Heme Synthesis Flashcards
(116 cards)
1
Q
Hypochromic Microcytic Anemia
Cause: Result: Sx: Tx: Dx: Keywords:
A
Cause: Deficiency in Iron (Ferrochelatase), Copper, Pyridoxine (ALA Synthase); Lead Poisoning; Any enzyme defect in the Heme Synthesis pathway
Result: RBCs are small and lack color due to poor hemoglobin content
2
Q
Lead Poisoning
A
Cause: Lead inhibits 2 steps in heme synthesis:
•ALA Dehydrase
•Ferrochelatase
Result: •Accumulation of ALA or Protoporphyrin IX (depending on which enzyme is affected)
•Deficiency in Heme
Sx: Microcytic Hypochromic Anemia
3
Q
Acute Intermittent Porphyria
A
Cause: Deficiency in Porphobilinogen Deaminase/Hydroxymethylbilane Synthase (Hepatic disorder)
Result: Accumulation of ALA, and PBG…oxidized by light
Sx: GI and neuropsychiatric symptoms, PBG and ALA in urine > Dark urine upon standing, Peripheral neuropathy (motor neurons); NO PHOTOSENSITIVITY!
Tx: Symptomatic: Hemin; inhibits ALA Synthase> no buildup of PBG or ALA; NO BARBITUATES > activates CytP450 enzymes
4
Q
Congentinal Erythropoietic Porphyria
A
Cause: mutation > lack in Uroporphyrinogen III Synthase
Result: Accum of Hydroxymethylbilane > Uroporphyrinogen I > urine > oxidized spontaneously (without light) to Uroporphyrin I
Sx: Congenital disorder (PINK diaper!), Dark urine on voiding (uroporphyrin) and in skin & teeth, Photosensitivity
Tx: No sun, Vit C & E against oxidants, transfusions, bone marrow transplants
Dx: reddish brown urine, inc uroporphyrin I in urine & RBC, normal ALA and PBG, high uroporphyrin in RBCs.
5
Q
Porphyria Cutanea Tarda
A
Cause: Inhibitor of Uroporphyrinogen III Decarboxylase synthesized in the Liver (autosomal dominant)
Result: Uroporphyrinogen III (accum)>spont. oxidized to Uroporphyrin III (depend on Fe2+ accum in liver
Sx: (4th-5th decade), chronic, Blistering skin lesions, Hypertrichosis, Hyperpigmentation, Photosensitivity, Dark urine on voiding, Uroporphyrin III in the urine, Normal levels of PBG
Tx: Symptomatic: Phlebotomies and/or blood transfusion to reduce hepatic iron load (anaemia)
Dx: reddish/brown urine (Uroporphyrin III); normal PBG
6
Q
Kernicterus
A
Path: high Bilirubin in blood/tissues
Resulting defect: deposition in brain and tissues or excreted
Sx: neurological/retardation
7
Q
Pre-hepatic Jaundice
A
Path: unable to bring bilirubin into liver due to defect/saturation of transportation mech OR too much bilirubin [ Think hemolysis = anemia]
Resulting defect: Conjugated/insoluble bilirubin in brain/tissues
Sx: Neurological, yellow eyes, high bilirubin in plasma, high urobilin in urine/sreicobilin in feces, no bilirubin in urine, N AST/ALT and no liver damage
Dx: Anemia/low Hb + Sx above
8
Q
Hepatic Jaundice
A
Path: Damaged hepatocytes/obstructed canaliculi > unconjugated bilirubin leaks to blood = could be hepatitis/hepatocellular carcinoma
Resulting defect: high bilirubin in plasma, but low in feces/urine
Sx/Dx: high AST/ALT due to liver damage + see result
9
Q
Post-Hepatic Jaundice
A
Path: unable to excrete conjugated bile into GIT OR damage/obstruction of bile canaliculi due to a tumor
Resulting defect: high conjugated bilirubin in plasma/urine = dark/orange urine, low urobilin/stericobilin, high ALP marks obstruction when AST/ALT nl
10
Q
Neonatal Physiological Jaundice
A
Path: premature liver/bilirubin-UGT + hemlysis due to hypoxia during birth
Resulting defect: high unconjugated bilirubin in plasma + nervous system (basal ganglia) = toxic encephalopathy > mental retardation + kernicterus
Tx: UV > makes bilirubin soluble w/o conjugation
11
Q
Criger Najar Syndrome (I &II)
A
Path: Type I - lack of bilirubin-UGT (fatal); Type II - partial def (not fatal)
Resulting defect: inability to conjugatebilirubin > unconjugated hyperbilirubinemia
Sx: severe conjugated jaundice, fatal within 12-15 months
Tx: Type I - phototherapy (temporary), liver transplantation (perm); type II - barbituates (phenobarbital) > ER hypertrophy > enhances conjugation & release of bilirubin
12
Q
Gilbert Syndrome
A
Path: mild def of bilirubin-UGT, usually undiagnosed bc 30% activity is enough, more in males
Resulting defect: fluctuating hyperbilirubinemia due to vriable hemolysis due to mental/physical stress
Tx: barbituates
13
Q
Dubin Johnson Syndrome
A
Path: Decreases secretion of conjugated bilirubin into biliary tract - Autosomal recessive & benign
Resulting defect: Fluctuating conjugated hyperbilirubinemia causing jaundice
14
Q
Rotor Syndrome
A
Path: Multiple defects in hepatocellular uptake and excretion of bile pigments, benign disorder
Resulting defect: Fluctuating conjugated hyperbilirubinemia causing jaundice
