Biochem Flashcards
Orotic aciduria
Inability to convert orotic acid –> UMP (pyrimidine synthesis)
Sx: Inc orotic acid in urine megaloblastic anemia (does NOT improve w/ B12) NO hyperammonemia (vs. OTC)
Adenosine deaminase deficiency
AR
Accumulation of adenosine, ATP, dATP
dATP inhibits Ribonucleotide reductase –> inhibits DNA synthesis –> dysfxn T & B-cells
SCID
SELF-MUTILATION
Gout
Choreoathetosis
Retardation
Lesch-Nyan syndrome
- HGPRT deficiency
- Guanine & hypoxanthine can’t –> GMP & IMP = Gets degraded to uric acid –> hyperuricemia
- Excess IMP & GMP –> excess purines –> CNS damage
Nucleotide excision repair defect
Xeroderm pigmentosum
Mutation of DNA mismatch repair
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
- AD
- recognizes UNmethylated new strand mismatches
- 80% –> CRC
- PROXIMAL colon alway involved
Cerebellar (ataxia)
Spider angiomas
IgA deficiency
Ataxia telangiectasia
- ATM gene - DNA repair enzymes
alpha-amantin
Inhibits RNA Pol II (mRNA)
Found in death cap mushrooms –> liver failure
Aminoglycosides
Bind 30S
Inhibits formation of initiation –> misread mRNA
Chloramphenicol
Inhibits 50S peptidyl transferase
Macrolides
Binds 50S –> Blocks translocation
Clindamycin & Chloramphenicol block?
Peptide bond formation
Tetracyclines
Bind 30S
Prevent aminoacyl-tRNA synthetase attachment
I-Cell Disease
Inherited lysosomal storage disorder
Failure to + Mannose-6-Phosphate –> secrete enzymes vs. –> lysosome
Sx:
Coarse facial features
Clouded corneas
Restricted joints
Fatal in childhood
Pyogenic infections - staph, strep
Albinism
Peripheral neuropathy
Chediak-Higashi Syndrome
- Failure of phagosome & lysosome fusion
- Defect Lysosomal Regulator Trafficking gene (LYST) = microtubule polymerization
- AR
Kartagener’s Syndrome
Dynein arm defect (retro –> -)
Immoble cilia
Infertility
Bronchiectasis
Recurrent sinusitis
Assoc w/ situs inversus
Oubain
Inhibits binding to K+ site –> inhibits Na/K pump
Cardiac glycoside MOA
Inhibit Na/K pump –> inhibits Na/Ca exchange –> Inc Ca –> Inc contractility
Scurvy
Lack of Vit C
Required for hydroxylation of collagen w/ proline or lysine
Type I collagen defect
Osteogenesis imperfecta
Type I = AD
Type II = Fatal
Type I collagen (glycosylation)
- Multiple fx
- Blue sclera
- Hearing loss
- Dental imperfections
Type III Collagen defect
Ehlers-Danlos
Type III collagen defect (cross-linking)
- Hyperextensible joints
- Easy bruising
- Berry anyuerysms
- Hyper mobile joints/dislocation
Basket-weave GBM, Type IV collagen defect
Alport syndrome
- Deafness
- Nephritis
- Ocular disturbances
Defect in Fibrillin
Marfan’s Syndrome
- Tall w/ long extremities
- Pectus excavatum
- Long, tapering fingers & toes (Arachnodactyly)
- Medial necrosis of aorta –> dissecting AAs & aortic insufficiency
- Floppy mitral valve
- Subluxation of lens
Locus heterogeneity w/ MEN 2B, homocystinuria
alpha-1 anti-trypsin deficiency
Misfolded protein aggregates in heptocyte ER –> cirrhosis
PAS + globules in liver
Dec elastic tissu in lungs –> PANACINAR emphysema
Codominant trait
Southern Blot
DNA
Southwestern Blot
DNA-binding proteins (transcription factors)
Microarray
Level of gene expression
ELISA
