located on Chrom ____

14-02-13

Von Willebrand Disease

Presenta9on:
- Easy bruising
- Nosebleeds
- Bleeding gums
- Heavy menstrual periods (females)
Type 1: Quan9ta9ve defect in vWF (Majority of cases)
Type 2a: Qualita9ve defect (normal quan9ty)
Type 2b: Hyperbinding of vWF to glycoprotein 1
Type 3: Complete absence of vWF (most severe)

Von Willebrand Disease

Diagnosis:

Measure vWF quan9ty in a vWF an9gen assay
Measure vWF func9onality with any of (glycoprotein
1b binding assay, collagen binding assay, ristoce9n
cofactor ac9vity)

Mgmt: Desmopressin
MOA: S9mulates release of vWF from Weibel Palade
bodies of endothelial cells + increases vWF levels

Osteogenesis Imperfecta
Qualita9ve or quan9ta9ve deciency of type 1
collagen (decreased structural quality of
collagen)
Glycine is replaced with bulky amino acids

Osteogenesis Imperfecta
Type 1 MILD COL1A1 gene
Type 2: LETHAL.. COL1A1 & COL1A2 gene
Type 3: Progressive/deforming
Type 4: Deforming, normal sclera
Type 5: Similar to type 4 (histology = mesh-like)
Type 6: Similar to type 4 (histology = Fish scale)
Type 7: CRTAP gene, car9lage associated protein
Type 8: Severe/lethal, Leprecan protein (LEPRE1
gene)

14-02-13

Osteogenesis Imperfecta
Findings:
- Bone fragility
- Spinal curvature
- Loose joints
- Poor muscle tone
- Blue sclera (see underlying choroidal veins)
- Hearing loss

Hypokalemic Periodic Paralysis

Management:
- Focuses on preven9ng future atacks
- Avoid high-carb meals, strenuous exercise,
other triggers

K+ sparing diure9c like ________________
can keep K+ levels elevated

Hypokalemic Periodic Paralysis

Defect in CNA4A gene
Defect in voltage-gated calcium channels
(blood K+ levels fall rapidly)
Main ndings:
- Muscle weakness/paralysis
- Lasts hours to days

Hereditary Spherocytosis
Defect in RBCs cytoskeleton (due to Spectrin
& Ankyrin abnormali9es)
Classic Manifesta9ons:
- Jaundice
- Hemoly9c anemia
- Splenomegaly

10

14-02-13

Hereditary Spherocytosis
Findings:
- Oval-shaped RBCs (Elliptocytosis)
- RBC small/red, no central pallor
- Re9culocytosis / incr RDW / incr MCHC
Conrm with _____________ fragility test

Osler-Weber-Rendu Syndrome
Hereditary hemorrhagic telangiectasia
Findings: Telangiectasias in skin + mucus
membranes of the lips/oronasopharynx/
respiratory tract/GI tract/urinary tract

Rupture leads to epistaxis, GI bleeding,
hematuria

Li-Fraumeni Syndrome
Early cancer development due to p53 gene
muta9on
Requires inherited muta9on of p53 + soma9c
muta9on of 2nd allele
Look for mul9ple cancers in someone < 45yr
of age
MC tumors in breast, adrenal cortex, brain,
blood, & sarcomas

Essen9al Tremor
Worsens with ac9vity
MC in upper extremity

Classic nding: Improves with ___________
consump9on

Management: _________________
MOA: Non-selec9ve beta blocker
Why it works Suppresses tremor through beta-2
blockade

11

14-02-13

Autosomal Recessive Disorders

Autosomal Recessive Disorders

MC enzyme deciencies
There is a 25% chance of inheri9ng an AR
disorder

Autosomal Recessive Inheritance

12

14-02-13

CYSTIC FIBROSIS

Cys9c Fibrosis (Sweat Gland)

Muta9on of _______________ gene

Dele9on of 3 nucleo9des that code for ______
results in the loss of Phenylalanine
CFTR is an ______-binding transmembrane ion
transporter.. Pumps __________ ions out of the
epithelial cells.

Cys9c Fibrosis (Lungs)

Phenylketonuria (PKU)
Deciency of ______________ hydroxylase
Cannot convert Phe Tyr
If we cant make Tyr, we wont get:
- DA
- NE
- EPI
If we cant make Melanin, we see:
- Light skin
- Blonde hair
- Blue eyes

13

14-02-13

PKU
Accumula9on of the following:



** These account for the musty odor

Mgmt: Eliminate _____ from the diet, add
_____

Alkaptonuria
Deciency of Homogen9sic acid oxidase
Muta9on of ______ gene
Body cannot breakdown _______ & _______.

