histone methylation / acetylation
methylation - inactivates transcription
acetylation - relaxes coiling allowing for transcription
orotic aciduria
cant convert orotic acid into UMP (pyrimidine synth) due to defect in UMP synthase. AR inheritance
orotic acid in urine, megaloblastic anemia, failure to thrive
tx w/ oral uridine
adenosine deaminase def
excess ATP / dATP > feedback inhibition > dec DNA synth > dec lymphocyte count
Major cause of SCID **
AR inheritance
Lesch-Nyhan syndrome
absence of HGPRT (purine salvage) > excess uric acid production and de novo purine synth
x linked recessive
retardation, self mutilation, aggression, hyperuricemia, gout, choreoathetosis
direction of DNA synth, RNA synth, mRNA reading, protein synth
DNA synth: 5’ > 3’
RNA synth: 5’ > 3’
mRNA reading: 5’ > 3’
protein synth: N > C terminus
start codon
AUG
ribosomal subunits for eukaryotes and prokaryotes
eu: 40S + 60S > 80S (even)
pro: 30S + 50S > 70S (odd)
abx that block protein synth by binding to ribosomal subunits
aminoglycosides - 30s
tetracyclines - 30s
chloramphenicol - 50s
macrolides - 50s
p53 and hypophosphorlyated Rb usually do what in cell cycle?
inhibit G1 to S progression
mannose 6 phosphate is signal for transport to
lysosome
inclusion cell disease
inherited lysosomal storage disorder, failure to add mannose 6 phosphate to lysosomal proteins
coarse facial features, cloudy corneas, restricted joint mvmt, high plasma levels of lysosomal enzymes. often fatal in childhood
what kind of transport are COPI, COPII and clathrin used in, respectively?
COPI - retrograde
COPII - anterograde
clathrin - golgi > lysosome and PM > endosome
Chediak Higashi syndrome
mutation in LYST (lysosomal trafficking regulator gene) > can’t do MT assisted sorting of endosomal proteins into late endosomes
recurrent pyogenic infections + partial albinism + peripheral neuropathy
Kartagener’s syndrome
immotile cilia due to dynein arm defect
male infertility, female dec fertility, bronchiectasis, recurrent sinusitis, assoc w/ situs inversus
defect in type I collagen is what disease?
osteogenesis imperfecta
defect in type IV collagen is what disease?
alport syndrome
scurvy happens b/c vitamin C is needed for what process?
synth of collagen (hydroxylation of proline and lysine)
Ehlers Danlos is due to a defect in what step of collagen synthesis?
cross linking (extracellular)
osteogenesis imperfecta
abnormal type I collagen (usually AD)
multiple fractures w/ minimal trauma, blue sclera, hearing loss, dental imperfections
alport syndrome
abnormal type 4 collagen (XLR)
progressive nephritis and hearing loss, ocular disturbances
alpha 1 antitrypsin
blocks elastase from breaking down elastin
deficiency can result in emphysema
Southwestern blot
identifies DNA binding proteins
imprinting
differences in gene expression depend on whether mutation is of maternal or paternal origin
ex - prader-willi and angelman’s syndromes
dominant negative mutation
heterozygote produces nonfunctional protein that also prevents normal gene product from functioning
heteroplasmy
presence of both normal and mutated mtDNA resulting in variable expression in mitochondrial inherited disease
Hardy Weinberg eqn
p^2 + 2pq + q^2 = 1
in Prader-Willi and Angelman’s syndromes, which parent’s allele is not expressed, respectively?
