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
- 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
FGF receptor 3
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
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
B2 alternate name
B3 alternate name
B5 alternate name
B6 alternate name
B12 alternate name
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
Cheilosis (lips, mouth) and Corneal vascularization
B3/niacin is derived from ____ and requires ___ for synthesis
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
- 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?
Vitamin D's affect on calcium and PTH
Increases serum Ca and suppresses PTH
Vitamin E deficiency
hemolytic anemia, muscle weakness, neurodysfunction
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
- FA syntehsis
- HMP shunt
- Protein synthesis
- Steroid syntehsis (SER)
- (Heme synth, Urea cycle, Gluconeogenesis)
Rate-determining enzymes for glycolysis and gluconeogenesis
- (F-6-P <--> F-1,6-BP)
Rate determining enzyme for TCA cycle
- Isocitrate DH
- isocitrate to alpha-KG
Rate-determining enzyme for glycogenolysis
Rate-determining enzyme for fatty acid syntehsis
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
- 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)
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
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
- Essential fructosuria. Benign.
- Fructose in blood and urine
Galactose-1-phsophate uridyltransferase deficiency
- Galactitol accumulates
- FTT, jaundice, hepatomegaly, cataracts
- Galactitol accumulates if galactose is in diet. mild.
- Galactose in blood and urine, cataracts.
Sorbitol dehydrogenase function
Convert sorbitol to fructose
Essential amino acids
Maple syrup urine disease
Deficiency in alpha-ketoacid dehydrogenase, which requires thiamine
- von Gierke's disease
- hypoglycemia, glycogen in liver, high lactate, hepatomegaly
- Pompe's disease
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
- Ceramide trihexoside accumulates
- Peripheral neuropathy, angiokeratomas, CV/renal dz
- Glucocerebroside accumulates
- hepatosplenomegaly, aseptic necrosis of femur, tissue paper macrophages
- Sphingomyelin accumulates
- Foam cells, cherry-red spot
Hexosaminidase A deficiency
- GM2 ganglioside accumulates
- No hepatosplenomegaly (vs. niemann pick)
- Galactocerebroside accumulates
- neruopathy, DD, optic atrophy, globoid cells
Arylsulfatase A deficiency
- Metachromatic leukodystrophy
- Cerebrosid sulfate accumulates
- Ataxia, dementia (demyelination)
- 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
puts Acetyl-CoA into cytoplasm for FA synthesis
Puts acyl-CoA into mitochondria for beta-oxydation
- Can't transport LCFAs into mitochondria
- Wekness, hypotonia, hypoketotic hypoglycemia
activates LCAT to esterify cholesterol
binds LDL receptor, mediates VLDL secretion
Cofactor for lipoprotein lipase, which degrades chylomicrons
mediates CM secretion from intestine
mediates Extra remnant uptaet
B-100 and B-48 deficiency
- Abetalipoproteinemia: no CM secretion from intestine
- FTT, steatorrhea, acanthocytosis, ataxia, night blindness