Findings: Urine darkens upon standing (Dx factor)
Infant darkened urine in diaper
Adults Arthri9s, darkening of ear, dark spots on
sclera

Cys9nuria
Get forma9on of cys9ne stones in the kidney, ureter, &
bladder.

Muta9ons in _________ & _________ genes, which
encodes for transporter protein in kidney.

Findings:
- Flank pain
- Radia9ng pain to the groin
Mgmt: Fluids to dilate urine / lithotrypsy for big stones

Galactosuria
Benign spilling of galactose into the urine
Deciency of _______________ enzyme
Due to muta9on of the _______ gene, located on
Chrom _____.
Worrisome complica9on is CATARACTS, caused by
accumula9on of ____________ in the lens.

Mgmt: If cataracts we remove them
Eliminate ____________ & ____________ from the
diet.

14

14-02-13

Galactosemia
Deciency of _________________________
leads to accumula9on of Gal-1-Phosphate.
Lactase breaks down Lactose into these 2
sugars: 1. 2.

Gauchers Disease
MC lysosomal storage disease
Dysfunc9onal metabolism of sphingolipids

Deciency of ____________________ enzyme.
Defec?ve gene is the _____________________,
which is on Chrom 1q21.

See accumula9on of _________________ in the
lysosomes.

Galactosemia
Findings:
- Feeding problems
- Failure to thrive
- Liver damage/failure
- Bleeding
- Infec9ons
Without treatment, what happens to levels of ammonia?

Mgmt: Restrict ______________ in the diet.

Gauchers Disease
Three MC types:

Type 1: MC form
Non-neuropathic
Hepatosplenomegaly
Type 2: Acute infan9le neuropathic
Within 6 months of birth
H/S megaly
Neuro ndings
Type 3: Chronic neuropathic form
From childhood into adulthood
Slowly progressing neuro sx
Mgmt: Type 1 & 3 = Replace enzyme

15

14-02-13

Gangliosidoses
Lipid storage disorder whereby lipids are accumulated
TWO types (GM1 & GM2)
GM1: Deciency of Beta-Galactosidase
Early infan?le: Neurodegenera9on, seizure, H/S megaly,
coarsening of facial feat., skel abn.
Late infan?le: Between 1-3 yr, (ataxia, seizure, demen9a,
speech diculty)
Adult onset: Muscle atrophy, less severe/slower-
developing neuro ndings

Hartnups Disease
Muta9on of _______________ gene on Chrom
____.
Aects absorp9on of non-polar AAs (most
importantly: __________)

TRP needed because it converts to the following:
- Serotonin
- Melatonin
- Niacin

Gangliosidoses
GM 2: Deciency of Beta-Hexosaminidase
Enzyme found in lysosomes
Lipids accumulate in nervous 9ssue (leads to
neuro ndings)

Hartnups Disease
Findings:
- FTT
- Photosensi9vity
- Nystagmus
- Ataxis (intermitent)
- Increased AA in the urine
- Pellagra (4 Ds)
Mgmt: High ___________ diet (helps overcome deciency of neutral
AAs)
Avoid sunlight & drugs that cause photosensi9vity

Which drugs cause photosensi9vity?

16

14-02-13

Hurlers Syndrome
Lysosomal storage disease
Defect in the ________ gene which is on
Chrom _____.
Buildup of:
- GAGs (due to deciency of _____________)
- ____________ & _____________ sulfate.

Krabbes Syndrome
Defect in sphingolipid metabolism
Causes degenera9on of _________ sheath in
the CNS
Muta?on of ________ gene located on chrom__
Deciency of _________________ enzyme.