Ag-Ab reactivity
FISH
Localization of genes & visualize anomalies
Fluorescence = gene present
Incomplete penetrance
Not everyone w/ mutation shows sx
Pleiotropy
1 gene >1 effect
PKU
Loss of heterogeneity
Mutation in tumor suppressor gene - complimentary allele must be deleted –> cancer
Mosaicism
Cells in body differ d/t POST-fertilization loss of genetic material
germ-line –> disease not in parent’s cells
Hyperphagia, hypogonadism, hypotonia, Paternal deletion
Prader-Willi
- should be active
Maternal in inactivated
Seizures, ataxia, inappropriate laughter “happy puppet,” maternal deletion
Angleman Syndrome
- should be active
Paternal inactive
AR trait
1 generation
2-carrier parents
XR trait
No male-to-male
More severe in males
Sons of heterozygous mothers = 50%
XD trait
ALL females of affected father
Both MF affected
FGFR3 mutation
Achondroplasia
- enchondral ossification
Dwarfism
Short limbs
NORMAL trunk & head
Normal lifespan & fertility
Assoc w/ advanced paternal age
AD & sporadic
AD Polycystic Kidney Disease
Adults
BILATERAL MASSIVE kidneys
PKD1 - Chr16
Polycystic liver
Berry aneurysm
MVP
AR Polycystic Kidney Disease
Infantile
Congenital hepatic fibrosis & Liver cysts
Portal HTN
HTN
Familial Adenomatous Polyposis
APC gene - chr5 (5 letters in polyp)
Polyps after puberty –> cancer
Familial hypercholesterolinemia
Defect/absent LDL receptor –> inc LDL
Achilles tendon xanthomas
Severe atherosclerosis –>MI b4 20
Osler-Weber-Rendu (Herediatry telangiectasia)
Telangiectasias
Recurrent epistaxis
Skin discolorations
AVMs
Hereditary spherocytosis
Spectrin or Ankyrin defect
Inc MCHC
Cure = splenectomy
Huntington
CAG expansion
Chr4 (hunting 4 food)
caudate atrophy –> dec GABA & Ach
Choreiform movements, progressive dementia
Multiple endocrine neoplasias (MEN) gene mutation
MEN 2A/B - RET gene
Lisch-nodules
Cafe-au-lait
Neural tumors
Scoliosis
Neurofibromatosis Type I
B/L Acoustic schwannoma
Juvenile cataracts
Neurofibromatosis Type II
NF2 gene - chr22
2 ears - NF2 - Chr22
Facial acne, hypopigmented lesion mainly on trunk, Hammartomas, Renal angiomyolipomas, Cardiac rhabdomyomas
Tuberous sclerosis
- adenoma sebaceum
- “ash leaf” spots
- Inc astrocytomas
B/L renal cell carcinomas
Hemangioblastomas of retina, cerebellum, medulla
Von Hippel-Lindau Disease
- VHL gene on Chr3p
Recurrent pulmonary infections w/ PA & SA, Pancreatic insufficiency –> malabs of fat soluble vitamins, steatorrhea, FTT
AR CFTR gene
Chronic bronchitis
Bronchiectasis
Infertility
Inc Cl- sweat test
Tx = NAC to loosen mucus plugs
Pelvic girdle –> superiorly
Hypertrophy of calves
Gower’s maneuver
Duchenne’s Muscular dystrophy
- Frame-shift –> Deleted Dystrophin gene (DMD) –> muscle breakdown
- longest gene in body = high mutation rate
Dx: inc CPK & biopsy
MACRO-orchidism, long face, large jaw, MR
Fragile-X syndrome
- FMR1 gene methylation & expression
- CGG repeat
2nd most common cause of MR (Down)
Fragile-X - Xtra large testes
Down syndrome
Trisomy 21
Flat facies Prominent epicathal folds Simian crease Duodenal atresia ASD Inc ALL & Alzheimer
Inc beta-hCG
US = Inc nuchal translucency
Trisomy 18
Edward’s syndrome (Election age 18)
Rocker-bottom feet
Micrognathia