Prader Willi - paternal not expressed
Angelman’s - maternal not expressed
example of x linked dominant disease
Hypophosphatemic rickets
hypophosphatemic rickets
x linked dominant disorder
inc phosphate wasting in proximal tubule > rickets like presentation that does not respond to vit D
“ragged red fibers” on muscle biopsy
mitochondrial myopathy usually
achondroplasia mutated protein
FGF receptor 3
familial adenomatous polyposis mutated gene
APC gene
Osler Weber Rendu syndrome is also known as
hereditary hemorrhagic telangiectasia
NT changes in huntington’s
dec GABA and ACh in brain
marfan’s syndrome mutated gene
fibrillin-1
von Recklinhausen’s dz aka…
NF type 1
Lisch nodules
pigmented iris hamartomas seen in NF type 1
NF type 2 findings
bilateral acoustic schwannomas, juvenile cataracts
Tuberous sclerosis findings and inheritance type
AD (incomplete penetrance) facial lesions (adenoma sebaceum), ash leaf spots on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and angiomyolipomas, cardiac rhabdomyomas, astrocytomas
von hippel lindau findings
hemangioblastomas of retina/cerebellum/medulla, mult bilat renal cell carcinomas, other tumors
CF gene mutated
CFTR
mutated gene in duchenne’s and becker’s
dystrophin
Gower’s maneuver assoc w/
Duchenne’s muscular dystrophy
lab test to dx muscular dystrophies
inc CPK
fragile x mutated gene
FMR1 gene
top 2 MCC genetic mental retardation
Down syndrome
Fragile X
genetic disorder assoc w/ macroorchidism
fragile x
4 trinucleotide repeat disease
huntington’s - CAG
myotonic dystrophy - CTG
friedreich’s ataxia - GAA
fragile x syndrome - CGG
congenital heart dz in Down syndrome
ostium primum ASD
pregnancy screening for Down syndrome
dec alpha fetoprotein, inc beta HCG, dec estriol, inc inhibin A
ultrasound - inc nuchal translucency in 1st TM
Edward’s syndrome - genetic cause
trisomy 18
Edward’s syndrome findings
mental retardation, rocker bottom feet, micrognathia, low set ears, clenched hands, prominent occiput, congenital heart dz
death within first year of life usually
pregnancy screening for Edward’s syndrome
dec alpha fetoprotein, dec beta HCG, dec estriol, nl inhibin A
Patau’s syndrome - genetic cause
trisomy 13
Patau’s syndrome findings
severe mental retardation, rocker bottom feet, microphthalmia, microcephaly, cleft palate/lip, holoprosencephaly, polydactyly, congenital heart dz
death w/in first year of life usually
pregnancy screening for Patau’s syndrome
dec beta HCG, dec PAPP-A, inc nuchal translucency
Cri du chat syndrome genetic cause
microdeletion of short arm of chromosome 5
Cri du chat syndrome findings
microcephaly, mental retardation, high pitched crying/mewing, epicanthal folds, ventricular septal defect
Williams syndrome genetic cause
microdeletion of long arm of chromosome 7
Williams syndrome findings
elfin facies, intellectual disability, hypercalcemia, good verbal skills, friendly w/ strangers, CV problems
2 22q11 deletion syndromes
Digeorge syndrome and velocardiofacial syndrome
22q11 deletion syndrome findings
cleft palate, abnl facies, thymic aplasia, cardiac defects, hypocalcema 2/2 PTH aplasia
vit A def
night blindness and dry skin
vit A excess
arthralgia, fatigue, HA, skin changes, sore throat, alopecia, teratogenic
3 syndromes assoc w/ B1 def
Wernicke-Korsakoff
wet beriberi
dry beriberi
vit B1 is needed for…
breakdown of glucose / production of ATP
classic triad of Wernicke-Korsakoff syndrome
confusion, ophthalmoplegia, ataxia
dry beriberi
b1 def
polyneuritis, symmetrical muscle wasting
wet beriberi
high output cardiac failure, edema
vit b2 function
oxidation and reduction
vit B2 def
cheilitis and corneal vascularization
vit B3 is a constituent of what important metab molecule?
NAD (NAD derived from Niacin)
vit b3 def
pellagra: 3 D’s of B3
diarrhea, dermatitis, dementia
vit B5 is component of what metab molecule?
