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70 Cards in this Set

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Definition of inborn error of metabolism

Inherited biochemical variation resulting from a block in a metabolic pathway due to a genetic deficiency of an enzyme or protein.

How are IEMs classified?
1) Catabolic vs. Anabolic
2) Pathologic finding seen (e.g., lysosomal storage disease)
3) Pathway affected
4) Clinical course/Symptom
5) Organ affected
Most IEMs are from mutations in genes that encode ______


What %age activity below which you usually see IEM?
What is the typical inheritance pattern of IEMs?

autosomal recessive

Dominant negative effect
have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterised by a dominant or semi-dominant phenotype. In humans, Marfan syndrome is an example of a dominant negative mutation occurring in an autosomal dominant disease. In this condition, the defective glycoprotein product of the fibrillin gene (FBN1) antagonizes the product of the normal allele.

Also, if the gene must be in a polymer to function, the only ones that will be working will be the ones that have all subunits of active enzyme.
Symptoms of IEM

1) Acute illness following a period of normalcy
2) Changes in muscle tone (hyper or hypotonia)
3) Recurrent vomiting, diarrhea, dehydration
4) Unexplained cognitive, visual, hearing deterioration
5) Milestone Regression
6) Failure to thrive
7) Lethargy or coma
8) Unusual odor (organic acids typically have a particular odor)
9) Rule of sepsis or infection
10) Presence of + family history or consanguinity

Classes of proteins based on function: Interaction with small molecules
Enzymes, receptors, transporters
Classes of proteins based on function: Regulation

peptide hormones, transcription regulators

Classes of proteins based on function: Structure
Collagens, Fibrillin

Mutations in these genes are likely to be dominant
What happens in structural gene mutations?

Change in DNA sequence of a gene that resulting in altering the amino acid sequence of the protein thus the protein in structurally changed (change in open reading frame).

The altered protein is made in normal amount, but has less than 10% of normal activity.

The protein will differ from the normal protein in kinetics, pH, temperature stability, and electrophoretic stability.

Example: sickle cell anemia. Single point mutation of glutamic acid to valine.

What happens in regulatory gene mutations?
A structurally normal protein is made (same kinetics, pH, temperature stability, and electrophoretic stability as normal protein).

BUT the protein is made in reduced quantities, at the wrong time, in the wrong place.

Ex. Hereditary persistence of fetal hemoglobin.
Potential problems that may result from IEM/ways that a mutation can affect normal protein function.

1) Can affect transport system. A protein may need to cross into a cell membrane to work (mutation in membrane receptor protein).

2) Enzyme that changes A to B can be defective, leading to a buildup of A which could be toxic (eg., lysosomal storage diseases).

3) Because A isn't being converted to B, it could be converted to C, a product of a minor metabolic pathway. Too much C could be a problem (in PKU C is responsible for strange smells)

Example of a <b>transport defect.</b>
Defect is in the <b> renal absorption of cystine and the dibasic amino acids (lysine, arginine, ornithine) causing excess secretion of cystine leading precipitation in the kidneys/urine and stone formation! </b>

Results in cystine stone formation in kidneys and urine, most often in 2nd and 3rd decades of life.
Treatment of cystinuria

Take bicarbonate to make urine more alkaline which increases solubility of cystine.

Drink lots of water to dilute cystine.

Both of these help prevent stone formation.

Familial hypercholesterolemia
Example of a <b> receptor defect. </b>

Defects in LDL receptor mechanism, so LDL cannot enter cell normally. Via biochemical processes, the amount of LDL in the cell influences how much cholesterol is made (thru a feedback mechanism). Because LDL can't get in, cholesterol synthesis is in overdrive.

Symptoms include high plasma cholesterol (300-500 mg/dl for heterozygotes, 600-900 mg/dl for homozygotes), premature heart disease, xanthomas, atheromas, and cholesterol deposits around cornea (arcus corneae). Homozygotes usually die around 30 years old.

Heterozygote incidence is about 1 in 500, homozygote about 1 in 1,000,000.
Treatment for familial hypercholesterolemia

1) Statins to inhibit HMG CoA Reductase, a step in the biosynthesis of cholesterol.

2) Bile-acid binding resins increase excretion of cholesterol in poo. (e.g., cholestyramine.) This stimulates production of LDL receptors, which causes the uptake of more LDL-bound cholesterol.