Clenched hands
Death w/in 1yr
DEC beta-hCG
Trisomy 13
Patau syndrome (Puberty 13)
Rocker-bottom feet MicroOPHTHALMIA Cleft liP/Palate HoloProsencephaly Polydactyly
NORMAL enzyme levels
Robertsonian
Chr 13, 14, 15, 21, 22
2 acrocentric long arms fuse
2 short arms lost
Cri-du-chat
Deletion of short arm of chr5 (46, XX or XY, 5p-)
High pitched cry/mew
Epicanthal folds
VSD
Microcephaly
Williams syndrome
Deletion of long chr7
“Elfin” facies
HyperCa
EXTREME FRIENDLINESS w/ strangers
Vitamin A (retinol)
Source: liver, leafy vegetables
Deficiency: night blindness
Excess: Teratogenic, alopecia, fatigue
Vitamin B1
Thiamine
decarboxylation rxns –> ATP synthesis
Wernicke-korsakoff
Ber1-Ber1
Wernicke-Korsakoff
B1 (thiamine) deficiency
Ophthalmoplegia + ataxia + confabulation
Memory loss
Dorsal medial nucleus of thalamus & mamillary body damage
Wet Beri-Beri
High output cardiac failure (dilated cardio myopathy), edema
Dry Beri-Beri
Polyneuritis, symmetrical muscle wasting
Vitamin B2
Riboflavin
Cheilosis
Corneal vascularization
Vitamin B3
Niacin
NAD derived from B3 (B3 = 3ATP)
From tryptophan & requires B6
3 D’s of B3:
- Diarrhea
- Dermatitis
- Dementia
Tx hyperlipidemia –> FLUSHING
Vitamine B5
Pantothenate (5 = “pent”)
Component of CoA & FA synthesis
Deficiency: dermatitis, enteritis, alopecia, adrenal insufficiency
Vitamin B6
Pyridoxine
Impaired Hb synthesis + Fe excess –> Sideroblastic anemia
Convulsions
Hyper-irritability
Peripheral neuropathy
Vitamin B12
Cobalamin
Co-factor for homocysteine methytransferase
Animal products + microorganisms
Large reserve in liver
Deficiency causes:
- spure
- D. latum
- pernicious anemia
- No terminal ileum (Crohn’s)
Dx etiology = Schilling test
Sx:
Macrocytic, megaloblastic anemia (MCV >100)
Hypersegmented PMNs
Subacute combined degeneration
Folic Acid
–> THF (co-factor w/ B12 in methyl transfer)
DNA & RNA synthesis
Foliage
Small reserves
Deficiency causes:
1. Phenytoin, sulfas, MTX
Sx Macrocytic, megaloblastic anemia (MCV >100) Hypersegmented PMNs Most common vitamin deficiency Alcoholism & pregnancy
Biotin deficiency
excess egg whites - AVIDIN binds biotin
Vitamin C
Ascorbic acid
Oxidized Fe3 –> Fe2 = Iron abs
Hydroxylation of proline & lysine –> collagen synthesis
Deficiency causes:
1. Scurvy - collagen synthesis defect
Sx:
Swollen gums, bruising, hemarthrosis, anemia, poor wound healing
Excess:
N/V/D, iron toxicity, fatigue
Vitamin D
D2 = ergo = plants D3 = cholecalciferol = milk, sun 25-OH = storage 1,25-OH = active
Function = intestinal Ca+ & Phos abs, bone mineralization
Deficiency:
Rickets
Osteomalacia
INADEQUATE AMOUNT IN BREAST MILK
Excess:
Loss of appetite, stupor
Seen in sarcoid
Vitamin E
Protects erythrocytes from ROS
Deficiency:
Hemolytic anemia
Muscle weakness
Post column, spinocerebellar demyelination
Vitamin K
synthesized by intestinal flora
Required for clotting factor synthesis - II, VII, IX, X
Deficiency:
Inc PT & aPTT
Normal bleeding time
Neonates = sterile intestines = can’t make
NOT in breast milk = injection to prevent hemorrhage
After prolonged antibiotics
Zinc
Essential for many enzymes
Zinc fingers - transcription factor motif