CoA
vit b5 def
dermatitis, enteritis, alopecia, adrenal insufficiency
fn of vit b6
transamination and decarboxylation rxns
synth of heme, histamine, NTs
vit b6 def
peripheral neuropathy and siderblastic anemia
vit b9 is aka
folate!!
folate is vit…
b9
folate fn
synth of nitrogenous bases for DNA and RNA
folate def
macrocytic, megaloblastic anemia, neural tube defects in first TM
most common vit def in US
b9 (folate)
vit b12 def
macrocytic megaloblastic anemia, hypersegmented PMNs, neuro sx - paresthesia, subacute combined systems degeneration
s-adenosyl-methionine (SAM) is required for
converting NE to epi by donating methyl group
fns of vit C
antioxidant
keeps Fe in reduced state for absorption
hydroxylation of proline and lysine in collagen synth
cofactor for conversion of DA to NE
fn of vit D
inc intestinal abs of Ca and PO4, inc bone mineralization
vit D deficiency
Rickets in kids, osteomalacia in adults
hypocalcemic tetany
vit E function
antioxidant that protects Erythrocytes
zinc def
delayed wound healing, hypogonadism, dec adult hair, dysgeusia, anosmia
limiting reagent in alcohol metabolism
NAD+
fomepizole
inhib alcohol dehydrogenase to protect from methanol or ethylene glycol poisoning
kwashiorkor
protein malnutrition > skin lesions, edema, fatty change in liver
marasmus
energy malnutrition > muscle wasting, loss of subq fat, variable edema
3 metab processes that occur in both cytoplasm and mitochondria
heme synth
urea cycle
gluconeogenesis
biotin (b7) is needed for
carboxylase enzymes to work
net ATP from aerobic vs anaerobic metab of glucose
aerobic - 32
anaerobic - 2
NADPH is product of
HMP shunt
NADPH used in (4)
anabolic processes
respiratory burst
P450
glutathione reductase
hexokinase vs glucokinase
both start glycolysis (or glycogen synth in liver)
hexo - in most tissues, high affinity, low capacity, no change w/ insulin
gluco - in liver and beta cells of pancreas, low affinity, high capacity, induced by insulin
rate limiting enzyme of glycolysis
phosphofructokinase 1
2 enzyme/steps that req ATP and 2 that produce in glycolysis
require atp: hexokinase/glucokinase, phosphofructokinase 1
produce: phosphoglycerate kinase, pyruvate kinase
fasting and fed state regulation of glucose handling by F2,6BP
fasting: inc glucagon > inc cAMP > inc PKA > inc FBPase2, dec PFK2, dec glycolysis
fed: inc insulin > dec cAMP > dec PKA > dec FBPase2, inc PFK2, more glycolysis
2 purely ketogenic AAs
lysine and leucine
pyruvate dehydrogenase complex deficiency - most common inheritance pattern, main sx, tx
x linked
neuro deficits
inc intake of ketogenic nutrients
4 different metab paths that pyruvate can take
to alanine via ALT
to oxaloacetate to replenish TCA cycle
to acetyl CoA to enter TCA cycle
to lactate to finish anaerobic glycolysis
which makes more ATP - 1 NADH or 1 FADH2?
NADH (3 vs 2)
rotenone, CN, antimycin A, and CO have what effect (all same) on metabolism?
electron transport inhibitors
ATP synthase inhibitor
oligomycin
why can’t muscle do gluconeogenesis?
lacks glucose 6 phosphatase
3 products of HMP shunt
NADPH, ribose, glycolytic intermediates
where is the HMP shunt used?
lactating mammary glands, liver, adrenal cortex, RBCs
chronic granulomatous dz has a deficiency of what enzyme?
