-
Orotic aciduria defect
- Either orotic acid phosphoribosyltransferase or orotidine 5'-phosphate decarboxylase
- defect in orotic acid --> UMP (pyrimidine synthesis)
-
Orotic aciduria findings
- Increased orotic acid in urine
- megaloblastic anemia not improving with B12 or folic acid
- FTT
- NO HYPERAMMONEMIA
-
Ornitine Transcarbamoylase (OTC) deficiency findings
increased urine orotic acid WITH hyperammonemia
-
Purine salvage deficiencies
- Adenosine deaminase deficiency
- Lesch-Nyhan syndrome
-
Adenosine deaminase deficiency causes:
- Excess ATP and dATP feedback inhibit ribonucleotide reductase
- Lymphocyte count dives. Can cause SCID
-
What is Lesch-Nyhan syndrome?
- Defective purine salvage from XLR absence of HGPRT
- HGPRT normally converts hypoxanthine --> IMP and guanine --> GMP
- Excess uric acid production causing retardation, self-mutilation, hyperuricemia, gout
-
What can somebody with xeroderma pigmentosum not do?
Repair thymidine dimers (nucleotide Xcision repair)
-
Where is alpha-amanitin found and why is it bad for you?
In death cap mushrooms; inhibits RNA polymerase II and kills your liver
-
What fails in I-cell disease?
- The addition of mannose-6-phosphate to lysosome proteins.
- Coarse facial features, clouded corneas, stiff joints
-
What is defective in Chediak-Higashi syndrome?
Microtubule polymerization. Decreased ability to phagocytose pyogenic infections.
-
What is defective in Ehlers-Danlos?
Type III collagen (cross-linking)
-
What's the defect in osteogenesis imperfecta and which type of OI is worse?
Type 1 collagen (glycosylation)? Type II OI is fatal early.
-
Blotting procedures, compass-style:
- Southern: DNA (DNA probe)
- Northern: RNA (DNA probe)
- Western: Protein (Antibody probe)
-
What is pliotropy?
1 gene has more than 1 effect on a person's phenotype
-
What is locus heterogeneity?
When a trait has several potential genetic causes, e.g. marfanoid habitus or albinism
-
Achondroplasia mutation
FGF receptor 3
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Autsomal-dominant polycystic kidney disease mutation and associated problems
- APKD1 on chromosome 16; 16 letters in polycystic kidney
- Polycystic liver, berry aneurysms, mitral valve prolapse
-
Familial adenomatous polyposis mutation
APC gene on chromosome 5. 5 letters in polyp
-
What findings are there in hereditary hemorrhagic telangiectasia (AKA Osler-Weber-Rendu syndrome)?
Telangiectasia, recurrent epistaxis, skin discolorations, AVMs. It's a disorder of BVs.
-
What repeats and on what gene for Huntington's disease?
CAG repeats on chromosome 4. (Decreased GABA and ACh)
-
Findings and chromosome for NF-1
cafe-au-lait spots, neural tumors, Lisch nodules (iris hemartomas), scoliosis, optic gliomas, pheo. Chromosome 17.
-
Findings in NF-2 and chromosome
Bilateral acoustic neuroma, juvenile cataracts. Chromosome 22
-
What is tuberous sclerosis?
- Facial lesions, ash leaf spots on skin, cortical/retinal hamartomas, seizures, MR, renal cyts and angiomyoliposmas, cardiac rhabdomyomas, astrocytomas.
- There is incomplete penetrance with a variable presentation.
-
Von Hippel-Lindau disease: gene and findings
- VHL gene (tumor suppressor) deletion on chromosome 3 causes expression of HIF (a TF) and angiogenic growth factor activation.
- Bilateral RCC, hemangioblastomas.
-
Genetic problem in Fragile X syndrome
CGG trinucleotide repeats on the X chromosome affecting methylation/expression of FMR1 gene.
