Unit 6 Diseases Flashcards
Von Gierke Disease (Type I) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
Von Gierke Disease
Defective Enzyme: glucose-6-phosphatase (or transport system)
Organ affected: Liver & kidney
Glycogen in the affected organ: Increased amountl normal structure
Clinical features: massive enlargement of liver, failure to thrive, severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia
Anderson Disease (Type IV) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
Anderson Disease
Defective Enzyme: branching enzyme (a1-4 to a1-6)
Organ affected: Liver and spleen
Glycogen in the affected organ: normal amount, very long outer branches
Clinical features: progressive cirrhosis of the liver. Liver failure causes death, usually before age 2
McArdle Disease (Type V) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
McArdle Disease
Defective Enzyme: Phosphorylase
Organ affected: Muscle
Glycogen in the affected organ: Moderately increased amount, normal structure
Clinical features: Limited ability to perform strenuous exercise b/c of painful muscle cramps. Otherwise, pt is normal & well-developed
What happens when there’s a deficiency in Fructose-1-phosphate aldolase?
F-1-P aldolase is the only enzyme that will get fructose into the glycoysis cycle by doing aldol cleavage of F-1-P into glyceraldehyde and DHAP, which will then be converted in Glyceraldehyde phosphate & into glycosis. Hence, deficiency will lead to liver damage and hypoglycemia.
What happens when there’s a deficiency in galactose kinase?
Galactose kinase will phosphorylate galactose into galactose-1-phosphate which will be worked on by other enzymes to get it into glycolysis. Deficiency will cause formation of galacitol, which causes cataracts. Pt should remove lactose from diet.
What happens when there’s a UMP transferase deficiency?
UMP transferase aka galactose-1-phosphate uridylyl transferase catalyzes galactose-1-phosphate to form glucose-1-phosphate which phosphoglucomutase can change into glucose-6-phosphate and into glycolysis. Def in UMP transferase will lead to mental retardation and liver failure. Treatment includes newborn screening and removal of lactose from diet.
Where is the site of action of arsenite poisoning?
arsenite will irreversibly chelate with dihydrolipoamide, which is an impt prosthetic group of one of the 3 enzymes (dihydrolipoyl transacetylase) in the pyruvate dehydrogenase complex which is the complex responsbile for making pyruvate into acetyl coA. Without this, then the person can’t survive b/c won’t be able to do aerobic respiration.
NADPH is used in biosynthesis and detoxification. Cytochrome P450 uses NADPH in the small intestines to detoxify what?
xenobiotics (poisons, toxins)
What is the role of NADPH in red blood cells?
needed to detoxify reactive oxygen species
Over 400 million people have glucose-6-phosphate dehydrogenase (G6PDH) deficiency. It is the most common enzyme deficiency. What are the consequences?
G6PDH is the first enzyme in the pentose phosphate pathway which will catalyze the rxn from G-6-P to 6-phosphoglucono-delta-lactone, producing an NADPH. This enzyme deficiency will result in deficient levels of NADPH which is bad b/c NADPH is impt for detoxification of ROS, toxins, etc. They will have hemolytic anemia when they ingest fava beans (favism).
What is the evolutionary advantage of G6PDH deficiency?
it’s better to pay the metabolic cost of a faster rate of turnover of RBC’s than to die from malaria.
Explain the concept of “oxygen debt” in regards to the liver and its role in the cori cycle.
The cori cycle involves the production of lactate in muscle that needs more ATP. The lactate will be carried to the liver where it is converted to glucose (gluconeogenesis, using 1 ATP + 1 GTP). The glucose is released back into bloodstream. After exercise, this continues as muscle glycogen stores are replenished. The amount of O2 consumed in liver during this rebuilding process of muscle glycogen is called the “oxygen debt”
What is going on when you crack open an egg that’s been in the fridge for way too long?
We can smell H2S which is due to acidification of the tissues producing H2S gas due to iron sulfur proteins
Translocase (ADP/ATP, and Pi translocases) inhibitors inhibit oxidative phosphorylation. What do atractyloside and bongkrekic acid inhibit?
They inhibit ADP/ATP transport. Atractyloside prevents binding of ADP while bongkrekic acid prevents release of ADP. Both result in convulsions of a hypoglycemia nature, collapse and death.
-ADP/ATP translocase takes one ADP in and one ATP out, effectively removing one negative charge from the mitochondrial matrix (electrogenic)
Translocase (ADP/ATP, and Pi translocases) inhibitors inhibit oxidative phosphorylation. What do mercurous salts inhibit?
Inhibit Pi transport by rxn with essential -SH, leading to muscle spasms, depression, death from kidney failure usu w/in a week of exposure.
-Pi translocase moves 1 H+ and Pi- into the cell (electroneutral)
What is 2,4-dinitrophenol?
It is a uncoupler, which means it discharges the pH gradient, using O2 without the presence of ADP. People present with profuse sweating, collapse, death. Formerly used for weight reduction.
What is oligomycin?
A phosphorylation inhibitor, which prevents use of the electrochemical gradient to drive ATP synthesis by blocking Fo. It is fatal.
What is rotenone?
It is an etc inhibitor, inhibiting at 1st coupling site, causing nausea, vomiting, convulsions and death from respiratory paralysis.
What is amytal?
It is a barbiturate that inhibits chain ETC at 1st coupling site. Overdose causes the same symptoms as rotenone: nausea, vomiting, convulsions and death from respiratory paralysis.
What does cyanide do to the ETC? How to treat it?
Inhibits chain at cytochrome a3, blocking O2 binding by taking its place by binding to FeIII. It results in convulsions, unconsciousness, death from respiratory paralysis. An antidote is nitrite & thiosulfate IV and administer O2.
What is antimycin A?