NADPH oxidase - needed to initiate respiratory burst
G6PD def pathophys
less G6PD > less NADPH > less protection from oxidation, esp in RBCs > hemolyitc anemia when exposed to oxidizing agents (fava beans, etc) or infections
G6PD def inheritanced
XLR
2 PBS findings in G6PD def
Heinz bodies (oxidized Hgb) Bite cells (phagocytosed Heinz bodies in spleen leave "bite" in cell)
essential fructosuria
defect in fructokinase, AR, asymptomatic, fructose in blood and urine
fructose intolerance
def in aldolase B, AR
accum of fructose 1 phosphate > dec available PO4 > inhib glycogenolysis/gluconeogenesis
sx - hypoglycemia, jaundice, cirrhosis, vomiting
tx - dec intake of fructose and sucrose
galactokinase def
mild, AR
galactose in blood/urine. infantile cataracts. may not track objects or develop social smile
classic galactosemia
no galactose-1-phosphate uridyltransferase > accum of toxic substances
failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation
tx - dont eat galactose/lactose
cells at risk for sorbitol accumulation
schwann cells, retina, kidney
essential AAs
Met Val His
Ile Phe Thre Trp
Leu Lys
Cori cycle
muscle uses glucose and makes lactate, shuttle to liver, where it is turned back into glucose and reenters bloodstream
hyperammonemia
can be congenital or acquired. excess NH4 > inhib TCA cycle
signs of ammonia intox
asterixis, slurring, somnolence, vomiting, cerebral edema, blurry vision
ornithine transcarbamoylase deficiency
MC urea cycle disorder - XLR
can’t eliminate ammonia properly, buildup of orotic acid
inc orotic acid, dec BUN, hyperammonemia sx
catecholamine synth pathway
phenylalanine > tyrosine > dihydroxyphenylalanine (dopa) > dopamine > norepinephrine > epinephrine
dietary reqs of PKU
tyrosine becomes essential, strict phenylalanine restriction
sx of PKU
mental and growth retardation, seizures, fair skin, eczema, musty body odor
deficiency in PKU
phenylalanine hydroxylase or tetrahydrobiopterin cofactor
alkaptonuria
def in degradative pathway of tyrosine AR, benign dark connective tissue, brown sclera, urine turns black on prolonged exposure to air, debilatating arthralgias
3 causes of albinism
tyrosinase def
defective tyrosine transporters
lack of migration of neural crest cells
nutritition req in homocystinuria
cysteine becomes essential
3 forms of homocystinuria etiology
def cystathionine synthase dec affinity of cystathionine synthase homocysteine methyltransferase def
sx of homocystinuria
mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation, atherosclerosis
cystinuria
defect in one of the AA transporters in PCT of kidney
> precipitation of hexagonal crystals and renal staghorn calculi
AR
tx w/ good hydration and urinary alkalinization`
maple syrup urine dz
AR
blocked degradation of branched AAs due to dec alpha ketoacid dehydrogenase > inc alpha ketoacids in blood
CNS defects, mental retardation, death
urine smells like maple syrup
hartnup dz
AR
defective neutral AA transporter in kidney and intestines
tryptophan excretion in urine and dec absorption in gut > pellagra
intracellular messenger that glucagon/epi increases
cAMP
4 glycogen storage diseases
Von Gierke’s (type 1)
Pompe’s (type 2)
Cori’s (type 3)
McArdle’s (type 4)
general sx of lysosomal storage disorders
peripheral neuropathy / demyelination, neurodegeneration, hepatosplenomegaly, cherry red spot in macula
Fabry’s, Gaucher’s, Niemann-Pick, Tay-Sachs, Krabbe’s, Metachromatic leukodystrophy are examples of what kind of disorder?
lysosomal storage disease - sphingolipidoses
Hurler’s and Hunter’s diseases are what kind of disorders?
lysosomal storage disease - mucopolysaccharidoses
where does fatty acid degradation take place?
mitochondrion
carnitine deficiency
inability to transport LCFAs into mito > toxic accumulation
weakness, hypotonia, hypoketotic hypoglycemia
which ketone is not detected by urine dipstick?
beta hydroxybutyrate
rate limiting step of cholesterol synth
HMG CoA reductase
which way do these lipid particles go (liver > periphery or vice versa)? VLDL IDL LDL HDL
VLDL - TGs to peripheral tissue
IDL - TGs and cholesterol to liver
LDL - cholesterol to tissues
HDL - cholesterol to liver
familial dyslipidemias - type 1 hyperchylomicronemia
AR
pancreatitis, xanthomas, NO INC RISK FOR ATHEROSCLEROSIS
familial dyslipidemias - type 2a familial hypercholesterolemia
AD, absent or dec LDL receptor
accelerated atherosclerosis
familial dyslipidemias - type 4 hypertriglyceridemia
AD, hepatic overproduction of VLDL
pancreatitis
abetalipoproteinemia
AR
mutation in microsomal TG transfer protein (MTP) gene
dec chylomicron and VLDL synth > lipid accumulation in enterocytes
failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness