Biochemical Genetics

Tay-Sachs
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Terms in this set (20)
Tay-Sachs
TSD is caused by insufficient activity of an enzyme called hexosaminidase A 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, the lipids (gangliosides) accumulate in the brain and interfere with normal biological processes.
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.
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
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)
Cystinuria
Example of a transport defect.
Defect is in the 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!

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


TREATMENT=
1). Take bicarbonate to make urine more alkaline which increases solubility of cystine.

2). Drink lots of water to dilute cystine.

Both of these help prevent stone formation.
Familial hypercholesterolemia
Example of a receptor defect.

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=
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.
Alkaptonuria
Example of too much substrate interfering with normal cellular processes

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.

TREATMENT= Vitamin C can help.

It's not a fatal disease, just causes pain.
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.
Homocystinuria
Deficiency of cystathionine B-synthase, which uses vitamin B6 as a cofactor. About 1/3 cases recover with vitamin b6 therapy
Lysosomal Storage DisordersAccumulation of glycoproteins (accumulate due to enzyme deficiency), glycolipids or glycosamnioglycans within lysosomes in various tissues. Present later in infancy.Features of Carbohydrate Metabolism DisordersLow glucose levels, large spleen, lactic acidosis or ketosis Inability to metabolize specific sugars, defective glycogen synthesis or disorders of gluconeogenesis Ex. Galactosemia (GALT enzyme absent, no breakdown of galactose)Symptoms of Urea Cycle DefectsSEVERELY high ammonia levels, respiratory alkalosis Vomiting, poor feeding, coma, hypotonia, seizures Caused by inability to detoxify and excrete nitrogen, clear the waste (i.e. nitrogen) from AA metabolism ex. Citrullinemia, OTCSymptoms of AminoacidopathiesFEATURES: poor feeding, lethargy, growth failure, coma, seizures Present similarly to organic acidemias Enzyme deficiency to metabolize certain AA causes toxic accumulationFeatures of Fatty Acid Oxidation DefectsLow ketones, high ammonia Problems making glucose and fats into ketones Type of organic acid disorder Treatment = avoid fasting, take carnitine supplements MCAD= most common IEMOrganic AcidemiasFEATURES: vomiting, poor feeding, hypotonia, DDs. Could be acute/recurrent crises OR chronic. Abnormal metabolism of proteins, fats or carbohydrates. Marked metabolic acidosis (because of too much plasma acid) with ketosis, increased lactate, increased ammonia (mild to moderate) Most of these disorders are caused by buildup of BCAA VOMIT = valine, methionine, isoleucine, threonineGlycogen Storage Disorders12 types of GSDs Cause= defect in enzymes Regulating synthesis and degredation of glycogen All GSDs can present with hepatomegaly, cardiomegaly, muscular weakness, CNS deterioration (symptoms caused by glycogen accumulation in tissues)Maternal Complications Associated with Beta-Oxidation DefectsHELLP syndrome= Hemolysis, Elevated Liver enzymes, Low Platelets AFLP = Acute Fatty Liver of Pregnancy 16% of pregnancies with FAOD fetus --> deveop AFLP or HELLP HELLP= most likely caused by something other than LCHAD AFLP = likely caused by LCHAD 75% chance of maternal liver disease in LCHAD affected pregnancy 30% HELLP, 30% AFLP, 15% pre-eclampsia, etc.TyrosinemiaAmino acidopathy defective FAH enzyme Increased succinylacetone in blood and urine Increased Tyr, Phe, Met plama levels Type I = rotton eggs/cabbage smellGalactosemiaCarbohydrate metabolism defect (GALT enzyme) Increased galacitol in urine Increased galactose-1-phosphate in RBC Treatment= lactose and galactose restricted diet