Part III

Autosomal Recessive Dz’s Sickle Cell Disease

Genetics and Cell Level: Point mutation in Beta-globin

chain

Glutamic acid to Valine

Africans are most commonly affected

Autosomal Recessive Dz’s

Sickle Cell Disease

Clinical Presentation:

○Heterozygotes usually clinically silent but added protection to malaria

○ requires > 90% HbS to sickle in systemic vasculature exception is in the renal papilla where oxygen tension is low enough to induce sickling but sometimes renal papillary necrosis

Autosomal Recessive Dz’s Sickle Cell Disease

Clinical Presentation:

○ Homozygotes

Presents with sickle cell vaso-occlusive crises

Chest pain , bone pain

Fever, stroke

Abdominal pain

○ gallstones

Dactylitis

○ painful swelling of the hands and feet

Question

Patients with the diagnosis of sickle cell

anemia make a specific type of hemoglobin

known as HgbS. This mutation results in the

sickling of their red blood cells when

exposed to inciting factors such as hypoxic

conditions. Patients are often treated with

hydroxyurea,

Which of the following has direct effects on

their hemoglobin physiology ?

1. Increases oxygen carrying capacity of Hb.

2. Decreases oxygen carrying capacity of Hb.

3. Increases levels of fetal hemoglobin (HbF)

4. Decreases levels of HbS

5. Decreases levels of fetal hemoglobin (HbF)

Question A 7-year-old girl with a history of painful crises and

impaired growth presents for evaluation of sickle cell

disease. You perform hemoglobin gel electrophoresis,

and diagnose her with homozygous sickle cell

disease. Which of the gel electrophoresis lanes in the

image is hers?

1. Lane 2

2. Lane 3

3. Lane 4

4. Lane 6

5. Lane 7

Question A 17-year-old African-American male presents to his family

physician after noticing red-tinged urine the week before,

when he was suffering from a cold. The patient states that he

had experienced that before. His father is with him and says

that this happens to him on occasion as well.

What is the most likely diagnosis for this patient?

1. Acute cystitis

2. Acute interstitial nephritis

3. Sickle cell trait

4. Acute glomerulonephritis

5. Hemophilia

X-Linked Recessive Dz’s

Fragile X (most common inherited form of retardation)

Genetics and Cell Level:

○ Expansion of CGG on chrom X (FMR1 gene), full mutation is > 200 repeats

○ Associated with chromosomal breakage (hence the name)

http://www.yourgenesyourhealth.org/fragx/cause.htm

X-Linked Recessive Dz’s

Fragile X

Clinical Presentation

Large Head

Large Ears

Large Testicles (Macroorchidism)

Mental Retardation

Testing: PCR, Southern Blot, Cytogenetic analysis

Question A 4-year-old boy presents to his pediatrician

for severe developmental delay. On exam he

is noted to have macroorchidism, large

protruding ears, a large jaw, and a long thin

face. Suspicious of what the diagnosis may

be, the pediatrician orders a PCR and DNA

sequencing. The results reveal an expansion

of 250 repeats of CGG.

What is the diagnosis of the boy?

1. Huntington's disease

2. Fragile X syndrome

3. Freidrich ataxia

4. Myotonic dystrophy type 1

5. Spinal and bulbar muscular atrophy

X-Linked Recessive Dz’s

Hemophilia A

Genetics and Cell Level:

○ Loss of Factor VIII

○ Increased PTT but normal PT and bleeding

time

X-Linked Recessive Dz’s

Hemophilia A

Clinical Presentation: Increased PTT but

normal PT and bleeding time

○ Bleeding can occur into many sites

most common are joints, brain,

muscles, and GI tract

Treatment is with Factor VIII

○ If dz is caused by low levels of Factor

VIII and not loss then desmopressin

can be used.

X-Linked Recessive Dz’s

Hemophilia B aka Christmas Dz

Genetics and Cell Level:

○ Loss of Factor IX

Clinical Presentation: Increased PTT but

normal PT and bleeding time

○ Bleeding can occur into many sites

most common are joints, brain,

muscles, and GI tract

REVIEW THE CLOTTING CASCADE

X-Linked Recessive Dz’s

Hemophilia C aka Rosenthal Syndrome

Genetics and Cell Level:

○ Loss of Factor XI

○ Ashkenazi Jews

Clinical Presentation: Increased PTT but

normal PT and bleeding time

○ Bleeding does not occur in joints!!!

○ Occurs while doing surgery

REVIEW THE CLOTTING CASCADE

X-Linked Recessive Dz’s

G6PD (aka Favism)

Genetics and Cell Level:

X-Linked Recessive Dz’s

G6PD (aka Favism)

Genetics and Cell Level:

○ Defect in glucose 6-phosphate dehydrogenase

Clinical Presentation:

○ Prolonged neonatal jaundice can be complicated by kernicterus

○ Acute hemolytic anemia in the presence of simple infection, fava beans, or rxn with certain medicines (antibiotics, antipyretics, and antimalarials)

Misc: Look for Heinz bodies on peripheral smear in active process

X-Linked Recessive Dz’s

G6PD (aka Favism)

Genetics and Cell Level:

Muscular Dystrophies

Duchenne’s Genetics and Cell Level:

○ Frame shift mutation in dystrophin gene (DMD) leads to deletion and accelerated muscle breakdown.

