Exam VI- Genetic Diseases

Question 1

G Banding

Answer 1

Dark bands: AT rich
Light bands: GC rich
using Giemsa dye
block cells in mitosis using colchine to establish a karyotype analysis

Question 2

Q Banding

Answer 2

Quinacrine (mepacrine, atabrine) requires fluorescence microscope; intercalating agent
Green-yellow fluorescence at pH 4.5
Heterochromatin-(A-T): increase fluorescence
GC inhibit fluorescence

Distinguish between:
Euchromatin contains active genes
Heterochromatin, AT rich, fluoresces more contains inactive genes

Question 3

R-banding

Answer 3

Reverses the white-and-black pattern seen in G- and Q-bands using the Giemsa stain & acridine orange
Requires heat treatment of chromosomes to melt the DNA helix in the AT rich regions and remaining GC-rich regions are darker stained
Detects deletions when combined with G-banding
Heat will separate the bonds between AT and GC; the AT bonds will dissolve first because only 2 H bonds, so the dye is opposite (light) and CG is darker
It provides clarification about gene regions in the telomeres neighborhood

Question 4

C-banding

Answer 4

completely denature DNA + Giemsa
Stains constitutive heterochromatin close to the centromere
CBG-staining requires: Giemsa staining + mild alkali treatment
Used for identification of:
Centromere
Satellite DNA
Repetitive DNA sequences
Distal portion of the Y chromosome
Most significant bands on chromosomes 1,9,16 and Y

Question 5

NOR stain

Answer 5

silver stain
Nucleolar organizing region stain highlights the stalks and satellites of acrocentric chromosomes and nucleolus
Ag-stain accumulate in the nucleolus organizing regions
Chromosomes 13, 14, 15, 21 and 22

Question 6

Heterochromatin vs. Euchromatin

Answer 6

Activity of the cell shows two forms of chromatin (DNA/protein):
Euchromatin is prevalent in transcriptionally active cells
Heterochromatin is abundant in cells with less activity or no transcriptional activity at all
Heterochromatin stains dark; seen as scattered spots in the nucleus and grouped close to nuclear envelope

Question 7

Meiotic Nondisjunction

Answer 7

In meiotic nondisjunction two chromosome homologs migrate to the same daughter cell instead of disjoining and migrating to different daughter cells
Can occur during meiosis I or II
Fertilization with normal gamete produces
Monosomic or
Trisomic offspring

Question 8

Trisomies

Answer 8

Many trisomies are not compatible with survival
Trisomy 21 is the most common surviving trisomy
Trisomies of the 13th and 18th chromosomes are much less common at birth
They are sometimes compatible with survival to term
More than 95% result in spontaneous abortion
Phenotype produced is much more seriously affected
Mortality in the first year of life is 90%

Question 9

Down Syndrome: General Information

Answer 9

Trisomy 21
Most common autosomal aneuploidy among live births
Extra chromosome 21 contributed by the mother in 95% of cases
Mosaicism: 1-3% of DS cases; usually milder phenotype
Problems: mental retardation, GI tract obstructions, congenital heart defects which can lead to leukemia, and respiratory infections

Question 10

Down Syndrome: Characteristics

Answer 10

Upslanting palpebral fissures
Almond-shaped opening between the upper and lower eyelids
Epicanthic fold; also Brushfield spot that is light smudgy opacity of the pupil; both make vision less efficient
Redundant skin of the inner eyelid
Low nasal bridge
Simian crease across the entire palm

Question 11

Mosiacism

Answer 11

Condition in which an individual organism has two or more genetically distinct cell lines
Derived from a single zygote
Their difference due to mutation or nondisjunction
A condition in which tissues of genetically different types occur in the same organism.
Most of the time it is beneficial
How does this happen? Mistake similar to nondisjunction or mutation (sometimes); occurs during MITOSIS because when the cell divides we usually have equal division of chromosomes during metaphase, and when you have three 21 chromosomes, one cell may get 2 and the other 1

Question 12

Trisomy 18

Answer 12

Edwards Syndrome
This disease is associated with growth inhibition during development in the uterus
Prevalence: 1/6000 at birth
Male/female = ¼; female more likely
Intrauterine growth retardation, microcephaly, small mouth, palpebral fissures, cardiac defects, overlapping fingers, omphalocele (intestines outside of body in membrane/congenital herniation of viscera into the base of the umbilical cord)
Still born/most die w/in 2 months; <10% survive 1 year

Question 13

Trisomy 13

Answer 13

Patau Syndrome
Newborns: cleft palate, atrial septal defect, inguinal (groin) hernia, postaxial polydactyly of the left hand, deaf, legally blind
Sometimes can also have due to midline defects:
Cyclopia - single eye/eye socket without an eye
Proboscis - the projecting tissue just above the eye

Survival beyond the 1st year is rare
Born alive is rare
Occurs in only 1 in 6000 live births
Multitude of anomalies make compatibility with life difficult

