Bioc 212 Final 4/19

Basic Cause: Metabolic disorder characterized by hyperglycemia as well as long-term vascular complication. Appears to inherited, but no specific "diabetes gene" is known.

Biochemical Cause: Autoimmune destruction of the pancreatic beta cells which produce insulin.

Effect: No insulin produced. Onset usually under 20 years of age. Obesity uncommon. Hyperglycemia. Ketoacidosis.

Treatment: Administration of insulin. [Insulin is a hormone that regulates entry of glucose from blood into many cells.]

Basic Cause: Metabolic disorder characterized by hyperglycemia as well as long-term vascular complication. No consistent inheritance pattern, but strong hereditary component.

Biochemical Cause: Tissue-wide insulin resistance, can progress to loss of beta cell function.

Effect: Resistance to insulin, usually presenting over 40 years of age. Obesity common. Hyperglycemia. Ketoacidosis possible as result of major stress.

Treatment: Diet, exercise, perhaps insulin eventually.

Basic Cause: Metabolic disorder characterized by hyperglycemia as well as long-term vascular complication.

Biochemical Cause: Hormones of pregnancy cause insulin resistance in women genetically predisposed to developing this condition.

Effect: Hyperglycemia in mother. Baby at risk of: excessive birthweight, hypoglycemia, type II diabetes later in life, preterm birth & respiratory distress syndrome.

Treatment: Diet, exercise, perhaps insulin.

Basic Cause: Neurological & cardiovascular [metabolic] disorder caused by a deficiency in thiamine (vitamin B1).

Biochemical Cause: Thiamine helps make up Thiamine pyrophosphate (TPP), a coenzyme of the pyruvate dehydrogenase complex, which converts pyruvate into acetyl CoA. Affects the following metabolic processes...

Pyruvate dehydrogenase (bridge b/w glycolysis & TCA)

Alpha-ketoglutarate dehydrogenase (TCA)

Transketolase (pentose phosphate pathway)

Alpha-ketoacid dehydrogenases (catabolism of aliphatic AAs)

Effect: Characterized by pain in the limbs, weakness of the musculature, distorted skin sensation, possible enlarged heart & low cardiac output.

Treatment: Thiamine supplements & follow-up blood work.

Basic Cause: Metabolic disorder caused by exposure to mercury & arsenite.

Biochemical Cause: Mercury & arsenite have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the E2 component of the pyruvate dehydrogenase complex, which is inhibited.

Effect: Similar symptoms to Beriberi... Limb pain, weakness of the musculature, distorted skin sensation, possible enlarged heart & low cardiac output.

Treatment: Administration of reducing agents such as 2,3 mercaptopropanol, which can bind the metal ions & form a product that can be excreted in the urine.

Basic Cause: Inhibits Complex I (NADH dehydrogenase) of electron transport chain.

Biochemical Cause: Inhibits transfer of electrons from iron-sulfur centers in Complex I to Ubiquinone (CoQ) by blocking oxidation of Fe-S clusters of Complex I. Prevents use of NADH as substrate. Complex I is unable to pass off its electron to CoQ, creating a buildup of electrons in the mitochondrial matrix. Cellular oxygen is reduced to the radical, producing ROS which damage DNA & other mitochondrial components.

Effect: Apoptosis of affected cells. Human intoxication very rare. Symptoms of exposure include irritation of mucosa, can cause vomiting.

Treatment: Decontamination/cessation of exposure, supportive care to diminish symptoms.

Basic Cause: Inhibits Complex I (NADH dehydrogenase) of electron transport chain.

Biochemical Cause: Inhibits transfer of electrons from iron-sulfur centers in Complex I to Ubiquinone (CoQ) by blocking oxidation of Fe-S clusters of Complex I. Prevents use of NADH as substrate. Complex I is unable to pass off its electron to CoQ, creating a buildup of electrons in the mitochondrial matrix. Cellular oxygen is reduced to the radical, producing ROS which damage DNA & other mitochondrial components.

