Repro Exam 2: Griffith Genetics And Counseling

Front 1

What Thatcher sent in an email about this lecture

Back 1

As far as Dr. Griffith’s stuff, I have submitted two questions:
one for treatments
and one for counseling.
Dr. Griffith presented a third that’s specific to PKU.
My questions should be easy. I think the information is very important but not particularly challenging. In each case I described a scenario and ask you to recognize the:
type of treatment,
or the proper response for counseling.
Dr. Griffith’s question is a little more challenging, but it’s not a killer

Front 2

He said on the audio you need to know the different treatments so that is what we are going to learn

Back 2

Treatments for Genetic Diseases

Front 3

Repair of cleft lip

Surgical repair of congenital heart disease

Prophylactic mastectomy or colonoscopy for patients with familial histories of breast or colon cancer

Back 3

Tx: Surgery

Front 4

Liver transplants (many disorders, e.g. alpha-1-antitrypsin deficiency)

Kidney transplant in autosomal dominant polycystic kidney disease

Bone marrow transplant (hematopoietic stem cell transplantation)

Back 4

Tx: Organ Transport

Front 5

Cessation of cigarette smoking in a patient with alpha-1-antitrypsin deficiency

Avoidance of hot environments in patients with anhydrotic ectodermal dysplasia

Medication avoidance in G6PD deficiency

Back 5

Tx: Avoidance/Modification of the Environment

Front 6

Restriction of phenylalanine in PKU****

Restriction of lactose or fructose in hereditary lactose or fructose intolerance

Back 6

Tx: Dietary Restriction

Front 7

Tyrosine supplementation in PKU****

Arginine supplementation in patients with argininosuccinic aciduria

Citrulline supplementation in patients with ornithine transcarbamylase deficiency

Back 7

Tx: Dietary supplementations

Front 8

Vitamin B-12 replacement with B-12 responsive methylmalonic aciduria

Folate supplementation in patients with 5,10-methylenetetrahydrofolate reductase deficiency

Back 8

Tx: Cofactor supplementation

Front 9

Allopurinol to inhibit xanthine oxidase in patients with HGPRT deficiency (Lesch-Nyhan syndrome)

Use of HMG CoA Reductase inhibitors in patients with hypercholesterolemia due to LDL receptor defects

Back 9

Tx: Inhibition of Enzyme activity

Front 10

Phenobarbital in treatment of Gilbert Disease (a disorder of mild unconjugated hyperbilirubinemia associated with a decreased activity of hepatic bilirubin-UDPglucuronosyl transferase)

Back 10

Tx: Induction of enzyme activity

Front 11

Use of chelation therapy (penicillamine reduces hepatic copper in patients with Wilson disease)

Phlebotomy (bleeding) to reduce iron load in patients with hereditary hemochromatosis

Back 11

Tx: Removal of toxic materials

Front 12

Sodium benzoate and/or sodium phenylbutyrate in the treatment of patients with hyperammonemia secondary to urea cycle defects

Back 12

Tx: Use of Alternative Metabolic Pathways

Front 13

Replacement of specific clotting factors (e.g. factor VIII for patients with hemophilia A)

Replacement of alpha-1-antitrypsin

Back 13

Tx: Protein replacement

Front 14

What are the objectives for Genetic Diseases Genetic Counseling?

Back 14

1. recognize strategies for treating genetic disorders
and list examples of diseases treated by these

2. Discuss principles for providing approviate genetic counseling

3. Recognize what GINA does and does not cover

Front 15

What are the various steps for genetic counseling?

Back 15

MOST IMPORTANT****
Consult patient
Always get informed consent and understanding of confidentiality
This is NON-DIRECTIVE!*** (in red)
Let the patient make the dissension

Front 16

What is GINA?

Back 16

Genetic Information Non-Discrimination Act
2010

Front 17

What is LNA?

Back 17

Large Neutral Amino Acids

- Competes with phenylalaine
- prevents phenylalaine from crossing the BBB
- when phenylalainine crosses the BBB is it converted into tyrosine and then turned into Dopamine
- allows for a more balanced diet

Front 18

What is your number one goal in genetic counseling?

Back 18

- Be non-directive
- Cannot say - do not do something!
- Cannot tell a pt

Front 19

What is 23 and me?

Back 19

- Put spit in a tube and screens you for many different abnl
- get a clinical report
- 23 and me is NOT FDA approved

Front 20

What is key for PKU?

Back 20

Start early outcome
start dietary restriction but confirm

Front 21

What aa needs to be eliminated in PKU?

Back 21

pheylalanine

Front 22

Why do you need to worry about protein and diet products?

Back 22

contain Phenylalanine

for severe PKU pts want about 200mg

Front 23

What converts phenylalanine to tyrosine?

Back 23

Phenylalanine hydroxylase****

Front 24

What should you do for your pts?

Back 24

refer to a support group
help with diet and compliance

Front 25

What is a Guthrie test?

Back 25

The Guthrie test, also known as the Guthrie bacterial inhibition assay, is a medical test performed on newborn infants to detect phenylketonuria, a disorder [inborn error] of amino acid metabolism.

Dx: PKU

Mass spec can also be used but is not widely available or cheap

Front 26

What are the consequences of treating PKU with dietary therapy?