Deficiency: Delayed wound healing Hypogonadism Ded adult hair Dysgeusia ANOSMIA
Fomepizole
Inhibits alcohol dehydrogenase (0-order kinetics)
antidote for methanol or ethylene glycol OD
Disulfram (antabuse)
Inhibits acetaldehyde dehydrogenase –> acedalhedhye accumulates = hangover
Kwashiorkor
Protein malnutrition
Edema
Fatty liver change d/t dec APO synthesis
Marasmus
ENERGY malnutrition
Tissue & muscle wasting
Loss of subq fat
Electron transport inhibitors
Rotenone
CN-
Antimycin A
CO
ATPsynthase inhibitors
Oligomycin
Uncoupling agents
Inc membrane permeability –> dec H+ gradient
Produces heat
2,4-DNP
Aspirin
G6PD Deficiency
NADPH required to keep glutathione reduced
Glutathione detoxifies ROA & peroxides
Dec NADPH –> HEMOLYTIC ANEMIA
Most common human enzyme deficiency
XR
Common among Blacks
Inc malarial resistance
- Heinz bodies*
- Bite cells*
Essential fructosuria
Defect in fructokinase
AR
Benign, Asx condition
Fructose appears in urine
Fructose Intolerance
AR deficiency of ALDOLASE B
Fruc-1-P accumulates –> less phis –> inhibits glycogenolysis & gluconeogenesis
Sx: Hypoglycemia Jaundice Cirrhosis Vomiting
Galactokinase deficiency
AR deficiency in galactokinase
Galactitol accumulates
Sx:
Galactose in urine
Infantile cataracts
Failure to tract objects or develop smile
Classic galactosemia
AR absence of Galactose-1-P Uridyltransferase
Sx: FTT Jaundice Hepatomegaly *Infantile cataracts*
Tx = exclude galactose & lactose
Lactase deficiency
Age or hereditary loss (Blacks & Asians)
Loss of brush border enzyme
Oxidizing agents for G6PD deficiency
Oxidizing agents:
- Fava beans
- Sulfonamides
- Primaquine
- Anti-TB
Sorbitol dehydrogenase deficiency
Glucose –> sorbitol (aldose reductase)
Sorbitol –> Fructose (sorbitol dehydrogenase)
Sorbitol accumulates
- cataracts
- retinopathy
- peripheral neuropathy
Acidic A.A.
Asp
Glu
Negatively charged at body pH
Basic A.A.
Arg
Lys
His
Arg & His = growth
Arg & Lys = histones
His = no charge at body pH
Rate-limiting step in Urea Cycle
NH4 –> Carbamoyl Phos
Carbamoyl phosphate synthetase I
Cori cycle
Lactate produced from pyruvate in anaerobic conditions instead of ATP
Transported to liver to undergo gluconeogenesis back to glucose
Hyperammonemia
Excess NH4+ –> depletes alpha-KG –> inhibits TCA
Tx:
Limit protein
Lactulose acidifies GI & traps NH4+ for excretion
Ammonia intoxication
tremor slurring somnolence vomiting cerebral edema blurred vision
OTC deficiency
XR
Can’t eliminate ammonia (urea cycle)
Excess carbamoyl phos –> orotic acid
*Musty odor* MR Growth retardation Seizures Fair skin Eczema
PKU
- AR Dec Phenylalanine hydroxylase
- Tyrosine become essential
- Excess phenylketones in urine
Dark CT
Brown sclera
Urine turns black on exposure to air
Alkaptonuria
- Congenital deficiency of homogentisic acid
(no degradation of Tyr –> fumarate)
Albinism
Lack of:
- Tyrosinase (no melanin from Tyr)
- Defective tyrosine transporters (dec Tyr = dec melanin)
Lens subluxation
atherosclerosis
MR
Tall w/ kyphosis
Homocystinuria
- Cystathione synthase deficiency
- Inc cysteine, B12, Folate - Dec affinity of cystathione synthase
- Inc B6 - Homocysteine methyltransferase deficiency
- B12
Cystinuria
AR