Effect: Used to treat insomnia, anxiety, sometimes epilepsy.

Treatment:

Basic Cause: Rare, because biosynthesis & dietary intake provide sufficient CoQ for healthy individuals.

Biochemical Cause: Limits passing of electrons on to Complex III.

Effect: Muscle weakness, encephalopathy, seizures.

Treatment: Oral CoQ supplementation.

Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferric state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: Supportive medical care.

Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferric state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: Cyanide antidote, oxygenation, continuous cardiac monitoring.

Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferrous state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: O2 administration.

Basic Cause: Exogenous uncoupler, creating heat instead of ATP

Biochemical Cause: Proton uncoupler that transports protons back into the mitochondria, dissipating the proton gradient & bypassing ATP synthase - ATP not generated. Stimulates oxidation of more fuel, because system attempts to restore the proton gradient.

Effect: "Literally cooking to death". Skin rash, jaundice, severe BO, cataracts.

Treatment: Supportive care, glucocorticoids therapy, & hemoperfusion [method in which blood is pumped through device outside of patient's body, in efforts to remove toxins].

Basic Cause: Arsenic interferes with metabolic processes in multiple ways, resulting in multi-system organ failure.

Biochemical Cause:

Arsenate ion competes with G3P in glycolysis to inhibit ATP production.Arsenite ion inhibits the PDH complex (link b/w glycolysis & TCA cycle).Arsenic inhibits succinate dehydrogenase at level of TCA cycle.Arsenic competes with phosphate to uncouple oxidative phosphorylation.Arsenic inhibits heme synthesis.

Effect: These metabolic interferences lead to death from multi-system organ failure probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage.

Treatment: Supplemental potassium decreases risk of serious heart rhythm problem. Chelation therapy.

Basic Cause: Disorder of oxidative phosphorylation - enzyme deficiency somewhere b/w PDH/ATP synthase

Biochemical Cause: ETC enzymes typically affected, either nuclear or mitochondrial DNA.

Effect: Characterized by movement disorders. Lactic acidosis common [Low BP, high HR, vomiting, rapid breathing]. Neuropathological issues - crucial cells in brain stem & nasal ganglia are affected. Individuals usually only live into mid-teens.

Treatment: No cure, treatments include variations of vitamin & supplement therapies.

Basic Cause: Disorder of oxidative phosphorylation

Biochemical Cause: Common cause is mutations in the X-linked E1 alpha gene [pyruvate dehydrogenase!!]

Effect:

Metabolic form - Lactic acidosis [Low BP, high HR, vomiting, rapid breathing]

Neurological form - aspects similar to Leigh's Disease

Treatment: Seizure control, ketogenic diet [high fat, low protein, low carbs. - forces body to use ketones for energy instead of glucose], sodium bicarbonate to alkalize metabolic acidosis.

The primary cause of mitochondrial disorders is a problem with the ETC. These are the most common neurometabolic disorders in children. They affect ~1 in 5,000 to 1 in 10,000 kids, are are typically progressive & very difficult to diagnose & treat.

Mutations in Complex I are the most common, including impaired NADH utilization, or poor electron transfer to Q.

More recently, mitochondria have also been found to play a central role in apoptosis. One thought is that the accumulation of mutations in mitochondrial genes over the course of decades contributes to aging, degenerative disorders, & cancer.

Basic Cause: Autosomal recessive defect. Deficiency in phenylalanine hydroxylase, which hydroxylates phenylalanine.

Biochemical Cause: In order to be degraded & enter normal metabolism, phenylalanine must be hydroxylated. Without sufficient phenylalanine hydrozylase - chronically high levels of phenylalanine & some of its breakdown products (phenylpyruvate, phenyllactate).

Effect: Light skin, differences in gait, stance, posture, high frequency of epilepsy, brain damage, severe mental retardation.