15
Q
Haemophelia
A
Path: def of factor VII (A), IX (B), OR XI (C) ; X-linked
Resulting Defect: Inefficient clotting
Sx: Increased APTT, easy bruising & bleeding into joints and bleeding after trauma/surgery
Tx: transfusion of deficient clotting factors
Dx: bleeding time, platlet count, & prothrombin time, APTT nl; use ind factor assay for type of haemophelia; Ashkenazi Jews
16
Q
Von Willenbrand Disease
A
Path: VWF factor def, qualitative and quantitative
Resulting defect: no platelet plug, instability of factor VIII
Sx (highly indicative of Dx): increased APTT and bleeding time; nl platelet count, PT, and factor VIII
17
Q
Bernard Soulier Syndrome
A
Path: Qualitative OR quantitative defect; GP1b receptor defect
Resulting defect: Can’t bind VWF @ GP1b receptor > no plug/adhesion
Sx: nl VWF & factor VIII; increased bleedign time
18
Q
Thrombasthenia of Glanzmann & Naegeli
A
Path: qualitative defect; GPIIb/IIa receptor defect V on platelet membrane
Resulting defect: Can’t bind fribrinogen @ GPIIa/IIb receptor > no platelet plug
Sx: inc bleeding time; nl platelet count, PT, and APTT
19
Q
Carbon Tetrachloride (LFT)
A
Path: poison that causes liver cancer
20
Q
Aflatoxin B1
A
Path: Mold toxin (Aspergillus Flavus); activated in liver by CYP 3A4 or CYP 1A2 or 2,3-epoxide
Effect: 2,3-epoxide forms adducts with guanine nucleotides > affect the p53 gebe > liver cancer (Sx:)
Cure: avoid moldy food
21
Q
Paracetamol overdose
A
Path: XS paracetamol > turned into NABQI by CYP2E1 (enhanced by alcohol) > toxic: adducts with Sulphur side chains of proteins
Effect: Free radical > phospholipid peroxidations > hepatocellular membrane damage > cellular necrosis
Tx: N-Acetyl-Cysteine scavenges free radicals and enhances GLutathione-S-Transferase > which conjugates NABQI
22
Q
Methanol Poisoning
A
Path: Methanol ingested > turned into formaldehyde by Alcohol Dehydrogenase > then into Formic Acid.
Effect: high formic acid > blindness & metabolic acidosis
Tx: Give Ethanol (higher affinity) > competes with Methanol for Alcohol Dehydrogenase
23
Q
Ethylene Glycol Poisoning
A
Path: ingestion of Ethylene GLycol > turned into Glycoaldehyde by Alcohol Dehydrogenase in the liver > metabolized into Glycolate & Oxalate > interferes with liver enzymes > metabolic acidosis and hepatic enzyme problems
24
Q
B12 Deficiency
A
Path: Dietary insufficiency (Vegans/Alcoholics), IF, or ileal disease (absorption)
Effect: Methylmalonyl-CoA acc > weird FA > demyelination, hyperhomocystinemia, def in SAM > hypomethylation > acc of odd chain FAs in neurons > demyelination
Sx: Pernicious anemia (Folate trap), high homocysteine > cardiac defects, Demyelination > tingling/numbness/irritability/MEGALOBLASTIC MADNESS
Tx: B12 + Folate
Dx: High Methylmalonic Acid in urine & in blood > B12 def or Methylmalonyl-CoA mutase def
25
Folic Acid Deficiency
Path: Diet (grean leafy veggies, folate trap, GI abs, high need (pregnancy), Folate antagonists (Methatrexate, antibiotics).
Effect: Neural tube defects for fetus, purine synthesis > megaloblastic anemia
Tx: supplements
Dx: Formiminoglutamate (FIGLU) excreted in urine; Histidine > FIGLU > Glutamate
26
Duchenne's Muscular Dystrophy
Path: frameshift mutation on x-chromosome > Lack of dystrophin protein > sacrolemma breaks down > Ca2+ flux > myonecrosis
Sx: early 5-12y/o wheelcahir, muscle tissue > fibrofatty tissue, Cardiomyopathy/respiratory problems> heart failure
Tx: tracheostomy, orthopedic devices, gene therapy
Dx: high CK-MM, muscle biopsy, immunostaining absent in DMD
Gower's Maneuver?
27
Becker's Muscular Dystrophy
Path: point mutation > abnormal & def Dystrophin protein > sacrolemma breaks down
Sx: can walk beyond 15y/o & live to 40-50y/o
Tx: Tx: tracheostomy, orthopedic devices, gene therapy
Dx: high CK-MM, muscle biopsy, immunostaining low in BMD
28
Muscle Sclerosis
Path: Autoimmune on Oligodendrocytes > demyelination (CNS) > build up of plaques (Scleroses) > Poor nerve conduction
Note: characterized by relapse and prolapse
29
Alzeheimer's Disease
path: longer Amyloid prot precursor for Beta-Amyloid peptid > neurofibrillary tangles + B-Amyloid plaques, Apo-E variant genetic risk, hypercalcemia > hyperphosphorylation of Tau > tangles
Effect: neurodegeneration, brain size reduction, elevated Ca2+
Sx: dementia + memory loss
Dx: only after death, CAT & MRI show reduced brain size
10-30% higher risk in Japanese and Caucasian over 75y/o
30
Prion Disease (transmissible Spongifor encephalopathies)
Path: PrPc --> PrPsc accelerated by congential defect (CJD) or exposure to PrPsc stimulus (Scrapie or Madcow).
