Genetic Basis Of GI Disorders-1/25/16

Question 1

This form of Hirschprung disease is characterized by aganglionosis extending proximal to the sigmoid colon

Answer 1

Long-segment

Question 2

What plexuses are destroyed in Hirschprung disease

Answer 2

Myenteric (auerbach) and Submucosal (Meissner) plexuses

Question 3

You are observing a radiograph of an infant patient of korean descent. The image shows an intestinal obstruction, colon distention from a lack of peristalsis, and the baby has failed to have meconium. What is a likely diagnosis?

Answer 3

Hirschprung disease

Question 4

These types of patients are more likely pre-disposed to Hirschprung disease:

Answer 4

Down Syndrome babies

Asians (1.4/5000) more likely than blacks (1.05/5000) and whites (.75/5000.

Male: Female 4:1

Question 5

Name the Gene, MOI, chromosomal location, Protein function, and frequency involved in Hirschprung disease:

Answer 5

Gene=RET
MOI=AD
Location=Chr 10q11.2
Function=Tyrosine Kinase receptor
Frequency=70-80%, 50% is familial, 15-20% is sporadic

Question 6

RET gene is expressed in ___ cells and is this type of gene that codes for proteins that help regulate cell-growth: ___

Answer 6

Neural crest

Proto-oncogene

Question 7

What type of mutation in RET is responsible for Hirschprung disease?

Answer 7

Loss-of-function–> results in reduced or abolished protein function

Question 8

Without ____ protein signaling, enteric nerves do not develop properly

Answer 8

RET

Question 9

Fe is bound and transported in the body via ___ and stored in ___ molecules in the liver and heart

Answer 9

Transferrin

Ferritin

Question 10

List 2 possible reasons for Fe overload:

Answer 10

Too much Fe is absorbed–> Fe in excess of transferrin-binding capacity; deposited in liver, heart, and some endocrine tissues; can lead to tissue damage and fibrosis

Too many erythrocytes are destroyed –> Accumulated in reticuloendothelial macrophages first, tissue parenchyma after macrophages

Question 11

____ is a build-up of Fe due to anemia, chronic liver diseases, often a result of Hep C infection or alcoholism, frequent blood transfusions

Answer 11

Secondary hemochromatosis

Question 12

This gene is responsible for the most common form of Fe-overload: Hemochromatosis

Answer 12

HFE–> Chr 6p21.3, MOI=AR

Question 13

___ gene is responsible for most cases of juvenile hemochromatosis; rare but has severe Fe overload

Answer 13

HJV–> Chr 1q21, Hemojuvelin protein, MOI=AR

Question 14

___ gene is less common but with similar clinical presentation to HFE mutations

Answer 14

TFR2–> chr 7q22, Transferrin receptor 2 protein, MOI=AR

Question 15

___ gene is for Hepcidin, an Fe-regulating hormone critical for absorption

Answer 15

HAMP–> Chr 19q13, Hepcidin protein, MOI=AR

Question 16

List factors that increase Fe absorption

Answer 16

Inadequate diet
Impaired absorption
Celiac disease
GI bleeding
Anemias, decreased Erythropoiesis
Hypoxia

Question 17

List factors that decrease Fe absorption

Answer 17

Regular blood transfusion
High Fe diet
Fe loading vitamins

Question 18

____ functions to regulate circulation Fe uptake by regulating the interaction of TFR 1/2 with transferrin

Answer 18

Human hemochromatosis protein (HFE)

Question 19

___ is a key regulator of entry of Fe into the circulation

Answer 19

Hepcidin

Question 20

___ is an Fe-binding blood plasma glycoprotein that controls the level of free Fe in biological fluids

Answer 20

Transferrin

Question 21

___ is a protein required for Fe import from transferrin into cells by endocytosis

Answer 21

TFR1

Question 22

___ is a protein involved in the uptake of transferrin-bound Fe into cells by endocytosis

Answer 22

TFR2-its role is minor compared to TFR1

Question 23

___ is a transmembrane protein that transports Fe from inside of a cell to outside of cell. It is inhibited by hepcidin, results in retention of Fe