Treatment: Low phenylalanine diet, supplemented with tyrosine.

Basic Cause: Autosomal recessive, defect in homogentisic acid oxidase, which degrades homogentisic acid. Homogentisic acid (alkapton), degradation product of phenylalanine & tyrosine, accumulates.

Biochemical Cause: Homogentisic acid cannot be converted to acetyl CoA fumate, & accumulates.

Effect: Accumulation of homogentisic acid in tissues, progressive arthritis. Effects on skin most noticeable in areas where the body is exposed to the sun & where sweat glands are located. Skin takes on a blue-black speckled discoloration. Sweat can actually stain clothes brown. Vision is not usually affected, but pigmentation in the white part of the eye is evident in most patients by their early 40s.

Treatment: Reduce intake of phenylalanine & tyrosine.

Basic Cause: Autosomal recessive defect causing deficiency of the branched chain alpha-keto acid dehydrogenase (BCKDH), which degrades branched-chain amino acids.

Biochemical Cause: Accumulation of branched chain amino acids (leucine, isoleucine, valine) & their corresponding alpha-ketoacid & alpa-hydroxy acids.

Effect: Sweet-smelling urine, neurological damage & mental retardation, coma, death.

Treatment: Low-protein, carbohydrate-based diet.

Basic Cause: Autosomal recessive defect resulting in lack of melanin production.

Biochemical Cause: Type I albinism is due to a deficiency in tyrosinase. Dihydroxyphenylalanine (DOPA), a melanin precursor, is not formed.

Effect: Due to the lack of melanin, albinos lack pigment in their skin, hair, or eyes.

Treatment: Treatment of associated eye conditions is possible. Individuals with albinism are extremely sensitive to sunlight & should minimize exposure.

Basic Cause: Autosomal recessive defect causing a deficiency in cystathionine beta synthase, which degrades homocysteine.

Biochemical Cause: The transfer of sulfur from homocysteine to serine does not occur, & homocysteine levels become elevated in serum & urine.

Effect: Often vague in infants - physical deformities, mental deficiencies, psychiatric disorders. A high level of blood serum homocysteine is considered to be a marker of potential CVD.

Treatment: High doses of vitamin B6, low methionine diet, treatment with trimethylglycine (betaine), supplemental cysteine & folic acid. Trimethylglycine is used as a cofactor in a secondary pathway of homocysteine to methionine conversion with the enzyme betaine-homocysteine methyltransferase.

Basic Cause: Autosomal recessive defect, causing a deficiency in an aa transport system (Cys, Orn, Arg, Lys).

Biochemical Cause: Aas in the urine are poorly reabsorbed because of these deficiencies in proteins of the transport systems for cysteine & dibasic aas in the kidney.

Effect: Formation of kidney stones (calculi).

Treatment: Restrict dietary intake of methionine, a metabolic precursor of cysteine, stay well hydrated to keep urine dilute, drugs to prevent cystine formation.

Basic Cause: Liver dysfunction... Primary - deficiency in urea cycle, Secondary - deficiency elsewhere. Toxic levels of ammonia (NH3) diffuse into cells & across BBB.

Biochemical Cause: Alpha-ketoglutarate converted to Glu & Gln. High Glu & Glu-derived NTs. Low alpha-KG results in inhibition of TCA cycle.

Effect: Increases pH to dangerous levels. Inhibits ozidative phosphorylation by acting as an uncoupling agent. Interferes with redox balance. Neurologic disease, confusion, coma, death.

Treatment:

Basic Cause: Autosomal recessive, urea cycle deficiency. One of most severe. CPS converts ammonia (NH3) to carbamoyl phosphate.

Biochemical Cause: Deficiency in carbamoyl phosphate synthetase (CPS). Glutamate dehydrogenase-derived ammonia is not brought into the urea cycle & increases in tissues.

Effect: Hyperammonemia (10-20X increase). Low blood urea nitrogen (BUN). Normal urine orotic acid.