Classic Phenylketonuria (PKU)
Example of <b> too much substrate causing toxicity. </b>

Deficiency of phenylalanine hydroxylase , the enzyme that converts Phe to Tyr. Phe accumulates and is toxic in high amounts.

Also an example of <b> too little product influencing subsequent enzyme reaction.</b> A product of phenylalanine hydroxylase is tyrosine, which is precursor to melanin. therefore ppl with PKU are often pale. Tyrosine is also a precursor to DOPAMINE and EPINEPHRINE, probably responsible for the mental retardation seen in this disorder.

Also, an example of <b>too much minor metabolite causing toxicity.</b> Because so much Phe builds up, a minor metabolic pathway (conversion to phenylpyruvate an phenylactate) builds up and is excreted in urine, causing the characteristic musty smell. Too much of these are toxic to the cell.

Symptoms: mental retardation, seizures, behavioral problems, musty smell to urine, high plasma Phe levels.

Can be treated if identified early and given low-Phe diet.
Autosomal recessive, about 1 in 10,000.
Treatment of classic PKU

1) Low Phe diet can reduce problems if initiated very early in life. However, Phe can't be totally eliminated because it is an essential amino acid.

Example of <b> too much substrate interfering with normal cellular processes </b>

Deficiency is in homogentistic acid oxidase which converts homogentistic acid (a metabolite of tyrosine) to maleylacetoacetic acid. Homogentistic acid accumulates and is deposite in connective tissue, interfering with collagen formation.

Symptoms are pigment deposition in collective tissue (ochronosis), turning sclera and ear cartilage dark, dark urine, degenerative joint disease.

The deposition of pigment in connective tissue observed in alkaptonuria.

Treatment for alkaptonuria
Vitamin C can help.

It's not a fatal disease, just causes pain.
Treatment for IEMs at level of clinical phenotype

Basically this is treatment of the symptoms.

People are educated to avoid certain things that may exacerbate the condition (e.g., specific meds in G6P deficiency, avoid sun in albinism).

Certain medications are given (e.g., beta blockers, other things to reduce stress on the heart vessels in Marfan syndrome)

Surgical interventions (e.g., colectomy in familial adenomatous polyposis coli syndrome (FAP))

Maple syrup urine disease: definition and how it's treated
Deficiency of branched chain ketoacid dehydrogenase (substrates are leu, ile, and val). Treatment involves restriction of these amino acids in diet.
Galactosemia: definition and how it's treated

Deficiency of galactose-1-P uridyltransferase that converts galactose eventually to glucose. Treatment involves elimination of galactose from diet(including no dairy, tomato sauces, or candy).

Hemochromatosis: definition and how it's treated
too much iron. Phlebotomy to take out iron.

Actually a fairly common disorder but has low penetrance.
Biotinidase deficiency: definition and how it's treated

Inability to recycle the b-vitamin biotin, thus patients develop multiple carboxylase deficiencies.

treatment, obviously, involves supplementation with large doses of biotin.

Deficiency of cystathionine B-synthase, which uses vitamin B6 as a cofactor. About 1/3 cases recover with vitamin b6 therapy
Protein replacement therapies

Give patients the missing protein by infusion.

Example: hemophilia A - administer Factor VIII.

Several lysosomal storage diseases are treated this way (fabry, gaucher)

Organ replacement therapies
Idea is to supply the missing protein.

Eg., bone marrow transplant for B thalassemia.

Liver transplant for FH or ornithine transcarbamylase deficiency
Criteria for Newborn Screening

1) Disease must be serious

2) Must NOT be readily recognized at birth

3) Rapid, simple, and accurate test must exist

4) Screening must be cost-efficient

5) Early treatment before symptom onset reduces or eliminates severity

TSD is caused by insufficient activity of an enzyme called <b>hexosaminidase A</b> that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexosaminidase A is no longer functioning properly,<b> the lipids (gangliosides) accumulate in the brain and interfere with normal biological processes. </b>
Causes a relentless deterioration of mental and physical abilities that commences around six months of age and usually results in death by the age of four.