• Identical primary and post-trans mod. But altered 2nd & 3rd structures
Effect: PrPsc screws other PrP > neurodegenetation
31
Creutzfelt-Jacob disease (Brain Atrophy)
Path: PrPc --> PrPsc accelerated by congential defect (CJD) or exposure to PrPsc stimulus (Scrapie or Madcow).
• Identical primary and post-trans mod. But altered 2nd & 3rd structures, transmitted by eating contaminated cow meat.
Effect: Degeneration of the cerebral cortex with spongiform vacuolar degeneration (hallmark) > neuronal loss
32
Vitamin A Deficiency
Path: abs + fat-free diets
Effect: mucus epi, night blindness, growth, reproduction, innate immunity
Sx: night blindness, Xeropthalmia (dryness of the conjunctiva and cornea, Bitot's spots, Keratomalacia [corneal erosion]), recurrent pulmonary infections, weakened immunity
Tx: supplements
33
Vitamin A Toxicity
Path: hypervitaminosis, too much! (found high in polar bear liver), avoid esp during pregrnancy (teratogenic)
Sx: Increased intracranial pressure [psudotumour cerebri]: seizures, papillodema, headaches, nausea, vomiting)
•Dry pruritic skin & dry mucous membranes + weight loss
•Hepatomegaly >portal hypertension > cirrhosis
34
Rickets
Path: Deficiency of Vitamin D in children
•Fat malabsorption
•No sunlight
Effect: poor bone development
```
Sx: •Bow-leggedness
•Frontal Bossing
•Rachitic Rosary
•Pigeon chest deformity
•Soft, Pliable bones"
```
35
Osteomalasia
Path: def of Vit D in adults
Effect: re-abs bone > weak bones
Sx: frequent fractures, pigeon chest + rachitic rosary but no soft bones
Tx: Supplements
36
Vitamin E Deficieny
path: Fat malabsorption, Fat-free diets (RARE)
Effect: low defense against ROS in lipid membranes
Sx: Hemolytic Anemia, Axonal degeneration, loss of deep tendon reflexes and problem with gait
37
Hemorrhagic Disease of Newborns
Pat: no gut flora > no Vit K made > def of Vit K up to 1 week
Effect: no clotting factors > Bleeding at various parts of the body including skin, umbilicus and viscera; [Intra-cranial bleeding (most serious)]
Tx: Routine intramuscular injections of Vitamin K
38
Vit K deficiency in Adults
Path: Malabsorption, loss of gut flora due to prolonged use of broad spectrum antibiotics or Warfarin, diffuse liver disease
Effect: Bleeding
Sx: Non-specific bleeding symptoms( hematouria, melena [stools], ecchymoses [easy bruising], gums)
Tx: supplements
39
Scurvy
Path: Vit C deficiency (diet and alcoholism)
Effect: Iron abs def, no defense against ROS, Defects in CT (cross linking collagen weak due to not adding hydroxyl groups to lysine and proline by lysyl hydroxylase, lysyl and prolyl oxidases)
Sx: spongy bleeding gums, loose teeth, fragile blood vessels > Pinpoint (parafollicular) hemorrhaging, joint bleeding, & easy bruising, and Impaired wound healing
Tx: Vit C supplements
40
Wernick-Korsakoff Encephalopathy
Path: Vitamin B1 (Thiamine) Deficiency > think alcoholics and poor diet
```
Effect: Some enzymes can't work:
•Branched-Chain alpha-Keto Acid Dehydrogenase
•alpha-Ketoglutarate Dehydrogenase
•Transketolase
•Pyruvate Dehydrogenase
```
Sx: Acute (reversible): mental retardation & delerium, Confabulation, Confusion, Opthalmoplesia w/ Nystagmus, amnesia, Ataxia
Chronic (irrevensible): Korsakoff Psychosis > anterograde amnesia
Tx: Acute: Supp
Dx: give TPP & measure RBC Transketolase activity
41
Beri-Beri Disease
Path: B1 def (refined foods like polished rice, white flour/sugar).
```
Effect: Some enzymes can't work:
•Branched-Chain alpha-Keto Acid Dehydrogenase
•alpha-Ketoglutarate Dehydrogenase
•Transketolase
•Pyruvate Dehydrogenase
```
Sx: Polyencephalopathy, cadiovascular symptoms.