Treatment: Limit protein intake. Reduce bacterial producers of ammonia in gut (antibiotics, acidifying agents). Administer compounds that tie up ammonia directly - soluble molecules that can be excreted in urine & take ammonia with them [benzoate & phenylacetate].

Basic Cause: X-linked urea cycle deficiency, most common, & one of most severe. OTC incorporates carbamoyl phosphate into urea cycle, combining with ornithine to produce citrulline.

Biochemical Cause: Carbamoyl phosphate can't be incorporated into urea cycle - diffuses into cytosol & drives orotic aciduria.

Effect: Hyperammonemia. Low BUN. Serum Increased Orn, Gln, Ala. Low Citrulline. Increased urinary orotic acid (orotic aciduria).

Treatment: Limit protein intake. Reduce bacterial producers of ammonia in gut (antibiotics, acidifying agents). Administer compounds that tie up ammonia directly - soluble molecules that can be excreted in urine & take ammonia with them [benzoate & phenylacetate].

Basic Cause: Autosomal recessive, urea cycle deficiency. AS incorporates aspartate into urea cycle, combining with citrulline to produce arginosuccinate.

Biochemical Cause: Citrulline builds up due to lack of arginosuccinate synthetase (AS).

Effect: Hyperammonemia. Citrullinemia. Increased urinary orotic acid.

Treatment: Limit protein intake. Reduce bacterial producers of ammonia in gut (antibiotics, acidifying agents). Administer compounds that tie up ammonia directly - soluble molecules that can be excreted in urine & take ammonia with them [benzoate & phenylacetate]. Supplemental arginine to promote the production of citrulline.

Basic Cause: Autosomal recessive, urea cycle deficiency. AL converts arginosuccinate into arginine to continue cycle & also fumarate.

Biochemical Cause: Arginosuccinate accumulates due to lack of Arginosuccinate Lyase (AL or argininosuccinase). Arg & Orn are low.

Effect: Hyperammonemia. Low BUN. Increased serum Lys, Gln, Ala, Cit. Increased arginosuccinate.

Treatment: Limit protein intake. Reduce bacterial producers of ammonia in gut (antibiotics, acidifying agents). Administer compounds that tie up ammonia directly - soluble molecules that can be excreted in urine & take ammonia with them [benzoate & phenylacetate]. Supplemental arginine to promote the production of citrulline.

Basic Cause: Autosomal recessive, urea cycle deficiency. Arginase converts arginine into urea, and also ornithine to continue cycle.

Biochemical Cause: Arg & Orn can increase due to lack of arginase, but mitochondrial lack of ornithine may result in build up of carbamoyl phosphate, leading to orotic aciduria.

Effect: Mild hyperammonemia (3-4X increase). Low BUN. Increased Orn, Arg, Lys, Cys. Mild orotic aciduria.

Treatment: Dietary restriction of Arg & protein to decrease flux through urea cycle.

Basic Cause: Defects in long-chain fatty acid oxidation. [Disease of lipid metabolism.]

Biochemical Cause: Carnitine assists in transport of long chain acyl CoA molecules across inner mitochondrial membrane into mitochondrial matrix.

Effect: Life-threatening, featuring hypoketotic hypoglycemia, liver damage, hyperammonemia, cardiomyopathy, & muscle weakness.

Treatment: Carnitine supplementation, frequent high-carbohydrate feeding, & avoiding fasting.

Basic Cause: Autosomal recessive deficiency of MCAD, which processes medium-chain fatty acids. [Disease of lipid metabolism.]

Biochemical Cause:

Effect: Hypoketonic hypoglycemia. High concentrations of medium chain carboxylic acids & acyl carnitines in plasma & urine. Hyperammonemia may also be present from liver damage. Life-threatening during fasting, because hypoglycemia develops when fats would normally be metabolized to provide energy for gluconeogenesis.

Treatment: Carnitine supplementation, frequent feeding, avoid fasting.

