Disorders Affecting the GI system - Genetics

Question 1

Which disease is known to be a neurocristopatholgy where aberration in neural growth, migration and differentiation of neural crest cells during embryological development is the cause of the disease.

Answer 1

Hirschprung disease

Question 2

In short-segment form of Hirschprung disease, the agnaglionic segment is limited to what location?

Answer 2

to the sigmoid and rectum. Not does extend beyond the upper sigmoid. this is also the 80% of cases of the disease

Question 3

The Hirschprung disease, which plexuses is missing, myenteric or submucosal?

Answer 3

Both are missing. but it’s the myenteric that gives it the name megacolon

Question 4

What is the clinical presentation of Hirschprung disease?

Answer 4

1. intestinal obstruction -> megacolon
2. Colon distention due to lack of peristalsis
3. variability depends on region affected

Question 5

Which congenital syndrome is most commonly associated with Hirshprung disease?

Answer 5

Down syndrome - about 12%

Question 6

In what gender is Hirshprung more common in?

Answer 6

Male. it’s a 4:1 ratio

Question 7

What gene mutation is associated with Hirshprung disease?

Answer 7

RET

Question 8

WHat role does RET play at a molecular level?

Answer 8

It’s a tryrosine kinase receptor

Question 9

In terms of cell cycle and growth, RET is is a _.

Answer 9

proto-oncogne which code for proteins that help regulate cell growth

Question 10

For RET mutation, is it the gain of function or loss of function of the gene that leads to Hirshprung disease?

Answer 10

Loss of function. Without RET working, it can act as a tyrosine kinase receptor in the neural crest cells and thus cells are arrested

Question 11

What role does the RET gene play in cell signaling?

Answer 11

RET gene provides instructions for producing a protein that is involved in signaling within cells, including nerves in the intestine.

Question 12

What protein transports iron and what molecule is responsible for storing iron commonly in the liver and heart?

Answer 12

Transferrin transports

Ferritin stores.

Question 13

What physiological mechanism excrete iron from the body?

Answer 13

There is no physiological mechanism for excreting iron. Few ways iron can be excreted include: enterocyte shedding, menses, pregnancy.

Question 14

What does it mean by too much iron overload as seen in hemochromatosis?

Answer 14

It means iron in excess of transferrin binding capacity. The excess iron is deposited in liver, heart, and some endocrine tissues.

Question 15

What are some secondary hemochromatosis causes?

Answer 15

Anemia, chronic liver disease (eg. hep C), infection, alcoholism, frequent blood transfusion. Not genetics.

Question 16

Which gene mutation is the most common cause of HH?

Answer 16

HFE

Question 17

The gene HJV is responsible for what type of hemochromatosis?

Answer 17

Responsible for most cases of juvenile hemochromatosis.

Question 18

Mutation in HAMP gene can also need to hemochromotosis. What role does HAMP play?

Answer 18

HAMP is a gene responsible for hepcidin which is a iron-regulating hormone critical for absorption

Question 19

The enterocytes normally are very good at regulating how much iron it lets into the body, due to mutation in this gene, that regulatory capacity of enterocytes are lost. What gene is that?

Answer 19

HFE.

Question 20

What are some factors that will increase iron absorption?

Answer 20

• inadequate diet
• impaired absorption
• celiac disease
• GI bleeding
• anemias, decreased erythropoiesis
• hypoxia

Question 21

What is the role of HFE protein on the enterocyte?

Answer 21

It regulate circulating iron uptake by regulating the interaction of TFR 1/2 with transferrin.

Question 22

What is the role of TFR1/2?

Answer 22

TFR1: protein required for iron import from transferrin into cells by endocytosis.
TFR2: Protein involved in the uptake of transferrin-bound iron into the cells by endocytosis, although its role is minor compared to TFR1.

Question 23

What is the role of hepcidin?

Answer 23

It is a key regulator of the entry of iron into the circulation

Question 24

What is the role of transferrin?

Answer 24

It is a iron-binding blood plasma glycoprotein that controls the level of free iron in biological fluids

Question 25

What is the role of ferroportin, and what inhibits it?

Answer 25

It is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell i.e. to the blood. It is inhibited by hepcidin, results in the retention of iron.

Question 26

Explain what happens to hepcidin, and ferroportin during iron deficiency, and during iron overload?

Answer 26

During low iron, Hepcidin levels go down and ferroportin is then able to bring iron from enterocyte to blood. During iron overload, hepcidin levels increase and it internalizes ferroportin and breaks it down as a result iron is not able to enter the blood.

Question 27

How does mutation in HFE, HJV or TFR2 effect hepcidin level?

Answer 27

Mutation results in low hepcidin levels despite high iron levels and inappropriate continued transport of iron into the plasma.

Question 28

During high levels of iron, Transferrin and HFE compete for binding sites at which receptor and who wins?

Answer 28

TFR1 receptor on hepatocyte and other cells. Transferrin wins because it has a higher affinity.

Question 29

elevated unbound HFE on cell surface stimulates expression of what?

Answer 29

Hepcidin

Question 30

When theres too much Fe2+, it cause TFR2 to be produced more than TFR1. TFR2 binding of Fe2 + stimulates expression of what?