Dx: give TPP & measure RBC Transketolase activity
42
B2 (Riboflavin) Deficiency
Path: diet def
Effect: FMN, FAD lack stops ETC rxns
Sx: Chelosis, glossitis, facial dermatitis
Tx: supp
43
Niacin (B3) Deficiency
Path: Alcoholism, chronic dis, & diet rich in corn (unusable niacin)
Effect: NAD+/NADP+ lack in redox rxns
Sx: Presents as Pellagra (4 D's): Diahrrea, Dermatitis, Dementia , Death
Tx: supp
44
Vitamin B6 (PLP) Deficiency
Path: Diet, TB treatment isoniazid inactivated PLP
```
Effect: PLP needed for:
•ALA Synthase (heme synthesis)
•Aminotransferases (AA metabolism)
•Decarboxylases (NT synthesis)
•Homocysteine -> Cysteine
```
Sx: Microcytic Hypochromic Anemia, Peripheral Neuropathy, Homocysteinuria -> Increased risk of cardiovascular disease, & Seizures
Tx: PLP supp along with Tb treatment
45
Copper deficiency
Path: Diet
Effect: Cu2+ Needed for: Lysyl Oxidase, Cytosolic Superoxide Dismutase, Dopamine B-Hydroxylase (along w/ Vit C), Cytochrome C Oxidase (IV), Tyrosinase
Sx: •Microcytic Anemia (cannot absorb and transport iron)
•Degradation of vascular tissue >easy bruising
•Defects in hair (keratin filaments)
•Peripheral neuropathy
46
Menke's Syndrome
Path: X-Linked Disease (only male infants) > abnl copper immobilization from gut > Cu2+ deficiency
Effect: NS, CT & vasculature effects due to unstable collagen)
Sx: Kinky, wirey hair, fatal in infancy
47
Hereditary Haemochromatosis
Path: Mutation in the HFE gene > enterocyte can't sense sytemic iron balance (common)
Effect: too much iron
Sx: Fe acc in liver/pancreas -> ROS acc -> Lipid peroxidation and DNA damage > digestive problems + diabetes, Cardiac dysfunction, Acute synovitis, Brown skin, high iron on and ferritin
Dx: Inc Transferrin & Ferritin
Tx: if caught in precirrhotic stage > do regular phlebotomy > normal life expectancy
48
Iron (Fe2+) Deficiency
Path: defect in: Nutrition (meats) and absorption, Vitamin C, Copper, pH balance of Stomach
Risk for: Infants, Pregnant women and Blood donors.
Effect: Low Heme synthesis (ferrochelatase) > affects Cytochrome P450 enzymes, ETC complexes
Sx: Microcytic Hypochromic Anemia (weakness, fatigue, pallor, brittle nails etc.)
•Pica: appetite for soil
49
Manganese
Path: Nutritional
Effect: Lack of activity in Mitochondrial Superoxide Dismutase AND Pyruvate Carboxylase
50
Molybdenum
Path: Nutritional
Effect: lack of activity of Xanthine Oxidase
51
Selenium
Path: Nutritional
Effect: Lack of activity of Glutathione peroxidase > Myopathy
52
Kwashiorkar Disease (oedematous malnutrition)
Path: low protein (generally high carb) diet, hepatomegaly, Poor wound healing, loss of body hair
+ <60% normal body weight, scaly skin + dermatitis, distended abdomen
Tx: FLUID AND ELECTROLYTE BALANCE MUST BE RESTORED FIRST! then give (8:1 sugar:salt tea spoon/L of water plus oral K+, Zn++, Mg++, and vit and mineral supplements)
53
Marasmus
Path: Protein Energy Malnutrition due to overall shitty diet: Breast fed + water gruels of various cereals (deficient in protein AND calories), 1-5 years
Sx: •NO OEDEMA but...Muscle wasting (low insulin), Stunted growth, Anemia, Proteolysis, Triceps skin fold <60-80% normal body weight, wrinkled skin, hair loss and emaciated appearance
Tx: FLUID AND ELECTROLYTE BALANCE MUST BE RESTORED FIRST! then give (8:1 sugar:salt tea spoon/L of water plus oral K+, Zn++, Mg++, and vit and mineral supplements)
54
Marasmus
2
55
Anorexia Nervosa
Path: Psychological issues > Low energy long time; self-induced vomiting or use of laxitives
Effect: BMI < 17.5
Sx: Nutritional deficiencies: hypo-minerals, Muscle wasting, Kidney stones and failure, constipations and bloating, Thin and brittle hair & nails, buising & dry skin
Endocrine system effects:
Low sex hormones; High cortisol; Low thyroid
CNS effects: cognitive and psy
Cardiovascular: heart and Hypotension.
56
Bulimia Nervosa
Path: Binge eating (2000 Calories Daily) followed by Laxatives and Self-induced vomiting > weight loss
Sx:
•Weight loss
•Damage to gut lining and enamel of teeth + Electrolyte imbalance and dehydration due to vomiting
57
Cachexia
Path: Loss of appetite due to chronic disease ( AIDS & Cancer)
Effect: Low appetite > malnutrition
Sx: Marasmus-like symptoms but + protein loss
- Tumors metabolize glucose to Lactate > gluconeogenesis > high proteolysis
- High cytokines > activates uncoupling proteins > thermogenesis
- CACHEXIN (TNF-alpha): protein from tumors > inc BMR + loss of body protein
58
HyperOsmolar Non-Ketotic coma (HONK)
Path: Diabetes (type I & II)
Effect: hyperglycaemia > high blood osmolarity, water moves from ICF > EFC.