Hurlers Syndrome
Findings:
- Progressive deteriora9on
- H/S megaly
- Dwarsm
- Progressive mental retarda9on
- Death by end of __st decade of life
Mgmt: Enzyme replacement

Krabbes Syndrome
Findings: Start 3-6 months auer birth
- Irritability
- Fever
- Seizure
- Feeding diculty
- Vomi9ng
- Mental/motor regression
- Muscle weakness
- Spas9city
- Deafness
- Op9c nerve atrophy
Mgmt: BM transplant

17

14-02-13

Maple Syrup Urine Disease

Deciency of _________________________

Muta?on in 4 genes:
1. BCKDHA
2. BCKDHB
3. DBT
4. DLD

This enzyme required to breakdown BCAAs:

Metachroma9c Leukodystrophy
Lysosomal storage disease
Deciency of _______________ enzyme.
Altered G&D of myelin
Build-up of Sulfa9des in 9ssue (destroys myelin
sheath in CNS & PNS)
Several forms focus on: Late infan9le, Juvenile
form, Adult form

Maple Syrup Urine Disease

Findings:
Sweet-smelling urine
- Poor feeding
- N/V
- Dehydra9on
- Lethargy
- Hypoglycemia
- Ketoacidosis
- Neuro ndings
Mgmt: Avoid BCAAs & foods rich in them
Avoid nutrasweet

Metachroma9c Leukodystrophy
Late Infan9le: MC form seen
- Diculty walking around 2nd year
Juvenile Form: Between 3-10yr of age
- Progressive symptoms
Adult Form: Auer 16yr of age
- Psych disturbances
- Progress to demen9a
Mgmt: NO CURE (terminal illnesses)

18

14-02-13

Ataxia Telangiectasia
Defect in DNA repair genes
The ______ gene is aected
This gene manages the cells response to stress
induced _________ breaks.
Findings:
- Cerebellar atrophy
- Oculocutaneous telangiectasia
- Telangiectasia
- Immune deciency
- Increased cancer risk

Leukocyte Adhesion Deciency

Gene9c absence of CD___
Disturbs forma9on of Integrins
What are Integrins needed for?

Chediak-Higashi Syndrome
Diagnosed in childhood

Nuero defects include:
Immunodeciencies include:
Skin ndings include:

Leukocyte Adhesion Deciency

Findings:
- Late separa9on of _________________
(which is the major sign)
- Poor wound healing
- Recurring skin infec9ons
- Gingival inamma9on

19

14-02-13

Kartageners Syndrome
AKA primary ciliary dyskinesia

Dynein protein defect leads to dynein arm defect.

Findings: Any structure depending on mo9lity is
nega9vely aected
- Sperm
- Cilia
Situs invertus

Hemochromatosis
Iron overload in the following:
- Heart
- Pancreas
- Liver
TWO most worrisome complica?ons:
Liver cirrhosis
Hepatocellular carcinoma

Hemochromatosis
Muta9on to _____ gene on Chrom ____.
Abnormally high absorp9on of _____ in the GI
Where is the most important site for HFE gene
expression?

Wilsons Disease
Toxic accumula9on of Copper
Muta9on of the _______ gene on Chrom ____
Neuropsych sx:
- Parkinsonism
- Seizure/migraine
- Demen9a

20

14-02-13

Wilsons Disease
Organ-specic ndings:

Eyes: Kayser-Fleischer rings (Copper deposi9on
in Descemets membrane)
Heart: Cardiomyopathy
Kidneys: Renal tubular acidosis
Endocrine: Parathyroid dysfunc9on

Wilsons Disease
Making a diagnosis:
- Abnormal ______
- Bilirubin is _______
- AST is _______
- Albumin is ____________
- PT is ________________
- Ceruloplasmin levels are _______________
- Serum copper is _____, urine copper is ______

Conrm diagnosis when liver sample contains at least _____ug of copper
per gram of dried liver 9ssue.

Wilsons Disease
Overview of pathophysiology.

Normal physiology:
Copper membrane transporter (CMT1) allows for absorp9on in
stomach & duodenum
Once in the liver is incorporated into an alpha-2 globulin (forms
ceruloplasmin).. Via ATP7B protein
Released into plasma as circula9ng Copper
Pathophysiology:
Defect in ATP7B protein
Copper not incorporated into Ceruloplasmin
Copper accumulates in liver (leads to oxida9ve damage)

Sickle Cell Disease

MC AR disease in African Americans

Main ndings:
1. Hemolysis
2. Vaso-occlusive sx
3. Infec9ons

Mgmt: Diet low in copper-containing foods

Copper chelator ___________________ binds to copper and is excreted
through the urine.