More common in Ashkenazi Jewis, French Canadians, Cajuns, Amish where carrier frequency is 1/30. Carrier frequency is 1/300 in other populations.
Three cellular processes critical to cancer development
1) Growth - cell division
2) Senescence - stable cell arrest
3) Apoptosis - programmed cell death
Proto-oncogenes: Definition and examples
Defn: Genes that normally function to promote cell growth.

Examples: Growth factors (attach to receptors to regulate cell cycle); Growth factor receptors ( require binding of a ligand to stimulate cell cycle); signal transduction molecules (relay growth signals from growth factor receptors to promote cell growth), cyclins, cyclin dependent kinases (CDK), and inhibitors of CDKs.
Growth factors

attach to receptors to regulate cell cycle.

Eg. Platelet derived growth factor stimulates growth of mesenchymal cells to help form blood clots

Growth factor receptors
require binding of a ligand to stimulate cell cycle

E.g., tyrosine kinases.
signal transduction molecules

relay growth signals from growth factor receptors to promote cell growth

eg., G proteins, encoded by RAS genes

Family of proteins whose activity varies at different times during the cell cycle

Usually peaks to signal cell division and is minimal when cells aren't dividing
Cyclin-dependent kinases

Function by phosphorylating substrates at particular points of cell cycle.

The addition of Phosphate group can lead to things like condensation of chromatin, or other types of things involved in mitosis.

Have a cyclin and CDK subunit when active.

They're phosphorylated at specific amino acid residues and dephosphorylated at others representing another level of control.

Philadelphia chromosome aka philadelphia translocation
specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is the result of a reciprocal translocation between chromosome 9 and 22.

Brings together two genes, leading to increased expression of the gene that results in increased cell proliferation.

Gleevec is a drug designed to counter this mutation.
Tumor suppressor genes: definition and examples

Defn: Genes that normally function to inhibit cell growth

Examples: CDK inhibitors, checkpoint genes, P53

CDK inhibitors
Family of proteins that inactivate CDKs.
Checkpoint genes
Expressed during certain transition called checkpoints during the cell cycle (e.g., G1 to S). They function to halt the cell cycle if there has been DNA damage or other cellular stress.
A tumor suppressor gene that normally assists in the control of cell division and growth through action on the normal cell cycle.

Mutations are found in 50% of human tumors making it the most commonly altered cancer gene.

It's a transcription factor.
Apoptosis: Defn and Causes
Programmed cell death.

Can be triggered by certain signals. Apoptosis regulates the elimination of cells

1) produced in excess
2) that have developed improperly
3) that have sustained genetic damage
4) in the absence of growth factors
5) virus-infection and tumor cells. Also, some T-cells can induce apoptosis in target cells.
6) to sculpt the developing organism
7) that are potentially dangerous, such as self-reactive lymphocytes
How to distinguish between apoptosis and necrotic cell death?
Apoptosis is a controlled autodigestion resulting from activation of endogenous proteases.

Necrotic cell death is typified by rapid cell swelling and lysis.
What does the protease digestion during apoptosis result in?
1) Cytoskeletal disruption
2) Cell shrinkage
3) Membrane blebbing, though the membrane remains intact, avoiding inflammatory response
4)Condensation of the nucleus so it can be degraded by endonucleaes.

The dying cell is engulfed by macrophages or neighboring cells.
IAP proteins
Inhibitors of APoptosis.

Can inhibit apoptosis even in presence of many death-inducing signals by inhibiting caspases.
Cystein proteases.

Degrade proteins by cleavage after an aspartate residue. - CASPase.
Three Categories of “Cancer Genes”
1) Proto-oncogenes
2)Tumor Suppressor Genes
3) Repair Genes
Tumor suppressor genes: how are they involved with cancer?
Their ABSENCE, not presence, induces cancer.

Must be missing BOTH COPIES (so rarer as a cause of cancer than proto-oncogenes, which only need one copy to be messed up.)

<b> They act in a recessive manner during carcinogenesis.</b>
Microsatellite Instability
n cells with mutations in DNA repair genes, however, some of these sequences accumulate errors and become longer or shorter. The appearance of abnormally long or short microsatellites in an individual's DNA is referred to as microsatellite instability. Microsatellite instability (MSI) is a condition manifested by damaged DNA due to defects in the normal DNA repair process.

MSI is a key factor in several cancers including colorectal, endometrial, ovarian and gastric cancers. Colorectal cancer studies have demonstrated two mechanisms for MSI occurrence.