Sx: Hyperglycaemia, dehydration, and uraemia (renal shutdown due to neuropathy) without ketosis, polyuria > hypovolaemia
Tx: IV insulin + electrolytes/fluids
59
Fasting hypoglycemia
Eat more dummy!
60
Reactive (post-prandial) Hypoglycemia
Path: Insulin spike after fatty fat fatty ate too much pasta
Dx: high insulin/high C-peptide
61
Alcohol-Induced Hypoglycemia
Path: Alcohol increases NADH:NAD+ ratio therefore pathways reverse
Effect: No gluconeogenesis, No Beta-Oxidation, Ketogenesis (LOTS of Acetyl-CoA due to Acetic Acid -> Acetyl-CoA) still lower than in diabetes, Increased TAG Synthesis & Acc (DHAP -> G3P), Lactic Acidosis (Pyruvate -> Lactate)
Other Sx: hypoglycemia, Increase in VLDL (only until liver fails), Decrease HDL and other Anti-Oxidants
62
Factitious Hypoglycemia
Path: Injected too much Insulin/over use of hypoglycaemic agents (sulphonylureas/insulin injections)
Effect: hypoglycemia
Dx: normal/low C-peptide + high insulin when symptomatic
63
Hyperinsulinism
Path: benign pancreatic tumour involving giant iselts of langerhan's
Effect: Too much insulin produced > hypoglycaemia; High C-peptide (characteristic)
Dx: Whipple's triad: Adrenergic/neuroglycopenic symptoms, blood glucose <50mg/dL (2.6 mmol/L) when symptomatic, & improvement of symptoms after ingesting glucose
Tx: Surgery
64
Hypoglycemia of Insulinoma
Path: Tumor of B-cells love make insulin long time > hypoglycemia
Dx: high insulin/high C-peptide
65
Cystic Fibrosis
Path: AR mutation, 3 base pair deletion (Phenylalanine - position 508) in the long arm of chromosome 7; Defective CFTR ion transporter (ABC Transporter)
Effect: Lung Mucosa (blocked and bacteria grows) & intestinal Epi (Meconium Ileus in newborns):
Skin: (salty sweat; Na >70mM and/or genetics) = Dx
Pancreas: digest itself and > malabsorption
Reproductive: Azoospermia due to congenital bilateral absence of Vas Deferens
Tx: Pulmonary: Immunization against disease, Beta-Agonists to DILATE AIRWAYS, Mucolytic Agents such as Dornase Alfa, Antibiotics to treat infection
Intestinal: Modified diet (Vitamin A, K, E, D supplements), Pancreatic enzyme supplements, High caloric diet
66
Sickle Cell Anemia
Path: Point mutation in the gene for B-Globin; position 6; Homozygous Recessive
Effect: Glutamate > Valine; > HbS hemoglobin formed (B-chain connection site > they clot together)
Sx: RBC's rigid & clump together at low O2; Chronic pain, chronic hemolytic anemia and increased susceptibility to infections, ischemia
Sickling Crisis: XS removal of RBCs > anemia and pre-hepatic jaundice + SPLENOMEGALY!!
- XS Conjug. bilirubin exc > gall stones
Dx: Electrophoresis (bad RBC = less -ve)
- mutation > less MstII restriction site > FEWER FRAGMENTS in RFLP analysis
Tx: adequate hydration, analgesics, aggressive antibiotics for infections, O2 supply
67
GLUT-1 Deficiency
Path: Low GLUT-1 transporter
Effect: low glucose concentration in CSF <0.4 = Dx
Sx: Siezures, developmental delay & complex motor disorder
Tx: High fat, low CHO diet elevating blood ketone bodies so the brain get used to using ketone bodies instead of glucose for E.
68
Panic Attacks / Manic Depression
Excessive Serotonin > panic attacks
69
Clinical Depression
Decreased Serotonin
Tx: give SSRI's
70
Parkinson's Disease
Path: Decreased dopamine due to Decreased dopamine production in the Substantia Nigra
Tx: L-DOPA
71
Schizophrenia
Excessive Dopamine
72
Prion Diseases
Path: PrPc --> PrPsc reaction accelerated either due to congential defect (CJD) or exposure to PrPsc stimulus (Scrapie or Madcow)
Effect: Neurodegenerative diseases
73
Ehlers-Danlos Syndrome
```
Path: [diff Types] particular defects in processing enzymes or mutations in sequence amino acids of alpha-collagen chain.