○ Dystrophin anchors muscle fibers, primarily skeletal and cardiac muscles

Clinical Presentation: Dx by increased CPK and muscle biopsy, onset before age 5

○ Weakness begins in pelvic girdle and progresses superiorly

○ Pseudohypertrophy of calf muscles 2/2 fibrofatty replacement of muscle

Misc: Look for use of Gower’s maneuver

Gower’s maneuver

Muscular Dystrophies Duchenne’s

Muscular Dystrophies

Becker’s

Genetics and Cell Level:

○ Defect in dystrophin gene, less severe than

Duchenne’s defect

Clinical Presentation:

○ Progressive muscle weakness, onset later

than Duchenne’s

Note: Both Duchenes and Becker’s

are associated with Heart Condition

called Dilated Cardiomyopathy .

Reciprocal Translocation in germinal cells

can give rise to deletions, amplifications

The presence of this translocation is a highly sensitive test for CML, since

95% of people with CML have this abnormality.

Robertsonian Translocation

In humans, generally occurs in the five acrocentric chromosome

pairs, namely 13, 14, 15, 21 and 22

Robertsonian Translocation

Downs Mosiac

Autosomal Trisomies

Down Syndrome (Trisomy 21) (cont.)

95% of cases due to meiotic nondisjunction of homologous chromosomes

○ Associated with advanced maternal age 1:1500 at maternal age 20-24

1: 210 at maternal age 35-39

1: 25 at maternal age >45

4% of cases due to Robertsonian translocation

○ Long arm of chrom 21 is attached to another chromosome and is kept diploid during gametogenesis

1% of cases due to Down mosaicism

Autosomal Trisomies

Down Syndrome (Trisomy 21) Most common chromosomal disorder and most

common cause of congenital mental retardation

Diagnosis done by triple screen

○ decr a-fetoprotein, decr estriol, incr. b-hCG

○ Quad screen is above plus inhibin A (incr is +)

○ U/S shows increased nuchal translucency

Clinical Presentation:

○ Mental retardation, flat facies, prominent epicanthal folds, simian crease, duodenal atresia, congenital heart dz (septum primum type ASD), hypotonia

Misc: increased risk of ALL and Alzheimer's dz

Down Syndrome

Autosomal Trisomies

Edward’s Syndrome (Trisomy 18)

Edward’s = Eighteen

Most common trisomy in live birth after

Down syndrome (1:8000)

Clinical Presentation:

○ Severe mental retardation, rocker-bottom feet,

micrognathia, low-set ears, clenched hands,

prominent occiput, congenital heart dz (ASD &

VSD)

○ decr a-fetoprotein, decr estriol, decr b-hCG

○ Inhibin is also decr

Misc: Death usually within one year of age

Autosomal Trisomies

Patau’s Syndrome (Trisomy 13)

Incidence is 1:15000

Clinical Presentation:

○ Severe mental retardation, rocker-bottom feet,

microphthalmia, microcephaly, cleft lip/Palate,

holoProsencephaly, Polydactyly, congenital

heart dz (ASD & VSD) (anyone see a

theme??)

Misc: Death usually within 1 year of birth

Sex chromosomal Trisomies

Klinefelter syndrome

Are males having one copy

of extra X chromosome

47 XXY genotype

Lower IQ

Tall Stature

Poor muscle Tone

Gynecomastia

Small Testis (infertility)

Appear like normal females

Not diagnosed clinically

Diagnosed accidentally

Lyonization

47 XYY Syndrome

These guys are not superman

But they are tall

Have high achne level

Normal intelligence

Not aggressive as previously thought

Triple X Syndrome (47 XXX)

Trisomy would feel left out

without its partner!

Generally, if a chromosomal mutations occurs

during meiosis, one half of the gametes will

have monosomy and the other half will have

trisomy

Turner’s Syndrome

Females born with loss of 1 X chromosome

Genotype is 45 XO

Occurs due to non dysjunction

Turner’s Syndrome

Features includes short

stature, short broad neck, and

a broad chest.

• Intelligence does not seem

to be affected

• It is NOT linked maternal

age.

• Cardiac abnormalities

coarctation of aorta & Bicuspid

aortic valve

• Women with Turner's

syndrome can live relatively

normal lives, though they are

unable to bear children.

Turner’s Syndrome

Develop Osteoporosis?

No Ovaries (dysgenic

Ovaries, hence estrogen

deficiency

Hearing Loss

Horseshoe shaped Kidney

Lymphedema of feet

Cri-du-Chat syndrome Genetics and Cell Level:

○Congenital microdeletion of short arm of chromosome 5 (46 XX or XY, 5p-)

Clinical Presentation:

○Microcephaly, moderate to severe mental retardation, epicanthal folds, cardiac abnormalities

Misc: Cri-du-chat is French for cry of the cat. The disease is named this way as the children affected make a high pitched mewing/crying sound.

Cri du Chat

Cry of the Cat individuals

sound like cats crying.

Why? The larynx of the

child is improperly developed.

Williams syndrome

Genetics and Cell Level:

○Congenital microdeletion of

long arm of chromosome 7 (46

XX or XY, 7q-) which includes

the elastin gene

Williams syndrome

Clinical Presentation:

○ Distinctive “elfin”

facies

○ mental retardation

○ well-developed

verbal skills

○ cheerful

disposition,

extreme

friendliness with

strangers

○ cardiovascular

problems

END

PART III

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