* The first is in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch Syndrome, where an inherited mutation in a mismatch-repair gene causes a microsatellite repeat replication error to go unfixed. The replication error results in a frameshift mutation that inactivates or alters major tumor suppressor genes - key genes in the regulation of the cell cycle and, ultimately, the prevention of cancer.

* The second mechanism whereby MSI causes color
What can happen as a result of failure of apoptosis?
1) Cancer
2) Autoimmune disorders
What can happen as a result of too much apoptosis?
2) Neurodegenerative disorders
Microsatellites: defn
Areas or chromosomes involving repeating base pair themes.

Individuals can vary in number of these at any particular locus, but within individuals they're usually stable.

Each allele can be distinguished by a single band.
Telomeres and their relation to senescence
Defn: Repeated strands of DNA at the end of chromosomes.

During DNA replication, about 35 bases of DNA are not replicated, therefore not part of the new strand. As replication continues, the chromosomes get shorter and shorter.

Once they reach a certain length, this causes the DNA to stop dividing --> cell enters senescence.
Telomerase and relation to cancer
Telomerase adds bases to the ends of chromosomes to maintain sufficient length for continued growth.

If telomerase is inappropriately activated, cancer may results.
Do mutations in proto-oncogenes act in a dominant or recessive manner during carcinogenesis?
Epigenetic changes: methylation and its relation to cancer
Addition of methyl group to 5' cytosine results in loss of expression of associated genes.

Cancers usually show global HYPOMETHYLATION - too many genes gettin' expressed.

BUT cancer shows hypermethylation of the promoters of tumor suppressor genes (tumor suppressor genes get turned off!)
Epigenetic changes: histone modification and its relation to cancer
Histone modificiation (acetylation and methylation) may either directly influence the expression of cancer genes, or may modify the methylation status of cancer genes.
Cancer Genomics: defn and possible uses
Characterization of what is happening at the genetic level within tumors, using info about genetic changes to predict, detect, and treat cancer.
Cancer risk factors for most cancers
Approximately 1/3 behavioral/lifestyle like diet, exercise; 1/3 smoking; 1/3 inherited risk factors
Key characteristics of inherited cancer susceptibility
1) Younger than expected age at cancer diagnosis

2) Multiple primary cancers, or bilateral cancer in paired organs (e.g., breast cancer)

3) Familial clustering of cancer

Most are inherited in autosomal dominant.
Li-Fraumeni syndrome
Involves a mutation in tumor suppressor gene P53, yielding strong susceptibility to cancer (90% chance by age 60).
von Hippel-Lindau syndrome
Mutation in gene <i>VHL</i> thought to play a role in transcription. It also acts as a tumor suppressor gene.

Results in both benign and malignant cancers (hemangioblastoma, ataxia, seizures, pancreatic or renal cysts, pheochromocytomas).

Autosomal dominant
Lynch Syndrome (formerly Hereditary Nonpolyposis Colorectal Cancer)
Most common form of hereditary colon cancer (but still only 2-5% of all colon cancer.) Defect in mismatch repair.

Criteria recognized by 1-2-3
1) family must have at least 1 person with colon cancer diagnosed before age 50

2) Family must include at least 2 successive generations with colon cancer (autosomal dominant)

3) Must be at least 3 ppl with colon cancer in family, at least one must be a first degree relative of the other two.

Screening by microsatellite analysis, or look for presence of proteins in the cancer encoded by mismatch repair proteins by immunohistochemistry
Detection technique involves staining the tumor tissue with antibodies to proteins of interest.
DNA sequencing: how it works and problems
-Most comprehensive genetic testing technology available

Problems include false negatives - resulting from large deletions; another problem is variants of uncertain significance.
ACCE Framework
A method to evaluate genetic tests. Assesses
1) Analytic validity - how well test finds mutations
2) Clinical validity - how well the test identifies disease risk
3) Clinical utility - whether test results leads to evidence-based medical management
4) Ethical implications
What are goals of cancer genetic testing?
1) Provide risk assessment based on environmental, family history and validated risk assessment models.

2) Provide education about genetic testing (risks, benefits, availability, limitations)

3) Provide interpretation of results

4) Assess psychosocial history including family dynamics and potential psychological impact of testing

5) Discuss options for cancer screening and risk reduction