• Lysyl Hydroxylase (VI)
• Tenascin-X
• Procollagen N Proteinase
• COL1A1/1A2/3A1
```
Effect: Poor/deficient collagen production
Sx: Hyperextensible skin and joints, easy bruising, frequent dislocations
74
Osteogenesis Imperfecta
Path: Type I (OI Tarda)
• Often misdiagnosed as child abuse
• Mutation of COL1A1
• Quantitative deficit - in Type I collagen
Type 2
• Mutation of COL1A1/1A2 gene
• Qualitative deficit - Glycine is replaced with a bulky AA
Effect: Type I > low Type I collagen; Type II > normal levels of defective Type I collagen > degraded via ubiquitination
Sx: Type I > Multiple rib fractures, Brittle bone, Blue/Grey tint to sclera, Retarded wound healing
Type II > Most infants die in utero or shortly after birthy due to pulmonary hypoplasia
75
Marfan's Syndrome
Path: Mutation of Fibrillin-1 gene
Effect: Changes to ECM scaffolding properties of limbs and loss of control of certain growth factors (TGF-beta)
Sx: Skeletal abnormalities, ocular changes, cardiovascular complications (most often aortic hemorrhage)
76
Paget's Disease
Path: Increased ALP Levels, overactivity of osteoclasts > followed by uncontrolled osteoblast activity
Effect: disorganized bone growth/resorption > Deformities in skull and forhead + enlargement of the orbital ridge (side of hip)
77
Thalassaemia
Path: Mutation in either the alpha or beta subunit of haemoglobin
78
Anemias:
```
TYPES
Nutrional (B12), Hemorrhagic (bleeding), Aplastic (bone marrow destruction), Haemolytic
```
Effect: Lack of healthy red blood
Sx: Fatigue, shortness of breath, headaches, pale skin color
Tx: Blood transfusion (if serious enough)
79
Multiple Sclerosis
Path: Viral infection > autoimmune response > demyelination
Effect: Slowing of nervous transmission and development of hardened plaques in multiple regions
Sx: Extreme motor deficit; eventual death
80
Niemann-Pick Disease
Path: No sphingomyelinase > inability to recycle sphingomyelin
Effect: Sphingomyelin acc in the lysosomes; > enlarged liver/spleen, severe mental retardation, accelerated neurodegeneration and death.
81
Respiratory Distress Syndrome
Path: Premature birth > decreased/insufficient production of surfactant
Effect: Decreased lung compliance + extreme diffculty breathing
Tx: Administration of corticosteroids > inc foetal surfactant production. Surfactant can also be delivered intra-tracheally post-delivery
Surfactant: = Dipalmitoyl Phosphotidylcholine
82
Cholera Enterotoxin
Path: Constitutive activation of the alpha-subunit of the Gs protein via ribosylation (toxin inhibits GTPase)
Effect: Constant production of cAMP, stimulation of PKA and release of Ca2+ > lots of Cl- & water into gut
Sx: Severe diahorrea & fluid loss
83
Pertussis Toxin (Whooping Cough)
Path: Toxin (Gram -ve) ribosylates Cys352 of Gprotein, preventing the binding of GTP
Effect: Paralysis of cillia prevents clearing of mucous from respiratory tract
Sx: Chronic infection and terrible cough characterized by a whooping sound
84
Death Cap Mushroom Poisoning
Path: Inhibition of RNA Polymerase II in eukaryotes
Effect: Alpha-amanatin (toxin) forms a tight complex with RNA Poly II > stops DNA transcription
Sx: 4 phases of symptoms: Asymptomatic, Diahrrea & GI, Relief of symptoms, Hepatic & Renal failure; Urine test only effective within 48 Hours
Tx: Penicillin if caught early, liver transplant if caught late
85
Cholelithiasis (Cholesterol Gall Stone Disease)
Path: imbalance of chol and bile salts in gallbladder > Precipitation of cholesterol
Causes: malabsorption of bile salts, obstruction of the biliary tract, severe hepatic dysfunction or increased cholesterol excretion from liver into bile
Sx: pain
Tx: Surgery (Cholecystectomy; removal of the gall bladder)
86
Kwashiorkar Disease
Path: Diet deficient in protein
Effect: Lack of proteins for normal cellular/bodily functions
Sx: Growth failure, fatigue, dermatitis, oedema (low albumin)
Tx: Protein supplementation
87
Lactose Intolerance
Path: Primary: congenital deficiency in amount/activity of lactase.
Secondary: temporary intolerance due to another intestinal disease
Sx: not present in newborns untill 2-3 weeks after birth (uses enzyme & AB from mom's milk)
If chronic > severe diahrrea; intestinal disorders
Dx: Hydrogen breath test or presence of reducing sugars in the stool
Tx: Lactose free diet or supplemental lactase
88
Steatorrhea
Path: defective lipid metabolism due to: defective emulsification and absorption, digestion of lipids, or Chylomicron formation
Sx: Bulky and foul smelling stools (this itself is steathorrea) + bloating and abdominal pain
89
Gout
Path: Crystallization/deposition of Uric Acid (purine metabolic byproduct) in the joints
Effect: Causes inflammation > pain
90
Diabetes Mellitus
Path: •Type 1: inability to produce insulin
•Type 2: resistance to insulin
Effect: Hyperglycemia and glucosuria
Also > increased fatty acid metabolism > prod ketone bodies
Dx: Ketone breath, glucose test
Tx: insulin for Type I
91
Arsenate Poisoning
Path: Arsenate (AsO4^2-) is added to Glyceraldehyde-3-P in the place of an inorganic phosphate by Glyceraldehyde-3-P Dehydrogenase > broken down into 3-Phosphoglycerate.
Effect: substrate level phosphorylation of 1,3-BPG by phosphoglycerate kinase is bypassed > 0 ATP from Glycolysis > cell lyses.