21

14-02-13

X-linked dominant diseases

X-linked dominant inheritance

X-linked dominant diseases and transmited

through both parents
All female ospring of an aected father will
be aected
Both male and female ospring of an aected
female may be aected

X-linked dominant diseases

Alports syndrome
Rets syndrome
Vitamin D resistant rickets/Hypophosphatemic
rickets

Alports Syndrome
Muta9on of _______, ________, & _________
genes, located on Chrom ____.

Muta9ons lead to improper produc9on of type
____ collagen, which is required for basement
membrane forma9on.

Ini9al presenta9on is ouen ______________.

22

14-02-13

Alports Syndrome
Diagnosis: Based on nding 4/10 criteria
1. Bilateral sensorineural hearing loss
2. Muta9on in COL4An (n=3,4,5)
3. Family hx of nephri9s
4. Persistent hematuria
5. Immunohistochemical evidence
6. Ocular lesion
7. Gradual ESRD
8. Macrothrombocytopenia or granulocy9c inclusinos
9. Diuse leiomyomatosis of the esophagus
10. Glomerular BM abnormali9es
Mgmt: ACEIs for proteinuria, no known cure.

Ret Syndrome
Symptoms worsen and may include
Hypotonia
Gait diculty
Dystonia
Chorea
Bruxism
Mgmt:
- Surveillance for back problems
- Social skills development/work

Ret Syndrome
MC due to spontaneous muta9nos
Spora9c cases due to muta9on to the _______ gene, located on the X
chromosome.
Findings:
- motor/language regression (at ~ 6-18mnth)
- Au9sm-like behavior
ReZ specic ndings:
- Inconsolable crying ts
- Screaming ts
- Emo9onal inversion
- Speech regression
- Sensa9on problems

Vitamin D Resistant Rickets

Muta9on in the _______ gene sequence on
Chrom Xp___.
Leads to inac9vity in the _______ protein.
** Not responsive to vitamin D supplementa9on

Males develop outward bowing of knees
Females inward bowing of legs

Mgmt: Oral ____________ + _______________

23

14-02-13

X-linked recessive diseases

X-linked recessive pedigree

No male-to-male transmission
Sons of a heterzygous (carrier) mother have a
50% chance of transmission
Aected males always pass one diseased x
gene to the daughters (makes them a carrier)
ONLY MALES ARE AFFECTED

Red-Green Color Blindness

Inability to discriminate red & green hues

Cause Absence of red or green re9nal
photoreceptors


* Males >>>>> Females

Duchenne Muscular Dystrophy

Muta9on of ____________ gene, which is located on
the ____ chromosome.
Codes for protein ___________, an important
structural component of muscle 9ssue.
Dystrophin connects cytoskeleton of each muscle ber
to underlying basal lamina
Microscopically: varia9ons in muscle ber shape & size,
visualize regenera9ng bers, see increased amounts of
connec9ve 9ssue.

24

14-02-13

Duchenne Muscular Dystrophy

Main PHYSICAL sx: Seen 1st 9me they walk
- Eventually lose muscle func9on from neck down

Gowers Maneuver crawls hands up legs to straighten
torso
Toe Walking compensatory adapta9on to extensor
muscles of the legs
Muscle contractures
Progressive walking dicul?es eventual loss by 12yr
Pseudohypertrophy of calves muscle replaced by faty
9ssue

Beckers Muscular Dystrophy

Similar but less severe than Duchenne
Muta9on in ____________ gene that encodes Dystrophin

Important dierence: Only less Dystrophin made (Duchenne
there is none made)

Progressive muscle weakness
Toe-walking
Modied Gowers maneuver
Diagnosis: EMG + Check CPK levels

Duchenne Muscular Dystrophy

Diagnosis:
- Gowers sign
- Elevated crea9ne kinase
- EMG demonstrates muscle weakness (not nerve weakness)
- Gene9c tes9ng to ID Xp21 gene errors
- Muscle biopsy (ID absence of Dystrophin)
Mgmt: To control sx & improve quality of life
- Steroids
- Beta2 agonists
- No-impact ac9vi9es
- Orthopedic appliances
- Respiratory support
Prognosis: Max 25yr lifespan

Hemophilia A
Deciency of clong factor 8
Sx vary with severity
Most serious bleeding occurs into:
- Joints
- Muscles
- GI
- Brain
Diagnosis: Increased PTT, normal PT & normal bleeding 9me.

Mgmt: Severe cases required IV recombinant or plasma concentrate factor
___.
Mild cases managed with _________________, which works by released
stored factor 8 from the endothelial walls.