Answer 30

Hepcidin

Question 31

In iron regulation the ultimate action of hepcidin is to _.

Answer 31

down regulate transport of Fe out of enterocytes.

Question 32

In iron deficiency, there are is more bound HFE to transferrin which leads to decreased TFR2 receptors.. This results in decreased expression of what protein?

Answer 32

HAMP. This leads to decreased hepcidin and thus leading to increased Fe2+ transfer out of enterocytes.

Question 33

What are clinical signs and symptoms of hemochroatosis?

Answer 33

1. Early non-specific symptoms like fatigue, arthralgia, ED, increased pigmentation
2. Progresses to hepatospelnomegaly
3. increased liver damage leading to caricinoma
4. ENdorincopathies: diabetes, hypopituitarism, hypogonadims, hypoparathyroidism

Question 34

In hemochromatosis, destruction of islet cells of the pancreas leads to _.

Answer 34

Diabetes mellitus leading to decreased insulin to decreased GLUT 2

Question 35

Bronze skin, iron fist sign, are characterisitic of what disease?

Answer 35

hemochromatosis

Question 36

At a cellular level, explain why hemochromatosis cause damage?

Answer 36

with increased increased iron, there’s more activity of Fe2+ converting to Fe3+ and back to Fe 3+. every time it does than it creates free radical. Free radicals and peroxidation of phospholipids causes organelle damage (mt, lysosome, microsomes). with cell death, there’s more enzymes, and liver enzymes and increased collagen syntehsis leading to fibrosis and cirrhosis.

Question 37

What blood tests can be obtained to diagnose hemochromotosis?

Answer 37

Serum iron, serum ferritin and total iron binding capacity.

Question 38

What is the most common ways of decreasing iron levels and is used as a treatment option for hemochromotosis?

Answer 38

Phlebotomy.

Question 39

A patient is diagnosed with hemochromotosis, how can you tell if its the hereditary form?

Answer 39

Check for mutation of C282Y where cys is replaced with TYR and also if the patient has an northern european ancestery.

Question 40

Once copper is absrobed in the stomach and duodenum, how does it get to the liver?

Answer 40

Copper binds to albumin the serum and is carried to the liver.

Question 41

What is the primary copper carrying protein in the blood?

Answer 41

Ceruloplasmin  = 90%
albumin = 10%

Question 42

Cerulopasmin also plays a role in iron absorption, how?

Answer 42

Ceruloplasmin is an iron oxidoreductase which is important in iron absorption Fe2+ to Fe3+.

Question 43

Transferrin can only bind what form of isotype of iron and what plasma protein helps to get it to that form?

Answer 43

Transferrin can only bind Fe+2. Ceuloplasmin can convert Fe+3 into Fe+2.

Question 44

What two transporter are located on the apical and basolateral surfaces of enterocyte that which are important in copper absorption?

Answer 44

DMT1

CRT1

Question 45

What gene is mutated in Menkes syndrome?

Answer 45

ATP7A

Question 46

What is the normal function of ATP7A?

Answer 46

Move Cu from intestinal mucosa into the blood

Question 47

What happens if ATP7A is mutated?

Answer 47

Uptake of Cu is impaired leading to Cu2+ deficiency. And because Cu acts as a cofactor in many reactions, those reactions cannot take place leading to a whole host of loss of physiological reactions.

Question 48

What are some clinical presentation of Menkes syndrome?

Answer 48

Infants: healthy until age 2 or 3 then loss of developmental milestone, hypotonia, seizures, and failure to thrive. Infants will exhibit typical neurologic changes and concomitant characterisitic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented). Temp instability and hypoglycemia. Death by three years of age.

Question 49

A infant presents with steel wool like hair, and has severe loss of developmental milestone, vascular tortuosity on MRI, and laxity of skin. What is the most likely diagnosis?

Answer 49

Menkes syndrome.

Question 50

What gene is mutated in wilson’s disease?

Answer 50

ATP7B

Question 51

What transporter carries copper from the lumen of small intestine to the enterocytes?

Answer 51

Copper membrane transporter 1 (CMT1)

Question 52

What are two ways cupper can be excreted?

Answer 52

1. Cu bound to metallothionein in enterocytes and then enterocytes shedding.
2. Ceruloplasmin binds excess cu in the liver and is excreted out with bile.

Question 53

With ATP7B mutation, how is Cu levels affected?

Answer 53

With mutation in ATP7B, Cu is prevented from being released from hepatocytes. ATP7B mutation causes degradation of apoceruloplasmin and so ceruloplasmin levels decrease.

Question 54

How does Wilson’s disease present clinically?

Answer 54

1. Progressive lenticular degeneration –> neurological effects.
2. liver cirrhosis due to access copper.

Question 55

What are some symptoms of wilson’s disease?

Answer 55

1. Neurologic symptoms: movement disorder (tremors, poor coordination, loos of ifne-motor control, chorea,)
2. Psychiatric symptoms: depression, neurotic behaviors, disorganziation of personality, intellectual deteroiation
3. Kayser-Fleischer rings: copper deposition in descement’s membrane of the cornea.