Question 14

Monosomy X

Answer 14

Turner Syndrome
Caused by 45,X karyotype
Common at conception, rare among live birth
Spontaneous abortion is common
Mosaicism increase probability of survival to term
Stature is reduced
Swelling (edema) is seen in the ankles and wrists
Characteristically broad “webbed” neck
Reduced stature
Poorly developed sexual secondary characteristics
Usually infertile because of gonadal dysgenesis: “Streak ovaries“ or gonadal streak; functionless tissue replaces ovaries
Rarely undergo menarche
Estrogen treatment
Around 30-40% mosaic, mostly 45,X/46,XX

Question 15

Hydrops fetalis

Answer 15

Feature of many chromosomal abnormalities including monosomy X (Turner Syndrome)
Soft tissues are markedly edematous
Body cavities filled with effusions

Intrauterine fetal demise, signs of maceration (autolysis), slippage of the skin, reddened color
Hydrops: (ascites, anasarca, edema)
Excessive accumulation of clear, watery fluid in any tissue or cavity of the body

Question 16

Cystic Hygroma

Answer 16

Cystic hygroma of the neck; can be bilateral (2 of them)
Characteristic for the monosomy X fetus (Turner Syndrome)
Not a true neoplasm (abnormal growth of tissue) because it results from failure of lymphatics to form and drain properly
Cystic hygroma forms the “web neck” of TS women
Gray coloration from prolonged intrauterine demise

Question 17

47, XXY

Answer 17

Klinefelter Syndrome
Increased stature, gynecomastia (enlarged breast), feminine body shape, reduced IQ, usually sterile
Testosterone therapy and mastectomy

Question 18

Trisomy X

Answer 18

47, XXX; “Super Females”
Occurs in 1 in 1000 females with benign consequences
Sometimes: sterile, menstrual irregularity, mild mental retardation
Mostly result from nondisjunction in the mother
Incidence increases with the mother’s age
Females with more X chromosomes exist, but more is not better; each additional X chromosome leads to more mental and physical abnormalities

Variable Facial Characteristics:

(a) Epicanthic folds and hypertelorism (increased distance between the eyebrows) in 2 year old girl
(b) Hypertelorism in 9 year old girl
(c) Normal appearance of 19 year old without dysmorphic features

Question 19

Jakob Syndrome

Answer 19

These males tend to be taller
Have 10- to 15-point reduction in IQ- new studies say no or little difference?
Few physical problems
Notorious because 1/30 of prison population compared to 1/1000 in the general male population, but studies refute association with violent crime
Minor behavioral problems: hyperactivity, ADD, learning disabilities

Question 20

XX Male and XY Female

Answer 20

Result from mutation in the SRY (sex-determining region on the Y) or
Transfer of SRY from Y to X chromosome during crossing-over between the X & Y chromosomes in male meiosis
Female with XY chromosome: perfectly normal
Male with XX chromosome: perfectly normal

As long as you have the SRY gene, you will be male
When dad gives Y without SRY gene you get a female because no SRY; the Y chromosome is essentially empty and the X chromosome from mom will rule

Question 21

Albinism

Answer 21

Deficiency of the pigment melanin from skin, hair, eyes
Normally tyrosine is metabolized to make melanin (pigment); tyrosinase enzyme does not work to do this
Inability to produce or distribute melanin

Different forms of albinism and several modes of inheritance:
Autosomal recessive
Autosomal dominant
X-linked inheritance

Question 22

Tyrosinase-Negative Oculocutaneous Albinism

Answer 22

Complete Albinism - is the most severe form of albinism involves a total absence of pigment in hair, eyes, & skin
Affected people may have white hair, skin, and iris
Vision defects and photophobia
Sunburn easily- should never try to tan

Question 23

Ocular Albinism

Answer 23

Albinism of the eyes only
Skin color is normal
Eye color may be normal: brown, blue, green
BUT: No pigment in the retina

Question 24

Partial Albinism

Answer 24

Complex diseases include: Chédiak-Higashi syndrome 
Autosomal recessive
Silver hair, ocular albinism, immune system deficiency leading to infections of lungs, skin & mucosa
EBV can lead to child lymphoma
Nystagmus/ jerky eye movement
Muscle weakness
Nervous system
Tremors
Seizures
Ataxia/unsteady walking

Question 25

Hermansky-Pudlak Syndrome

Answer 25

Oculocutaneous albinism- autosomal recessive
Platelet storage pool defect causing ableeding disorder
Ashkenazi Jews and North Puerto Rican
Symptoms: vision impairment and eye problems, photophobia, nystagmus (fast uncontrollable movement of the eyes), strabismus/crossed eyes
GI involvement with granulomatous colitis
Bleeding, bruising- platelet issue
Cellular storage: waxy material accumulation causing damage of the tissue of lungs and kidneys

Question 26

Nystagmus

Answer 26

Involuntary rhythmic oscillation of the eyeballs
Pendular or variable with slow and fast components
Chédiak-Higashi syndrome (in partial albinism) and Hermansky- Pudlak Syndrome association

Question 27

Tuberous sclerosis

Answer 27

Characterized by:
Peri-ungual fibroma (PUF): fibrous growth at the edge of the nail
Hypopigmented patch of skin: white leaf macules
Spot on the skin that lost the pigment
is a rare multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.