92
Dental Caries (tooth decay)
Path: Anaerobic glycolysis by bacteria by their sucrose secretions > lots of lactic acid and pyruvate > degradation of enamel > tooth decay
Tx: Fluoride inhibits enolase, preventing the completion of glycolysis > stops buildup of pyruvate and lactic acid
93
Beri Beri Syndrome
Path: Severe deficiency in Thiamine (Vitamin B1)
Two types: Wet & Dry
• (oedema vs. no oedema)
Effect: Inability of PDH complex (E1) and alpha-Ketoglutarate to function > low ATP
Sx: Advanced neuromuscular and cardiac disorders including delirium, muscle weakness & atrophy, memory loss, peripheral vasodilation and increased venous return to the heart > death by high-output cardiac failure
Cause: eating polished rice
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Wernicke-Korsakoff Syndrome
Path: Severe deficiency in Thiamine due to alcohol abuse/poor diet
Effect: Inability of PDH complex (E1) and alpha-Ketoglutarate to function > low ATP
Sx: Initial Phase (Wernicke's Encephelopathy): Delerium, Mental derangement ataxia, Ophthaloplegia
Late Phase (Korsakoff Psychosis): Anterograde amnesia, Focal lesions in brain, irreversible
Tx: supp, if early
Dx: urine B1, measure transketolase activity; and lactate/pyruvate levels post glucose-intake
95
Fluoroacetate Toxicity
Path: Fluoroacetate > Fluoroacetyl-CoA,+ Oxaloacetate > Fluorocitrate, + aconitase > stops prod of Isocitrate
Effect: TCA cycle inhibited > Death
96
Malonate Toxicity
Path: Malonate is a homologue of succinate > binds to succinate dehydrogenase (Competitive Inhibitor) > blocking the TCA cycle
Effect: buildup of Succinate, alpha-Ketoglutarate and Citrate > death
97
Leber Hereditary Optic Neuropathy (LHON)
path: Mutation of Complex I > Inability of NADH to be run through ETC > low ATP
Sx: Loss of bilateral vision (late onset) due to neuroretinal degeneration [Optic nerve due to high energy demand > needs OxPhos
Additional info: Passed from affected mother to all offspring due to mitochondrial genetics
98
Myoclonic Epilepsy & Ragged Red Fiber Disease (MERRF)
Path: Mutation in the mitochondrial gene coding for the mitochondrial Lysine tRNA > lack of it
Sx: in late childhood: uncontrollable muscle jerking (myoclonus), enlarged mitochondria in muscle, ragged-red fibers, and epileptic seizures
Lactic acidosis, progressive dementia and cardiac problem may also be seen
99
Mitochondria Encephalomyopathy, Lactic Acidosis & Stroke-like Episodes (MELAS)
Path: Mutations in the mitochondria gene for Leucine tRNA > lack of it
Sx: Onset 5-15 y/o; neurodegenerative disease > stroke-like episodes, lactic acidosis, vomiting, tiredness and muscle weakness.
Repeated strokes may result in blindness, brain damage, dementia and loss of muscle control
100
Aminoglycoside-induced Deafness
Path: Mutation of the mitochondrial gene for mito's 12S rRNA subunit > increases affinity of aminoglycosides for host ribosomes
Effect: Lack of mitochondrial 12S rRNA subunit
antibiotics (particularly streptomycin and gentamycin) bind mito's rRNA > point mutation in the subunit's gene > interference with translation of mitochondrial genome > poor ATP Synthase translation
Sx: Cochlea of the ear (high energy demand) > deafness observed
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Type I GSD (Von Gierke Disease)
Path: G6Phosphatase deficiency (Type 1a); OR G6Phosphate transporter deficiency (Type 1b)
Effect: Glucose not leave liver & can't convert glucose from G6P > Glycogen acc; Hypoglycemia > TAG mobilization; Liver cannot recycling Lactate (Cori Cycle) > Acidosis; Lactate > Lipidogenesis > hyperlipidemia
Sx: Hepatomegaly, Hyperlipidemia, Metabolic acidosis, Neutropenia in Type 1b
Dx: Blood glucose, lactate, TAG, cholesterol concentrations, Ultrasound for liver size, Intestinal biopsy for assay G6Pase activity
Tx: Avoid fasting, complex carbs, Nasogastric infusion of sugar during sleep
102
Type II GSD (Pompe Disease)
Path: Lysosomal alpha1,4-glucosidase (Debranching Enzyme) deficiency
Effect: can't digest glycogen in lysosomes of all Glycogen storing tissue > lysosomes become engorged
•Infantile form, Juvenile form (partial activity), &Adult form
Sx: • Cardiomegaly
• Engorged Lysosomes
• Early death from heart failure if Infantile
* Juvenile presents in early childhood > death in 20s/30s
• Adult form > slow myopathy
Brain-stem and Spinal Cord are particularly affected; "Dead Baby"
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Type III GSD (Cori/Forbes Disease)
Path: Glycogen Debranching Enzyme deficiency in the Liver, Myocardium & Skeletal Muscle
Effect: milder than type I: Can't digest glycogen > variable degrees of hypoglycaemia in the fasted state
Sx: Hepatomegaly, Progressive myopathy, Asymptomatic hypertrophic cardiomyopathy (only in the elderly)