25

14-02-13

Hemophilia B
Muta9on of Factor 9 gene, leading to Factor 9 deciency
Less common than Hemophilia A
Aka Christmas Disease
Findings:
- Nosebleeds
- Easy bruisability
- Blood in urine & stool
- Excessive bleeding with minor injury
Diagnosis: Low factor 9, abnormal PTT, normal PT & normal bleeding 9me.

Mgmt: Infusion of factor ____.

X-Linked SCID
MCC of SCID
2nd MCC of SCID is __________________ def.

Defec?ve gene IL2-RG, located at ________
on the X chromosome
Litle produc9on of ___ cells and ____ cells.
Also leads to defect in B cells

X-Linked Mental Retarda9on

MC in males
Around ______ genes involved in this type of
mental retarda9on
In MALES, XL mental retarda9on accounts for
around ___% of all cases.

Glucose-6-Phosphate DH Deciency
Disorder of the HMP shunt
The amount of ____________ produced within the RBCs is
low impairs ___________-mediated inac9va9on of free
radicals
Findings:
- Hemoly9c anemia
Other Causes: drugs, fava beans, infec9ons

Microbiology: Peripheral smear demonstrates ______ cells &
Heinz bodies.

26

14-02-13

Ornithine Transcarbamoylase Deciency

Is XLR
Urea cycle defect
Due to a few muta9ons in OTC gene
Body cannot eliminate ammonia
Oro9c acid builds up

Mitochondrial diseases

Ornithine Transcarbamoylase Deciency

Findings:
- Lethargy
- Anorexia
- Temp/breath regula9on diculty


Mgmt: Low protein diet
Maintain adequate hydra9on
Nitrogen-scavenging meds (Sodium Benzoate, Sodium
Phenylbutyrate)
Bio9n supplementa9on

Mitochondrial diseases

Transmission is only through the mother

Father doesnt pass mitochondrial material
All ospring of an aected female may show
signs of being diseased

27

14-02-13

High-Yield mitochondrial diseases

Lebers hereditary op9c neuropathy

DM + Deafness (DAD) a combina9on
Leigh syndrome
MERFF syndrome (myoclonic epilepsy with
ragged red bers)

Lebers
Findings:
- Acute onset of visual loss (one eye at a 9me)
- Usually in younger adults
- Females present 5yr earlier than males
- Severe op9c atrophy + permanent visual
acquity disturbances

Lebers Hereditary Op9c Neuropathy

Any of 3 muta9ons in maternal mitochondrial
DNA (ND1, ND4, or ND6) genes of complex 1 of
the oxida9ve phosphoryla9on chain
Degenera9on of re9nal ganglion cells & their
axons
Leads to acute or subacute loss of central
vision

DAD Syndrome
Associated with ___________ gene

Causes:
- DM
- Sensorineural deafness

Mgmt: Idebenone

28

14-02-13

Leigh Syndrome
AKA subacute necro9zing
encephalomyelopathy
_______-1 gene is aected
Findings:
- Dystonia
- Motor ndings (tremor, rigidity, chorea)
- Later nding is renal/resp impairment

TRINUCLEOTIDE REPEAT DISORDERS

MERFF Syndrome
Several genes involved
MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, MT-TF
Findings:
- Progressive myoclonic epilepsy
- Ragged red bers
- Hearing loss
- Lac9c acidosis
- Short stature
- Exercise intolerance
Mgmt: No cure

Trinucleo9de repeat disorders

Diseases that result from trinucleo9de repeat
expansions
The genes are expanded beyond the point which
allows them to be stable
Trinucleo9de repeat disorders demonstrate the
phenomenon of an9cipa9on

An?cipa?on:

MOA:

29

14-02-13

MC trinucleo9de repeat diseases

Hun9ngtons disease (discussed earlier)

Spinocerebellar ataxia
Fragile x syndrome
Friedreichs ataxia
Myotonic dystrophy (DM1 = trinucleo9de,
DM2 = tetranucleo9de)

Spinocerebellar Ataxia
Findings:
- Slow progression of uncoordinated gait
- Poor coordina9on of hands/speech/eyes
- Inten9on tremor
- Cerebellar atrophy
- Lack of ne-motor coordina9on
Mgmt: no deni9ve cure
Manage symptoms as they occur