Answer 23

Ferroportin

Question 24

In states of Fe deficiency, Hepcidin levels are ___ in the liver

In states of Fe excess, Hepcidin levels are ____ in the liver

Answer 24

Low

Increased

Question 25

In states of Fe excess, hepcidin levels increase and this promotes internalization and degradation of ___ and results in decreased Fe absorption from the gut and decreased release from macrophages

Answer 25

Ferroportin

Question 26

Mutations in ____ result in low hepcidin levels despite high Fe levels and inappropriate continued transport of Fe into the plasma

Answer 26

HFE, HJV, TFR2

Question 27

A 47 year old male comes into your clinic complaining of general fatigue, has some minor arthalgia, states he has trouble getting and maintaining an erection, and has pain in the proximal and distal IP joints of his 2nd and 3rd phalanges. What does this patient most likely have?

Answer 27

Hemochromatosis Onset age 40-50 in males, later in females Can progress to hepatosplenomegaly, liver fibrosis and cirrhosis Increasing liver damage leading to carcinoma Endocrinopathies--> Diabetes, hypopituitarism, hypogonadism, hypoparathyroidism due to Fe deposition Increase incidence of infections with decreased hepcidin

Question 28

What tests are needed to obtain a hemochromatosis diagnosis?

Answer 28

Serum Fe Serum Ferritin Total Fe binding capacity--> Serum Fe/TIBC x 100% Transferrin-Fe saturation % --> usually 25-35% , much higher in those with Fe overload

Question 29

The vast majority (90%) of Hereditary Hemochromatosis is due to this mutation:

Answer 29

C282Y --> CYS to TYR mutation at residue 282

Question 30

Hereditary hemochromatosis is most likely to occur in what type of population?

Answer 30

Northern European ancestry--> 1:250 Blacks have a 1:6000 incidence

Question 31

In wilsons disease and menke's syndrome, which cofactor is of concern?

Answer 31

Cu--> absorbed in the stomach and duodenum, bound to albumin and transported to the liver

Question 32

These 2 genes are involved in copper homeostasis:

Answer 32

ATP7A ATP7B

Question 33

____ is expressed in liver, brain, kidney, and placenta and facilitates incorporation into apoceruloplasmin to yield ceruloplasmin

Answer 33

ATP7B

Question 34

___ is the major copper-carrying protein in the blood, and in addition plays a role in Fe metabolism

Answer 34

Ceruloplasmin

Question 35

Increased levels of ceruloplasmin are found during ___

Answer 35

Inflammation, infection, and trauma

Question 36

____ is located on the basolateral and apical surfaces of enterocytes so Cu2+ can enter from blood and intestines

Answer 36

CRT1

Question 37

In Menke's syndrome, ____ is mutated which leads to an impairment in Cu2+ uptake, Cu2+ deficiency, and co-factor deficiency and inefficient rxns.

Answer 37

ATP7A

Question 38

A newborn has reached normal developmental milestones until roughly 3 months of age when he begins to have flaccid muscles, seizures, and develops short, sparse, and coarse hair similar to a steel wool cleaning pad. Prognosis is poor and it is expected that he will have failure to thrive by age 3. What does this baby have?

Answer 38

Menke's syndrome

Question 39

In wilson's disease, ___ is mutated and prevents release of Cu2+ from hepatocytes

Answer 39

ATP7B

Question 40

Progressive lenticular degeneration (bilateral softening of lenticular nucleus and Liver Cirrhosis) is a clinical presentation of ____

Answer 40

Wilson's disease

Question 41

List symptoms of Wilson's disease: A) Neurological symptoms= B) Psychiatric symptoms=

Answer 41

A) movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis); Rigid distonia (mask-like facies, rigidity, gait disturbance) B) Depression, neurotic behaviors, disorganization of personality, intellectual deterioration

Question 42

A Kayser-Fleischer ring is characteristic of this disease:

Answer 42

Wilsons--> Cu2+ deposition in Descemet's membrane of the cornea, reflects high degree of Cu2+ storage in the body

Question 43

Menke's syndrome is a defect in ___ of copper Wilson's disease is a defect in ___ of copper

Answer 43

Intestinal absorption Biliary excretion

Question 44

This form of Hirschprung disease occurs in majority of cases (~80%) and the aganglionic segment does not extend beyond the upper sigmoid colon

Answer 44

Short-segment form