Tx: Stabilizing the hypoglycaemic state, Increased protein intake to fuel gluconeogenesis, Glucagon and epinephrine can raise blood sugar levels in the fed state NOT the fasted state
104
Type IV (Andersen Disease)
Path: Branching Enzyme Deficiency
Effect: Formation of long, abnormal glycogen without branching (amylopectin) > not soluble > precipitates in liver & heart > autoimmune attack
Sx: Hepatomegaly > liver cirrhosis
105
Type V GSD (McArdle Disease)
Path: Muscle phosphorylase deficiency
Effect: can't break down glycogen > limited ATP production + glycogen acc in muscle
Sx: Myoglobin in the urine; NO HYPOGLYCEMIA (only affecting muscle) ; NO LACTIC ACIDEMIA; Elevated CK-MM
Dx: assay phosphorylase activity, AEROBIC EXERCISE + O2 > oxidize FA's[
Tx: easy PA + Avoid strenuous activity to avoid muscle wasting; sucrose drink prior to exercise; creatine supp
106
Type VI (Hers Disease)
Path: Liver Glycogen Phosphorylase activity
Sx: Glycogenolysis is impaired > hepatomegaly not splenomegaly
milder than Type I (Von Gierke's) b/c liver can still turn pyruvate > glucose > export
• NO ACIDOSIS
107
Type VII (Tarui Disease)
Path: Muscle PFK-1 deficiency > partial deficiency in erythrocytes ( more than one isoform of PFK-1 in RBC's)
Effect: Can't phosphorylate Fructose-6-P > impaired glycolysis
Sx: • muscle cramping and weakness upon exercise
Dx: low hematocrit, no lactic acidemia after exercise
108
High Fructose Intolerance
Path: Aldolase B deficiency
Effect: Can't break down Fructose-1-P to Glyceraldehyde and DHAP > Depletion Pi levels > low gluconeogenesis
•Accumulation of Uric Acid + Glycolysis > acidosis • Sorbitol acc -> Death if untreated
Sx: once stopped breast feeding; Fructosuria; Hypoglycaemia; Jaundice, icterus & hepatosplenomegaly
Dx: Hypoglycaemia; Hyperuricaemia; *Urine test + for reducing sugars
Tx: Reduced fructose from the diet
109
Fructokinase Deficiency
Path: Fructokinase Deficiency > Inability to phosphorylate Fructose to Fructose-1-P > Fuctosuria
Important to note: Fructose will be metabolized by the Hexokinase pathway and Glycolysis • No Glucose or Galatose in the urine •No hepatomegaly
110
Classic Galactosemia
Path: Galactose-1-P-Uridyl Transferase deficiency/defect
Effect: Inability to metabolize Galactose-1-P (toxic) into Glucose-1-P > Acc > Depletion Pi levels
Sx: appear immediately after birth; Similar symptoms to HFI except more tissues affected • Galactosaemia • Galactosuria • Irreversible mental retardation • Liver damage • Cataracts due to Galactitol buildup
111
Galactokinase deficiency (Non-classical Galactosaemia)
Path: Galactokinase deficiency > Inability to phosphorylate Galactose --> Galactose-1-P
Sx: Cataracts due to Galactisol production
will not be toxic as your Pi levels are unaffected
112
Cataracts
Path: Acc Sorbitol (very osmotic) in the body > influx of water into the cells of the eye > cell swelling > denaturation of cystallins (structual organization impaired) >vision problems
More info: Excessive Glucose levels > Sorbitol; Due to greater activity of Aldose Reductase (Glucose-->Sorb) than Sorbitol Dehydrogenase (Sorb-->Fructose), Sorbitol will accumulate
113
Glucose-6-Phosphate Dehydrogenase Deficiency
Path: Inability to oxidize Glucose-6-Phosphate to 6-Phosphogluconate so can't reduce NADP+ to NADPH; RBC's susceptible
Effect: Inability to recycle Glutathione, > susceptible to ROS attack -> Severe oxidative stress when ingesting: Antibiotics • Antimalarials • Antipyryretics • Sulphamethoxazole • Fava beans • Infection
Sx: • Bouts of acute haemolytic anaemia • Jaundice (neonate mental retardation) • Weakness/fatigue • General malaise
Diagnosis: - Haemoglobin in the blood - Urine a dark brown - Heinz Bodies: clumps of denatured proteins due to sulfhydryl interactions
Note: Affected patients are protected from Malaria
114
Chronic Granulamtous Disease
Path: Phagocytes have defective NADPH Oxidase > cannot make Superoxide from O2 > Cannot fight bacterial and fungal infections
Sx: Recurrent bacterial and fungal infections; phagocytes will wall off structures because they can't actually defeat them - these are granulomas in the skin, GIT and genitourinary
115
Myeloperoxidase Deficiency
path: Deficiency of Myeloperoxidase enzyme (cannot make Hydrochlorous Acid [HOCl] from H2O2 > Cannot fight fungal infections
Sx: Recurrent fungal infections; 50% of patients are asymptomatic
Note: Occurs in a lot of diabetics
116
Amylotropic Lateral Sclerosis
Path: spontaneous mutations; One known cause is the misfolding of SOD-1 in the ER
Effect: • misfolded proteins aggregate --> cell death • Excess Superoxide accumulates (because you can't break it down) --> apoptosis
Sx: Weakness, atrophy of skeletal muscles, loss of motor nuclei
