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Disease Hypercholesterolemia
Cause
Symptoms
Defective clearance of LDL -High cholesterol levels particles (and cholesterol) -High LDL levels(2-4 times the from circulation due to: normal amount) 1. apolipoprotein B-100 defi- -May cause athersclerosis, ciency heart disease 2. LDL receptor defect (famil- -Treat with: ial hypercholesterolemia) 1. Statins (HMG-CoA reductase 3. PCSK9 deficiency inhibitor to decrease lipid syn4. ARH protein deficiency thesis) 5. Sitosterolemia 2. Clofibrate (inhibit cholesterol synthesis) 3. Ezetimibe (blocks cholesterol absorption in intestine) 4. Bile acid sequestering resins (break down more cholesterol to excrete) 5. Plasmapheresis Deficient Glucose-6-phosphatase (gluconeogensis) -liver unable to provide glucose to brain Deficient muscle glycogen phosphorylase -- cannot break down muscle glycogen for energy, must use alternative fuel (ie. fat) Autoimmune destruction of pancreatic B cells -- unable to produce/secrete insulin Fatal, heptaomegaly due to backed up glycogen in liver, ketoacidosis
McArdles Syndrome
-polyphagia (hunger) -polydipsia (thrist) -polyuria (urination) -Elevated HbA1c (glycosylated Hb) -May lead to ketoacidosis
Disease Type II diabetes (Insulin independent, adult onset) Kwashiorkor disease Marasmus
Cause Insulin receptors no longer sufficiently respond to insulin-binding Dietary protein deficiency (caloric sufficiency) Prolonged dietary deficiency of protein and calories
Symptoms -obesity (80%) -May lead to decreased insulin production -Edema, anemia, learning deficits -Anemia, wasting, weak, extended belly (liver doesnt synthesize albumin, which maintains vessels, so fluid leads into abdomen) Cys stones in kidney
Cystinuria
Genetic deficiency in basic amino acid transport Deficient neutral amino acid transport
Hartnups Disease
Mutation in superoxide dis-neurodegenerative mutase (protective enzyme -lose muscle strength and cooragainst ROS) -- accumulation dination of toxic free radicals Mutation on gene ATP7B -lose ability to export copper from liver, copper accumulates, leaks from hepatocytes and accumulates around body Iron overload in liver -- reacts with ROS -- mutations in DNA -neurological symptoms -liver cirrhosis -Kayser-Fleisher ring (eye(
Wilsons disease
Hemochromatosis
Liver cancer
Disease Homocystinuria
Cause Deficient cystathione synthase OR methionine synthase (Cys synthesis) Deficient cystathione lyase
Cystathioninuria Phenylketonuria
Absence of phenylalanine hy- mental retardation, neurodedroxylase OR dihydropterigenerative dine reductase (more severe) -- accumulation of neurotoxic phenylalanine derivatives -High Phe compete with Tyr in catecholamine synthesis (PKU neurotoxicity) Deficient enzyme in urea cycle -- increase NH4+ to toxic levels Neurotoxic -Treat with Benzoic Acid or Phenylacetic acid to rid body of nitrogen
Hyperammonemia
a-1-antitrypsin deficiency
-Deficiency in protease that -liver and lung disease inhibits elastase and confines -emphysema elastase damage into small space Deficient fructokinase -- inability to breakdown fructose Deficient Aldolase B enzyme -- accumulation of Fructose1-phosphate -- inhibits glucose-6-phosphate isomerase and aldolase (inhibit gluconeogenesis) and glycogen phosphorylase (inhibit glycogenolysis) -high levels of fructose in urine
Fructosuria
-hypoglycemia -elevated AST/ALT levels (diminished ATP production impacts biosynthesis in liver)
Disease Alkaptonuria
duct (build up conjugated/direct bilirubin) 2. Hepatocellular - liver disfunction (build up unconjugated/indirect bilirubin) 3. Hemolytic - accelerated RBC lysis (build up unconjugated bilirubin) 4. Newborn - slow maturation of conjugating enzymes in liver Gauchers disease Defective glucocerebrosidase enzyme -- accumulation of glucocerebroside in lysosomes of phagocytes
-Yellow skin, sclera -First three types, treat underlying problem -Newborn jaundice - treat with blue light -- unconjugated bilirubin becomes conjugated/H20soluble, can be excreted
-splenomegaly -hepatomegaly -skeletal lesions -CNS involvement (Types 2 and 3) Treat with: 1. enzyme replacement therapy
Disease Porphyria
Cause Lesions in heme biosynthesis -- accumulation of substrates; metals inhibit enzymes: 1. Acute intermittent porphyria (AIP) 2. Variegate Porphyria (VP) 3. Porphyria cutanea tarda (PCT) 4. Hereditary Coproporphyria (HC) 1.