Question 28

Waardenburg syndrome

Answer 28

Autosomal dominant inheritance
Prevalence: 1/40,000; 2-5% of congenital hearing loss cases
Lateral displacement of the medial canthi (corners of eyes)
Combined with dystopia of the lacrimal puncta
Prominent broad nasal root
Hypertrichosis of the medial part of the eyebrows
White forelock
Heterochromia iridis (absence of pigment in one or both irises)
Deafmutism- congential deafness which results in the inability to speak

Question 29

Heterochromia iridis

Answer 29

Autosomal dominant inherited Waardenburg syndrome type I
Circumscribed hypopigmentation of the skin
Heterochromia iridis
Absence of pigment in one iris
Sensorineural deafness
Dental aberrations
Missense mutation in PAX3 gene
Early diagnosis = successful medical care

Question 30

Marfan Syndrome

Answer 30

Autosomal dominant condition 

Examination includes the following:
Complete family history, medical history, genetic evaluation, complete physical examination, echocardiogram, annual eye examination, skeletal exam

Dx: tall stature with the span of the arms exceeding height, long fingers (arachnodactyly) and toes, flat feet, curved spine (scoliosis), chest wall deformity, excessive joint flexibility, reduced elbow extension, high arched palate, dislocation of the lens in the eye, nearsighted vision, narrow face

Question 31

Marfan Syndrome and Heart Disease

Answer 31

Enlargement of the aorta
Leakage of the aortic valve
Leakage of the mitral valve: mitral valve prolapse
Aortic dissection: tearing of the wall of the aorta as a result from extreme enlargement of the aorta (rare but very serious)

Question 32

Gene Linkage

Answer 32

Syntenic loci: located on the same chromosome
Linked gene loci: are on the same chromosome close enough together that they do not segregate independently
Linkage is a powerful tool in genetic counseling
It allows predictions of an outcome
Not just probabilities of an outcome

Establishment of linkage maps in humans has been delayed by: constraints of small family size, lack of available polymorphic loci for normal variation, and random mating patterns
Human linkage studies are based upon consequences of the chromosomal movement and recombination in meiosis

Question 33

Hemophilia A

Answer 33

X linked recessive disorder
Caused by deficient or defective clotting factor VIII and IX needed for fibrin formation
Bleeding into joints is common with loss of joint function
Intracranial bleeding is the leading cause of death
Severity of hemophilia A correlates with factor VIII level

Mutations that produce severe forms: nonsense mutation, deletions, chromosome inversions, missense mutations produce substitutions without severe effects

Question 34

Hemophilia A Treatment

Answer 34

Until 1994, factor VIII was derived from donor serum
In the 80’s many hemophiliac became infected with HIV
AIDS is now the most common cause of death in hemophiliacs
Since 1994 recombinant factor VIII replaced blood-derived F-VIII it eliminated the AIDS factor
Inhibitory antibodies to the recombinant factor is a problem

Question 35

Duchenne Muscular Dystrophy

Answer 35

Muscular dystrophy (MD)- progressive weakness and loss of muscle
Duchenne (DMD)- most severe form of MD where the patient has very low levels of dystrophin
Muscle infiltration with fat and connective tissue leading to muscle cell death

Death: respiratory and cardiac muscle loss
DMD genetics: cloned
X-linked recessiveinheritance
Gene cloned leading to product dystrophin

Question 36

Fragile X Syndrome

Answer 36

Most important X-linked dominant disease
Accounts for 40% of all X-linked mental retardation
Phenotypic traits: distinctive facial features, prominent large ears, long face, joints hypermobility macroorchidism

The X chromosome breaks near the tip of the long arm when cultured in folic acid deficient medium

Question 37

Fragile X Defect Cause

Answer 37

Diseased gene: FMR-1
Expanded repeat in the 5’ untranslated region
6-50 repeats in Normal individuals
50-230 repeats in Premutation individuals
230-1000 repeats in Full mutation causing methylation

Methylation of the CpG dinucleotides in the triplet repeats: shutting off of FMR-1 gene
Normal expression of FMR1 turned off and the disease develops

Question 38

Slippage and Repeat Formation

Answer 38

Slipped, mispaired DNA (SMP-DNA): structures formed by DNA regions with direct repeat symmetry

Mechanism: newly synthesized DNA strands unwind behind the DNA polymerase and realignment follows
Subsequent repairing of bases and single-stranded loop formation
more slippage = multiple loops
Following rounds of replication incorporate loops into new DNA strands

Question 39

Y Linked Inheritance

Answer 39

Y-chromosome carries few genes- only 24
SRY gene is most important = determines gender
Located in the pseudoautosomal close to tip of Y
SRY inactivation leads tofemale development
SRY translocation to X chromosome: male with XX karyotype or female with XY karyotype