-
Genetic problem in myotonic dystrophy
CTG repeats
-
What is Edwards' syndrome?
- Trisomy 18
- Specific findings: micrognathia, low-set ears, clenched hands
-
What is Patau's syndrome?
- Trisomy 13
- Specific findings: microphthalmia, microcephaly, cleft lip/Palate, holoProsencephaly, Polydactyly
-
Cri-du-chat gene and findings
- Microdeletion of short arm of chromosome 5
- High pitched crying, epicanthal folds, cardiac abnormalities
-
Williams syndrome gene and findings
- Microdeletion of chromosome 7, including elastin gene
- Elfin facies, MR, hypercalcemia due to increased sensitivity to vitamin D, extreme friendliness
-
DiGeorge syndrome, gene and embryological defect
- Microdeletion at 22
- Cleft palate, Abnormal facies, Thymic aplasia, Cardiac defects, Hypocalcemia 2/2 parathyroid aplasia
- Abberant development of 3rd and 4th branchial pouches
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B2 alternate name
riboflavin/FAD/FMN
-
B3 alternate name
niacin/NAD+
-
B5 alternate name
pantothenic acid/CoA
-
B6 alternate name
pyridoxine/PLP
-
B12 alternate name
cobalamin
-
Deficiency of B1/thiamine
ATP depletion, Wernicke-Korsakoff, beriberi
-
Beriberi, symptoms of both types
Polyneuritis, muscle wasting, high-output cardiac failure, adema
-
Thiamine is a cofactor for these enzymes
- pyruvate DH (glycolysis)
- alpha-KG DH (TCA cycle)
- transketolase (HMP shunt)
- branched-chain AA DH
-
B2/riboflavin deficiency
Cheilosis (lips, mouth) and Corneal vascularization
-
B3/niacin is derived from ____ and requires ___ for synthesis
Tryptophan, B6/pyridoxine
-
B3/niacin deficiency
Pellagra: Diarrhea, Dermititis, Dementia
-
Conditions causing niacin deficiency
- Hartnup disease (decreased tryptophan absorption)
- Malignant carcinoid syndrome (increased tryp metabolism
- INH treatment (decreases B6)
-
B5/pantothenate function and deficiency
- Component of CoA and fatty acid synthase
- Dermatitis, enteritis, alopecia, adrenal insufficiency
-
B6/pyridoxine function and deficiency
- Used in transamination (ALT/AST) decarboxylation reactions, glycogeno phosphorylase, cystathionine synthesis, heme synthesis, niacin synthesis.
- Convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemias
- INH and OCPs can induce deficiency
-
B12/cobalamin function
- cofactor for homocysteine methyltransferase and mehtylmalonyl-CoA mutase
- In other words, helps create methionine for the creation of dUMP from dTMP
- and helps create succinyl-CoA
-
How folic acid deficiency is different from B12 deficiency
No neurological symptoms, but still a megaloblastic anemia
-
What does S-adenosyl-methionine do?
- Transfers methyl units.
- Required to convert NE to epi.
- Made from methionine, which requires B12 and folate
-
Biotin is a cofactor for these carboxylation enzymes
- Pyruvate carboxylase (pyruvate to oxaloacetate)
- Acetyl-CoA carboxylase (acetyl-CoA to malonyl-CoA)
- Propionyl-CoA carboxylase (propionyl-CoA to methylmalonyl-CoA)
-
Vitamin C functions
- Facilitates iron absorption (keeps iron reduced to Fe2+)
- Hydroxylattion of proline and lysine for collagen
- Required for dopamine beta-hydroxylase
-
What form of vitamin D is the active form?