Spinocerebellar Ataxia
Several varia9ons of this disease
Many genes involved (SCA1, SCA2, SCA3)
All forms of the disease are polyglutamine
diseases (CAG repeat)
Both AD varie9es & AR varie9es

Fragile X Syndrome
MCC of mental retarda9on in males
2nd MCC of congenital mental retarda9on
(auer Downs)
Due to expansion of the ______ trinucleo9de
repeat on the _______ gene, on the _______
arm of the X chromosome

30

14-02-13

Fragile X Syndrome
Findings:
- Short-term memory decits
- Visual memory decits
- Visual-spa9al rela9onship dicul9es
Verbal abili9es rela9vely normal
Other Findings:
- Mild to severe mental retarda9on
- Elongated face
- Short height
- Joint laxity
- Scoliosis
- High-arched palate
- Large protruding ears
- Hypotonia
- Macroorchidism
- MVP

Friedreichs Ataxia
Signs & Anatomical Problems:
In the limbs
Dorsal columns
LMN lesions
Pyrimidal
Cerebellar ndings
Cardiac
Endocrine
Skeletal

* Death on average by 35th year of age

Friedreichs Ataxia
GAA repeats of the _____ gene
Aects the _____________ protein, which is an
iron-binding protein
Sclerosis & degenera9on of the dorsal root
ganglion, spinocerebellar tracts, lateral CS tracts,
& posterior columns
What does a low level of Frataxin lead to?

Where is the primary site of pathology?

Myotonic Dystrophy
Chronic, slow-progressing, mul9systemic
2 types (1 = Steinert disease, 2 = Proximal
myotonic myopathy)

Characterized by:
- Muscle was9ng
- Cardio/endocrine/visual disturbances

31

14-02-13

Myotonic Dystrophy
Type 1: Steinerts disease
- Aected gene is the _______ gene on the long
arm of Chrom _____
- Encodes the myotonic dystrophy protein kinase
- CTG triplet repeat

MONOSOMIES & TRISOMIES

Type 2: PROMM
- Defect in the ______ gene on Chrom ____
- Tetranucleo9de repeat disorder of CCTG
nucleo9des

MONOSOMIES Turner Syndrome

MONOSOMIES Cri-du-chat syndrome

45XO (one x chromosome is missing)

MCC is non-disjunc9on

Par9al dele9on of short arm of chromosome 5

MCC by spora9c muta9on

Common ndings:

Findings:

32

14-02-13

TRISOMIES Patau Syndrome

TRISOMIES Edwards Syndrome

Extra copy of chromosome 13

Caused by Robertsonian transloca9on

Trisomy 18
Rocker-botom feet

Findings:

Findings:

TRISOMIES Downs Syndrome

Trisomy 21
MC chromosomal abnormality
2nd MCC of mental retarda9on

Organ-Specic Findings
Cardiac :

Vascular:


Cancer:
Thyroid:
Gastrointes9nal:

Triple test at 16-18 weeks gesta9on we are

looking for low levels of ____________

Infer9lity:

Neurological:

33

14-02-13

Klinefelter Syndrome
47XXY karyotype
Due to meio9c non-disjunc9on during gametogenesis
Will cause:


Eunuchoid body habitus:


Cogni?ve ndings:

DiGeorge Syndrome
Dele9on of long arm of chromosome 22 (22q11.2)
Thymic aplasia and failure of parathyroid forma9on
Caused by defec9ve embryonic development of the 3rd
and 4th pharyngeal pouches
Findings:
Ini?al presenta?on:

CATCH 22:

IMPRINTING

HY Imprin9ng
Beckwith-Wiedemann:


Angelman syndrome:


Prader-Willi:

34

14-02-13

Alzheimers Disease
Early onset (<60yr)
Late onset (>60yr)

ALZHEIMERS DISEASE

HARDY-WEINBERG GENETICS

Muta?ons associated with early onset:

1.
2.
3.

Muta?ons associated with late onset:
4 allele of Apolipoprotein E (causes senile plaques)

Assump9ons
In order to maintain HW equilibrium, we assume
the following:

1.
2.
3.
4.

35

14-02-13

Major viola9ons to the HW

equilibrium

Hardy-Weinberg Equilibrium

Inbreeding:


Small popn size:


Assor9ve ma9ng:

HWE
p =

q =

p^2 =

q^2 =

2pq =

36