It is an ETC inhibitor that inhibits chain at 2nd coupling site. It’s fatal.
How does CO interrupt the ETC?
It inhibits chain at cytochrome a3, blocking O2 binding by binding to FeII. Death results from interaction w/ Hb before it can reach the respiratory chain. Dizziness, vomiting, increase then decrease pulse and respiration, collapse and death. Treatment is O2 administration.
What are 3 causes of steatorrhea (excessively fatty stools)?
1 - failure of bile production or blockage of bile flow
2 - exocrine pancreas dysfunction or obstruction of pancreatic duct
3 - failure of uptake into intestinal mucosal cells (enterocytes)
Hartnups disease
Background: there are 5 transporters located on intestinal epithelium that help in amino acid absorptions (either Na+ or H+ symporters)
Hartnup’s disease is caused by a deficiency in the transport of neutral & aromatic acids (e.g. phenylalanine, tryptophan). Therefore, more of these a.a. will be detected in urine
Symptoms: pellagra-like (dermatitis, diarrhea, dementia, death) b/c tryptophan is needed to build niacin & niacin deficency causes pellegra
Treatment: niacin
Cystinuria
Background: there are 5 transporters located on intestinal epithelium that help in amino acid absorptions (either Na+ or H+ symporters)
Cystinuria is caused by a defect in the transporter responsible for transporting basic a.as and cystine
Symptoms: cystine accumulations will lead to kidney stones
Treatment: penicillamine
Cystic Fibrosis is an AR disease that manifests with pulmonary and digestive issues. Explain the reason for the digestive issues.
There’s a defect in the chloride channels in the pancreatic secretory ducts. They harden and eventually block, leading to a lack of pancreatic enzymes in the intestinal lumen. These patients will not be able to digest proteins. They must be given oral supplements of pancreatic enzymes
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Which is the most common enzyme deficiency in the urea cycle? In this urea cycle disorder, what is found high in blood and urine?
OTC deficiency (OTC catalyzes the rxn from ornithine to citrulline in the mitochondria) is called Hyperornithinemia. Patient will have high levels of NH4, orotate and ornithine in blood, and high levels of ornithine in urine. They will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Which enzyme defect causes arginiosuccinic aciduria? what is found high in blood and urine?
Argininosuccinase deficiency (argininosuccinase breaks down argininosuccinate into arginine & fumarate) will lead to high levels of NH4 and argininosuccinic acid in blood, and high levels of arginosuccinic acid in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
What enzyme defect causes hyperammoniemia? what is found high in blood and urine?
Carbamoyl phosphate synthase deficency (the 1st step of the urea cycle converting NH4+ CO2 + 2ATP into carbamoyl phosphate) will result in high levels of NH4 in in blood, nothing detectable in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
What enzyme defect causes arginiemia? what is found high in blood and urine?
Arginase deficiency (arginase will break down arginine into urea + ornithine) will lead to high levels of NH4 and arginine in blood, and high levels of arginine, lysine, and ornithine in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Of the 5 urea cycle disorders we learn, which is the only one that causes mental retardation? what is found high in blood and urine?
Citrullinemia will cause mental retardation. It is due to a argininosuccinate synthetase deficiency. Argininosuccinate synthetase synthesizes argininosuccinate from citrulline + aspartate + ATP. There will be high levels of NH4 and citrulline in blood, and high levels of citrulline in urine.
Maple Syrup Urine Disease
Problem in the pathway of degrading branched amino acids (valine, isoleucine, and leucine), especially in the branched chain alpha-keto acid dehydrogenase enzyme. Patient’s urine will smell like maple syrup and will have seizures and other symtpoms. Treatment includes dietary restriction of valine, isoleucine and leucine. Some patients respond to high doses of thiamine (vit B1)
Phenylketonuria (PKU) vs Atypical PKU vs Maternal PKU
PKU - genetic defect in phenylalanine hydroxylase causing build up of phenylalanine, which can be converted into phenylpyruvate (bad!), leading to severe mental retardation. Dietary restriction of phenylalanine until 16 is advised to prevent mental retardation. In these patients, tyrosine becomes essential.
Atypical PKU -genetic defect is in BH2 (tetrahydrobiopterin) reductase, responsible for making BH4, which is a cofactor of phenylalanine hydroxylase. No treatment.
Maternal PKU -mothers with PKU should avoid phenylalanine b/c too much phenylalanine is bad for the fetus.
Homocystinuria
A defect in an enzyme called cystathionine synthase (homocysteine synthesis from methionine + serine). Patient presents with increased risk of atherosclerosis. Some die early of heart disease. There are mental disabilities as well. Giving patient Vit B6 (PLP) supplement can help (it’s a cofactor for the enzyme).
Cystathionuria
A defect in enzyme cystathionase part of the pathway in making cysteine from serine and methionine. Symptoms are increase risk of heart disease. Can be treated with Vit B6.
Alkaptonuria
Defect in homogentisate oxidate (part of pathway of converting phenylalanine into acetoacetyl CoA) leading to dark urine and arthritis.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Tay Sachs Disease.
- deficiency in b-hexosaminidase A or activator protein in some cases
- accumulation of gangliosides
rapid, progressive & fatal neurodegeneration, muscular weakness, seizures.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Gaucher Disease (MOST COMMON).
- deficiency in B-glucosidase (glucocerebrosidase)
- accumulation of glucocerebrosides
hepatosplenomegaly, osteoporosis in long bones, CNS involvement in infantile & juvenile forms
Treated with enzyme replacement therapy
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Metachromatic Leukodystrophy
- deficiency in arylsulfatase A & some times in activator protein
- accumulation of sulfatides
cognitive deterioration, demyelination, progressive paralysis & dementia in infantile form,