1,25-(OH)2D3 (Calcitrol)
-
Vitamin D's affect on calcium and PTH
Increases serum Ca and suppresses PTH
-
Vitamin E deficiency
hemolytic anemia, muscle weakness, neurodysfunction
-
Zinc deficiency
delayed wound healing, hypogonadism, decreased adult hair, dysgeusia, anosmia
-
Disulfiram inhibits this enzyme in this cell compartment
Acetaldehyde dehyrdogenase in the mitochondria
-
Ethanol's metabolic effects
- Increases the ratio of NADH/NAD+ in the liver
- Gluconeogenesis is inhibited and fatty acid synthesis is stimulated
- (Causes pyruvate to lactate and OAA to malate)
-
Processes occuring in the mitochondria
- FA oxidation
- acetyl-CoA production
- TCA cycle
- Oxidative phosphorylation
- (Heme synth, Urea cycle, Gluconeogenesis)
-
Processes occuring in the cytoplasm
- Glycolysis
- FA syntehsis
- HMP shunt
- Protein synthesis
- Steroid syntehsis (SER)
- (Heme synth, Urea cycle, Gluconeogenesis)
-
Rate-determining enzymes for glycolysis and gluconeogenesis
- PFK-1
- Fructose-1,6-bisphosphatase
- (F-6-P <--> F-1,6-BP)
-
Rate determining enzyme for TCA cycle
- Isocitrate DH
- isocitrate to alpha-KG
-
Rate-determining enzyme for glycogenolysis
Glycogen phosphorylase
-
Rate-determining enzyme for fatty acid syntehsis
Acetyl-CoA carboxylase
-
Rate-determining enzyme for fatty acid oxidation
Carnitine acyltransferase I
-
Hexokinase: action and personality
- Phosphorylates glucose
- Ubiquitous, high affinity (low Km), low capacity (low Vmax)
- Doesn't care if insulin is around
-
Glucokinase, action and personality
- Phosphorylates glucose
- Low affinity (high Km), high capacity (high vmax).
- Found in liver and beta cells of pancreas.
- GLUtton: cannot be satisfied or inhibited. induced by insulin
-
Glycolytic enzymes that ATP inhibits
- PFK-1
- Pyruvate kinase
- Pyruvate dehydrogenase
-
high levels of acetyl-CoA inhibit this glycolytic enzyme
Pyruvate dehydrogenase (pyruvate to acetyl-CoA)
-
High levels of alanine inhibit this glycolytic enzyme
Pyruvate kinase (PEP to pyruvate)
-
High levels of citrate inhibit this glycolytic enzyme
PFK-1 (F6P to F1,6BP)
-
Deficiency in pyruvate kinase or phosphoglucose isomerase causes this
Hemolytic anemia (RBC swelling and lysis from pump failure)
-
Cofactors required for pyruvate DH complex and alpha-KG DH
-
Arsenic inhibits this
lipoic acid (pyruvate DH complex)
-
Arsenic poisoning
Vomiting, rice water stools, garlic breath
-
Pyruvate kinase creates
pyruvate (created by)
-
Pyruvate dehydrogenase creates
acetyl-CoA (created by)
-
Pyruvate dehydrogenase deficiency
- Lactic acidosis, neurological defects
- Congenital or from B1 deficiency
- Tx: Lysine and Leucine, the only purely ketogenic amino acids
-
Things you can do with pyruvate
- 1. make alanine to carry amino group to liver
- 2. make OAA for TCA or gluconeogenesis
- 3. transition from glycolysis to TCA cycle
- 4. make lactate
-
Poisons causing a drop in proton gradient and block of ATP syntehsis
Rotenone, CN-, antimycin A, CO
-
Poison inhibiting mitochondrial ATPase, increasing proton gradient
Oligomycin
-
Things uncoupling oxphosph by increasing membrane permeability and decreasing the proton gradient
2,4-DNP, aspirin, brown fat
-
Irreversible enzymes of gluconeogenesis
- Pyruvate carboxylase (pyruvate to OAA)
- PEP carboxykinase (OAA to PEP)
- Fructose-1,6-bisphosphatase (makes F6P)
- Glucose-6-phosphatase (makes glucose)
-
Problem in G6PD deficiency
inadequate NADPH to reduce glutathione
-
Smear findings for G6PD deficiency
- Heinz bodies (oxidized hemmoglobin in RBCs)
- Bite cells (removal of heinz bodies by macrophages)
-
Aldolase B deficiency
- Same as Fructose-1-phosphate aldolase
- F-1-P accumulates, decreasing phosphate, inhibiting glycogenolysis and gluconeogenesis
- hypoglycemia, jaundice, cirrhosis, vomiting
-
Fructokinase deficiency
- Essential fructosuria. Benign.