Defect in PCT Cysteine, ornithine, lys, arg transporter
Can –> cystine kidney stones (staghorn calculi)
Tx: = acetazolamide to alkalinize urine
Maple syrup urine disease
Blocked degradation of BRANCHED A.A. Ile Leu Val "I Love Vermont maple syrup"
Severe CNS, MR, death
Hartnup disease
AR
Defective NEUTRAL A.A. transporter
Renal or intestinal epithelial cells
Tryptophan excretion
Dec abs in gut
PELLAGRA
Von Gierke’s Disease (Type I glycogen)
Deficiency = Glu-6-Phosphatase
Severe fasting hypoglycemia
Hepatomegaly (glycogen storage)
Inc blod lactate
Pompe’s Disease (Type II glycogen)
Deficiency = Lysosomal alpha-1,4-glucosidase
Pompe-Pump
Cardiomegaly
Cori’s Disease (Type II glycogen)
Deficiency = Debranching alpha-1,6-glucosidase
Milder type I w/ NORMAL lactate
McArdle’s Disease (type IV glycogen)
Deficiency = skeletal muscle glycogen phosphorylase
McArdle-Muscle
Painful muscle cramps w/ exercise
Myoglobinuria
High glycogen in muscle that can’t be broken-down
Fabry’s
Deficiency = alpha-galactosidase Accumulate = Ceramide trihexose
ONLY non AR lysosomal storage disorder = XR
Sx:
Peripheral neuropathy
Angiokeratomas
Aseptic necrosis of femur, crumpled MOs, hepatosplenomegaly
Gaucher’s
- Deficiency = Glucocerebrosidase
- Accumulate = Glucocerebroside
*Gaucher’s cells = crumpled tissue paper MO
Cherry-red spot on the macula + Hepatosplenomegaly (vs. Tay-Sachs)
Foam Cells
Niemann-Pick
- Deficiency = Sphingomyelinase
- Accumulate = Sphingomyelin
“No man Picks his nose with his Sphinger”
Cherry-red sopt on the macula W/O hepatosplenomegaly
Lysosomes w/ onion skin
Tay-SaX
- Deficiency = HeXosamidase A
- Accumulate = GM2 ganglioside
- hepatosplenomegaly (vs. Niemann-Pick)
Peripheral neuropathy
Optic atrophy
Globoid cells
Krabbe’s Disease
- Deficiency = B-Klactocerebrosidase
- Accumulate = Kalactocerebroside
Central + peripheral demyelination w/ ataxia
Dementia
Metachromatic Leukodystrophy
- Deficiency = Arylsulfatase A
- Accumulates = Cerebroside sulfate
Gargoylism
Corneal clouding
Airway obstruction
Corneal clouding
Hurler’s
- Deficiency = alpha-L-iduronidase
- Accumulate = Heparan sulfate, dermatan sulfate
- Corneal clouding (vs. Hunter’s)
Hunter’s Syndrome
Deficiency = Iduronate sulfatase Accumulate = Heparan sulfate, dermatan sulfate
Sx:
Mild Hurler’s + AGGRESSIVE BEHAVIOR
NO corneal clouding (vs. Hurler’s)
Abetalipoproteinemia
Hereditary inability to synthesize lipoproteins
- deficiencies in apoB-100 & apoB-48
Accumulation in enterocytes - can’t export lipids as chylomicrons
Sx: FTT Steatorrhea Night blindness Acanthocytosis Ataxia
Hypertriglyceridemia
Inc VLDL
Inc blood TGs
Hepatic OVERPRODUCTION of VLDL –> pancreatitis
Familial Hypercholesterolinemia
Inc LDL
Inc blood cholesterol
AD dec/absent LDL receptors
- -> accelerated atherosclerosis
- -> tendon xanthomas (achilles)
- -> corneal arcus
Hyperchylomicronemia
Inc Chylomicrons
Inc blood cholesterol & TGs
LPL deficiency OR
altered aopC-II
Sx:
Pancreatitis
Hepatosplenomegaly
Eruptive/pruritic xanthomas (NO risk for atherosclerosis)
DNA Methylation
Mute transcription
DNA Methylation
Mute transcription
Histone Acetylation
Euchromatin = active
Histone Acetylation
Euchromatin = active