Symptoms -Dark urine after time (metabolites accumulate) -Photosensitivity (porphyrin rings): blisters, rashes -Abdominal pain -Neuropsychiatric disturbances
Gout / hyperuricemia
defective PRPP syn-hyperuricemia thetase -- over-production of -sodium urate crystals deposit purine (therefore excessive in periphery (ie. joints) -- inflamuric acid) matory response (gouty arthri2. partially defective HGtis) PRTase -- doesnt effectively -Uric acid/ urate kidney stones metabolize PRPP -- over-pro- -Treatment: duction of purine (more hy- 1. Allopurinol = isomer of hypoxanthine = more substrate poxanthine; suicide inhibitor infor xanthine oxidase; activates xanthine oxidase (enIMP/GMP ratio decreases zyme that makes uric acid) decrease feedback inhibition 2. Cholcicine = MT inhibitor -on PRPP synthetase) blocks inflammatory response (negative side effects)
Cause X-linked. -completely defective HGPRTase -- doesnt effectively metabolize PRPP to make IMP and GMP from hypoxanthine and guanine -over-production of purine (more hypoxanthine = more substrate for xanthine oxidase; IMP/GMP ratio decreases - decrease feedback inhibition on PRPP synthetase) deficient galactose-1-phosphate-uridyltransferase -- accumulation of toxic galactose-1-phosphate
Symptoms -hyperuricemia, gout, kidney stones -Neurological deficit spasticity -Choreoathetosis -self-mutilation (eat mouth, fingers)
Galactosemia
-cataracts
ADA deficiency:
ADA (Adenosine deaminase) deficiency -- dATP and dGTP SCID (Severe combined im- accumulate and interfere with the RIBONUCLEOTIDE REmunodeficiency disDUCTASE that makes deease) oxyribo-acids from XDPs (specifically the dATP... so there's an accumulation and that product inhibits everything else, whereas the dGTP inhibits everything but dATP synthesis) PNP deficiency PNP (Purine nucleoside phosphorylase) deficiency Only cause a major increase of dGDP and thus dGTP
-Very severe -Extremely limited T and B cells -very sick, die from common infections
Symptoms -excessive excretion of orotic acid in urine -potential omegoplastic anemia - RBCs dont develop normally because cells cant replicate without pyrimidine -treat with: oral uridine -hyperventilating to try to increase pH -high blood sugar levels -lose consciousness -can be fatal
Ketoacidosis
High levels of ketone bodies (carboxylic acids) decrease blood pH -- in response to low glucose levels and need for cellular energy, oxidize fat to ketone bodies
Kidney stones
Respiratory distress Insufficient dipalmitoylcholine -lungs collapse due to insuffi(lipid) in lung surfactant in cient surfactant. Can monitor syndrome 0.5% of pre-term babies operation by comparing ratio of amniotic fluid to spingomyelin (decreases during gestation) Obesity Many. Encoded by ob gene -obesity (leptin output) or db gene (receptor) -decreased Leptin (hormone that signals satiety to hypothalamus)
Cause Cyanide, CO (cytochrome oxidase), Rotenone (NADH DH), DNP (uncoupler), Oligomycin (inhibits ATP synthase) Nuclear gene affecting mitochondriaal iron transport Maternally inherited mitochondrial DNA affecting NADH dehydrogenase Blindness
Friedreich's Ataxia
MELAS
Maternally inherited mitoDroopy eyelids (uses most chondrial DNA affecting mito- ATP), epilepsy, stroke chondrial tRNA Reactive oxygen free radicals Inactive mitochondria (heteroaffecting the mitochondrial plasmy), reduced muscle funcgenome tion. One of the alpha-oxidation enzymes are deficient and thus there is a buildup of phitanic acid LCAD deficiencies, accumulation of FA oxidation pruducts and blockage of FA oxidation and ketogenesis See name Blindness due to PA accumulation in the eye
Aging
Refsum's disease
(in infancy with low cloric intake... fatty liver, coma, cardiomyopathy)
Cause G-6-P DH deficiency in RBCs, reducing NADPH levels, lowered activity levels of glutathione reductase, buildup of GSSG, reduced levels of glutathione which maintains normal redox potential by converting peroxide Alcohol and malnutrition and a lack of B1. Km value of thiamine pyrophosphate is increased and transketolase activity is markedly reduced. Reversible Same as above (the more severe version). Irreversible
Symptoms Anemia following any oxidative stressors like things that produce peroxide like NSAIDs, sulfonomids, penicillin, certain foods.
Wernike's
Korsakoff's
Same as above, but severe memory loss and change in personality. Fatigue, vomiting, periphreal nervous system abnormalities, heart failure.
Beriberi
Vitamin b1 deficiency, failure of oxidative metabolism. Treat with thiamine hydrochloride Tetse fly tropanosomes (protozoa that keep glycolytic enzymes localized in glycosomes). Anti-troposomal meds target machinery in the glycosomes, but doesn't affect us because we have the spread out throughout cytosol. The meds contain arsenic
Sleeping sickness
Drowsiness during the day Fever Headache Insomnia at night Mood changes Sleepiness (may be uncontrollable) Sweating Treatment: Melanospirol (glycosome targeter) and DFMO (Ornithine decarboxylase inhibitor).
Symptoms
Problems in the pathway of IMP converstion to AMP or GMP Lack of tryptophan conversion to niacin or lack of typtophan in diet. Onchocerca volvulus microfilaria blocks GABA Genetic ARPTase deficiency Diarrhea, dermatitis, dementia, death
Pellegra
River Blindness