Basic Cause: Inherited disease of lipid metabolism.

Biochemical Cause: Deficiency in the 3rd step of beta-oxidation, the oxidation of a hydroxyl to a ketone, due to LCHAD deficiency.

Effect: Lipids can accumulate in liver, heart, musculature, kidneys, & interfere with their functions.

Treatment: Carnitine supplementation, frequent feeding, avoid fasting.

Basic Cause: Typically associated with type 1 diabetes. [Ketogenesis: During fasting, liver uses fatty acids as source of energy for gluconeogenesis]

Biochemical Cause: Glucagon promotes release of glucose from liver & fatty acids from adipose tissue. Shortage of insulin - can't suppress above process. Acidic ketone bodies produce from extensive fatty acid oxidation.

Effect: Potentially life-threatening symptoms; vomiting, dehydration, deep gasping breathing, confusion, coma.

Treatment:

Ethanol cannot be excreted, & must be metabolized, primarily by the liver.

In the human body, ethanol is first oxidized to acetaldehyde, & then to acetic acid. The first step is catalzyed by alcohol dehydrogenase in the cytoplasm, & the 2nd step by aldehyde dehydrogenase in the mitochondria.

Both of these rxns lead to the creation of NADH, which inhibits:

1. Gluconeogenesis, because lactate cannot

be oxidized to pyruvate without NAD+. The

result is hypoglycemia & lactic acidosis.

2. Fatty acid oxidation, b/c NADH generation

needs normally met by fatty acid oxidation

are being met by alcohol.

The excess NADH (plenty of energy) even signals that conditions are right for fatty acid synthesis in the liver. At first, the triglycerides are packaged with apolipoproteins & sent to other tissues, but eventually, triglycerides accumulate in the liver - leading to condition called "fatty liver".

Basic Cause: Extremely rare autosomal recessive disorder characterized by substantially reduced HDL levels.

Biochemical Cause: Caused by a mutation in the gene that encodes for CERP (ABCA1). [CERP = Cholesterol efflux regulatory protein. Facilitates efflux of free cholesterol particles from cells into HDL.]

Effect: Symptoms include [plasma HDL] <5 mg/dL, low total plasma cholesterol (below 150 mg/dL), & normal or high plasma triglycerides. Neuropathy. Enlarged, orange-colored tonsils (foam cells).

Treatment: No specific treatment has proven to be effective.

Basic Cause: Monogenic, autosomal dominant disorder caused by a mutation in the LDL receptor pathway.

Biochemical Cause: {Ex...} PCSK9 is part of normal LDL receptor pathway. Binds to LDL receptor & directs it to lysosome for degradation, when high intracellular cholesterol. Rare mutations increase its protease activity, reducing LDL receptor levels & reducing the uptakes of cholesterol into cells - more circulates.

Effect: Hypercholesterolemia or mixed hyperlipidemia. Homozygotes do not survive into teens without liver transplant. Increased CVD risk.

Treatment: Diet & exercise, cessation of smoking. Statins (inhibit HMG CoA reductase; up-regulate expression of cell-surface LDL receptors - lower total cholesterol & LDL cholesterol). Bile acid sequestrants (lower total cholesterol & LDL cholesterol). Niacin (lowers VLDL cholesterol & increases HDL cholesterol). Fibrates (usually used in conjunction with other lipid lowering agents - to raise HDL cholesterol & lower VLDL cholesterol).

Basic Cause: Affects 2% of North American population - most common cause of coronary artery disease in US.

Biochemical Cause: Mechanism incompletely understood, but believed to be caused by an over-production of apoB100, which results in increased production of VLDL. Sometimes increased LDL levels are observed, depending on the efficiency of LDL formation, uptake, or both.

Effect: Increased CVD risk. Hypercholesterolemia or mixed hyperlipidemia.