- Fructose in blood and urine
-
Galactose-1-phsophate uridyltransferase deficiency
- Galactitol accumulates
- FTT, jaundice, hepatomegaly, cataracts
-
Galactokinase deficiency
- Galactitol accumulates if galactose is in diet. mild.
- Galactose in blood and urine, cataracts.
-
Sorbitol dehydrogenase function
Convert sorbitol to fructose
-
Essential amino acids
- Val
- Arg
- His
- Ile
- Leu
- Lys
- Phe
- Thr
- Trp
-
Maple syrup urine disease
Deficiency in alpha-ketoacid dehydrogenase, which requires thiamine
-
Glucose-6-phosphatase deficiency
- von Gierke's disease
- hypoglycemia, glycogen in liver, high lactate, hepatomegaly
-
Lysosomal alpha-1,4-glucosidase
- Pompe's disease
- Cardiomegaly
-
Debranching enzyme (alpha-1,6-glucosidase)
Cori's disease. Milder von Gierke's with normal lactate
-
Skeletal muscle glycogen phosphorylase
- McArdle's disease
- Muscle cramps, myoglobinuria
-
alpha-galactosidase A deficiency
- Fabry's
- Ceramide trihexoside accumulates
- Peripheral neuropathy, angiokeratomas, CV/renal dz
-
beta-glucocerebrosidase deficiency
- Gaucher's
- Glucocerebroside accumulates
- hepatosplenomegaly, aseptic necrosis of femur, tissue paper macrophages
-
Sphingomyelinase deficiency
- Niemann-Pick
- Sphingomyelin accumulates
- Foam cells, cherry-red spot
-
Hexosaminidase A deficiency
- Tay-Sachs
- GM2 ganglioside accumulates
- No hepatosplenomegaly (vs. niemann pick)
-
Galactocerebrosidase deficiency
- Krabbe's
- Galactocerebroside accumulates
- neruopathy, DD, optic atrophy, globoid cells
-
Arylsulfatase A deficiency
- Metachromatic leukodystrophy
- Cerebrosid sulfate accumulates
- Ataxia, dementia (demyelination)
-
alpha-L-iduronidase deficiency
- Hurler's
- Heparan and dermatan sulfate accumulate
- DD, gargoylism, corneal clouding, hepatosplenomegaly
-
Iduronate sulfatase deficiency
- Hunter's syndrome
- Heparan and dermatan sulfate accumulate
- Mild Hurler's plus aggression. No corneal clouding
-
Citrate shuttle
puts Acetyl-CoA into cytoplasm for FA synthesis
-
Carnitine shuttle
Puts acyl-CoA into mitochondria for beta-oxydation
-
Carnitine deficiency
- Can't transport LCFAs into mitochondria
- Wekness, hypotonia, hypoketotic hypoglycemia
-
lipoprotein A-I
activates LCAT to esterify cholesterol
-
lipoprotein B-100
binds LDL receptor, mediates VLDL secretion
-
lipoprotein C-II
Cofactor for lipoprotein lipase, which degrades chylomicrons
-
lipoprotein B-48
mediates CM secretion from intestine
-
lipoprotein E
mediates Extra remnant uptaet
-
B-100 and B-48 deficiency
- Abetalipoproteinemia: no CM secretion from intestine
- FTT, steatorrhea, acanthocytosis, ataxia, night blindness
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