Back 26

Vitamin D therapy

commonly see osteopenia and become vitamin D def!!!

measure metabolite - Parathyroid hormone, calcium, or calcitrol

Front 27

What is the most common vitamin def in PKU pts?

Back 27

Vit B12

we find B12 in animal proteins

Front 28

What cofactors does Phenylalanine hydroxylase require?

Back 28

1. NAD
2. BH4

Front 29

What does BH4 do?

Back 29

tetrahydrobiopterin - BH4 drug

Front 30

What is PKU?

Back 30

Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional

Front 31

What is the problem with enzyme replacement therapy in PKU?

Back 31

- Suboptimal results
- we need to but the drug in the brain!
- we need phenylalanine hydroxylase into the brain
- males are easier to tx then women
- need phenylalanine to cross the BBB

Front 32

Patient Non-compliance in PKU

Back 32

One of the hardest diets to put a pt on

Front 33

Substrate reduction therapy for PKU

Back 33

- due to competition
- competes for transport in brain
- dietary supplementation

Front 34

What is the most commonly widely therapy prescribed thought for PKU?

Back 34

dietary

currently there are not pharmacological Rx for PKU
except....
bh4 and LAA

Front 35

If you have PKU you have disfunctional phenylalainine hydrogenase

cannot convert Phenylalanine into tyrosine

Phenylalaine-L accumulates

Phenylalanine inhibits the enzyme tyrosinase

tyrosinease converts tyrosine to melanin

so have HYPOpigmentation

Back 35

wow

Front 36

In a pregant mother what must PKU be dealt with?

Back 36

The placenta will transport amino acids 2x faster then nl amino acids to make proteins in the baby

If the mother has PKU then phenylalainine builts up
and crosses the placenta very easily

This damages the brain and fetal development

Front 37

Patients with hyperphenylalaninemias most likely have a genetic defect in which of the following enzymes?

Back 37

Phenylalanine hydroxylase

Front 38

The cause of suboptimal outcomes in patients with PKU treated with diet alone is caused by:

Back 38

Patient non-compliance

Secondary deficiencies associated with the diet

Lack of patient follow-up for other secondary problems

Lack of medical knowledge

Front 39

A patient with PKU often presents with hypopigmentation. Why?

Back 39

An abnormal chemical environment interferes with normal pigmentation

Front 40

Patients with PKU are treated with:

Back 40

A low protein diet

Front 41

Patients with hyperphenylalaninemias should avoid which of the following foods?

Back 41

Meat
Diet Coke
Bread
Lasagna
Corn

Front 42

What are the consequences of treating PKU with dietary therapy?

Back 42

Vit D def

Front 43

What is the most common treatment for PKU?

Back 43

dietary restriction.

Front 44

Sapropterin is an example of

Back 44

cofactor supplementation

Front 45

LNAA therapy is an example of

Back 45

substrate reduction therapy.

toxin removal.

dietary supplementation.

Inhibits Phe from crossing the blood brain barrier****

Front 46

Patients with hyperphenylalaninemias are most commonly diagnosed by

Back 46

A positive Guthrie test

Front 47

What is the greatest obstacle to using enzyme replacement therapy to treat PKU?

Back 47

crossing the blood-brain barrier

Front 48

A mother with PKU and a normal father have a child who appears normal at birth. Immediately after birth the parents send a sample of DNA to 23andMe for genetic evaluation. The test confirms that the child has a mutation in the PH gene. What is your treatment?

Back 48

Measure the amount of Phe in the patients serum
&
Suggest further genetic testing

Front 49

A 15-year-old with PKU is experiencing some difficulty in maintaining his diet. What would you recommend?

Back 49

Refer to support groups

Advise the patient of the consequences of diet incompliance.

Front 50

A patient with PKU develops suboptimal results due to non-compliance with her diet. How should her doctor counsel her?

Back 50

Explain to her the consequences of failing to adhere to the diet, and discuss pros cons of alternative treatments such as sapropterin and LNAA

Front 51

A woman with PKU becomes pregnant. Chorionic Villi Sampling demonstrates that the child is heterozygous, with a wild type PH allele and a mutant PH allele. How should her doctor counsel her?

Back 51

explain that she must adhere to the restricted diet because high phenylalanine levels from her blood can damage her fetus’s neurologic development.

Front 52

How does PKU present?

Back 52

PKU will often times go undiagnosed until a child presents clinically with albinism, seizures, or a “musty” odor. In addition, typically untreated children our normal at birth but soon fail to achieve developmental milestones and begin to develop major cerebral impairment. Another typical presentation is hypopigmentation or eczema which can also be observed in patients with PKU.

Front 53

forgot these examples at the beginning

Back 53

sorry :(

Front 54

(chaperone therapy, small molecule therapy)

Improves stability of residual enzyme

Enhances enzyme activity

Only useful if some enzyme protein is produced

CRM positive (cross-reacting material positive) mutations

Not where the gene of interest is deleted or severely truncated

Back 54

Tx: Enzyme Enhancement Therapy

Front 55

Uses chemical/pharmacological agents to partially inhibit the synthesis of substrates

Theory: with less substrate, less will accumulate in the face of an enzyme deficiency

Used with lysosomal enzyme defects

Back 55

Tx: Substrate Reduction Therapy

Front 56

Know there is also enzyme replacement therapy

Back 56

you replace a specific enzyme that is deficient