Treatment: Diet & exercise, cessation of smoking. Statins (inhibit HMG CoA reductase; up-regulate expression of cell-surface LDL receptors - lower total cholesterol & LDL cholesterol). Bile acid sequestrants (lower total cholesterol & LDL cholesterol). Niacin (lowers VLDL cholesterol & increases HDL cholesterol). Fibrates (usually used in conjunction with other lipid lowering agents - to raise HDL cholesterol & lower VLDL cholesterol).

Increased VLDL synthesis & consequent increase in IDL concentration.
LDL cholesterol is often normal; however, diabetic LDL may be more atherogenic b/c of changes in their size & density.
Diabetes/obesity also characterized by decreased HDL cholesterol. In contrast, alcohol abuse raises HDL cholesterol.

Basic Cause: Multiple causes - occurs when body does not make enough platelets, inappropriately destroys platelets, or is losing platelets. Results in decreased clotting ability.

Biochemical Cause: Potential causes include... Toxic chemicals, genetic status, cancer, viral infection, splenic sequestration, etc.

Effect: Unexpected bruising, bleeding from nose/gums, petechiae, heavier than usual menstrual periods, severe headaches, bloody vomit/stool, dizziness, pain in joints/muscles, increased weakness.

Treatment: Depend on cause of condition. Transfusion of platelet cells. Splenectomy. Medication such as glucocorticoids.

Basic Cause: Virchow's triad - Endothelial injury, stasis of blood flow (structural), hypercoagulability (Factor V Leiden).

Biochemical Cause: Genetic defects include - clotting factor inhibitor deficiencies (antithrombin III, protein C), decreased fibrinolysis, Factor V Leiden. Acquired defects - atherosclerosis.

Effect: Can be manifested as a transient, short-term or episodic event in individuals with chronic or recurrent clotting. Major cause of stoke & heart attacks. If a piece of a blood clot formed in a vein breaks off it can be transported to the right side of the heart and from there into the lungs. A pulmonary embolism can be fatal.

Treatment: Antiplatelet agents (ex: Aspirin) to block activation, aggregation, or intra-platelet agonist synthesis. Antithrombin agents (ex: Warfarin) to block thrombin directly or its formation by the inhibition of various steps in the coagulation pathway. Thrombolytic agents to promote fibrinolysis by increasing plasmin formation.

Basic Cause: Most common inherited (autosomal dominant) form of thrombophilia.

Biochemical Cause: Caused by a point mutation in the factor V gene, that results in a single Aa substitution in factor V (Arg 506 to Glu). This results in resistance of factor V to inactivation by activated protein C (APC).

Effect: Greatly increases risk of developing venous thrombosis.

Treatment: Blood thinner such as aspirin. Anticoagulant such as Coumadin/Warfarin.

Detection - genetic test. aPTT-based test. The time it takes for blood to clot is decreased in the presence of factor V Leiden mutation.

Basic Cause: X-linked recessive, caused by a deficiency in factor VIII. ~1/4 cases due to spontaneous mutation. ~7 times more common than Hemophilia B.

Biochemical Cause: Deficiency in factor VIII results in insufficient generation of factor Xa & therefore thrombin - leads to bleeding tendency.

Effect: Bleeding severity dependent upon level of active factor (1% or less is considered severe - spontaneous bleeding episodes).

Treatment: Administration of factor VIII concentrates (plasma-derived or recombinant). More likely to develop inhibitors.

Basic Cause: X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor IX.

Biochemical Cause: Several hundred different mutations associated with this disorder. Deficiency in factor IX results in insufficient generation of factor Xa & therefore thrombin - leads to bleeding tendency.

Effect: Spontaneous hemorrhage &/or excessive hemorrhage in response to trauma.

Treatment: Plasma-derived or recombinant factor IX (Abs may develop). Analgesics for pain. Immunosuppressants to down-regulate Abs against administered Factor IX. Recombinant coagulation factor VIIa (used when inhibitors develop). FEIBA (activated protein coagulation complex, used when inhibitors develop).