Fundamentals 1 Flashcards
Type 1 Diabetes
No insulin is made (pancreas is attacked – autoimmune disorder, potentailly) no insulin produced in pancreatic beta cells -> liver acts as if body is always in starvation state -> hyperglycemia plus gluconeogenesis, limited glucose uptake in muscle/adipose - also ketone bodies are produced (liver thinks it is starved because there is no insulin) – DKA w/out insulin
Type 2 Diabetes
Insulin level are normal:
Receptor defects
Processing
Reduced Kinase Activity
Immune system defects
Type A : antibodies to insulin. No free insulin available to bind to receptor
Type B : antibodies to insulin receptor, such that either insulin binding is blocked, or the antibody itself is stimulatory
Obesity related diabetes (down-regulation of insulin receptors; related to metabolic syndrome
IV fructose
low phosphate/Energy
elevated uric acid, lactic acidosis
Hypoglycemia
Lots F1P
essential fructosuria
fructosekinase can’t phosphorylate fructose
Hereditary fructise intolerance
no aldolase B, F1P backs up and inhibits glycogen phosphorylase; no degradation
can’t have fructose
low phosphate/Energy
high uric acid / lacitc acidosis
hypoglycemia (F1P inhibits the Glycogen Phosporylase)
(this often present when a child switches from breat milk to juice, resulting in hypoglycemia)
lactase deficiency
bad lactase
can’t have lactose, diarrhea, flatulence, stomach pain
classical galatosemia
no gal-1p uridylyl transferase
high blood galatose and galatitol – cataracts and mental retardation; hypoglycemia (note: gal-1P looks like G1P so no degrdation of G1P into glucose will occur)
nonclassical galactosemia
no galactokinase
high blood galactose/galactitol; cataracts (less severe than classical galactosemia as the nervous sytem is uneffected)
pyruvate kianse deficiencey
sugar enzyme (converts phosphoenol pyruvate to pyruvate producing an ATP
no pyruvate made
Hemolytic Anemia – not a great enough energy supply for the RBC
pyruvate dehydrogenase deficiency (Leigh Syndrome)
sugar enzyme – connecting glycolysis to the TCA cycle converting pyruvate into acetyl-CoA
no Acetyl-CoA made
LEthargy
Neuro Problems, Seizures
Poor Muscle Tone
Ataxia
TCA/OxPhos disease
mitochondrial/nuclear genome
muscle/nerve problems
Primary Carnitine Deficiency
lack of/defective membrane carnitine transporter (translocase) prevents carnitinve entry into cells, unable to transport FAs into mitochondria to make energy — causes weakness, cramping, fasting hypoglycemia,Triacyl-Glyeride accumulation in the muscle/liver cytoplasm (DHAP pathway), elevated Urine carnitine levels
might be treatable with axogenous carnitine to overcome the higher Km of the transporters
Secondary Carnitine Deficiency
defect in Carnitine-Acyl-Transferase-2 (CAT 2 or CPT 2), the carnitine cannot be removed from the FA inside the mitochondrai. Therefore the carnitine is stuck within the mitochondria bound to the FA and there is no free Carnitine. Therefore FA oxidation is blocked. This causes muscle weakness, cramping, fasting hypoglycemia, triacyl-glycerol accumulation in msucle/livercytoplasm; we ill also see elevated serum acyl-carnitine levels
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
fatty acid enzyme disease – displayed in elevated 6-10 carbon dicarboxylic acids, hypoketotic, hypoglycemic when glycogen stores are low – functions to break down medium chain fatty acids 8-12 carbons long (This is all a result of a point mutation in which Glu si change to Lys, changing the charge of teh amino acid, therefore destabiulizing the protein causing it to have an altered function.)
dicarboxylic acids build up; fasting hypoglycemia
Glucose-6-Phosphate dehydrogenase Deficiency
Enzyme for the HMP pathway which produces NADPH is lacking, Glutathione not replinished
X-linked, hemolytic anemia (bursting RBCs)
Adenosine deaminase deficiency (ADA)
severe combined immunodeficiency (SCID)
nucleotide salvage
no immune system cells (B or T cells)
Pneumonia, Diarrhea, Skin Rashes
Gout
to many purines
uric acid builds up; crytals resulting in inflammation
Reduce Purine Intake. Don’t eat liver. Also, Allopurinol is a Xanthine Oxidase Inhibitor which blocks the production or uric acid
Lesch-Nyhan Syndrome
nucleotide salvage
missing hypoxanthine guanine phosphoribosyltransferase 1 (HGPRT) – can’t salvage hypoxanthine/guanine
Neuro symptoms
Mental Retardation, Self-Mutilation
Hereditary Orotic Aciduria
pyrimidine synthesis problem
Missing UMP synthase (Orotic phosphoribosyl transferase + OMP decarboxylase)
Retarded growth, anemia and excessive urinary excretion of orotic acid
hyperammonemia
AA metabolism –> Often a urea cycle problem
ammonia in the blood
Elevate ammonia in the blood which can lead to several complications, including neurological problems
PKU (PhenylKetoUrea)
henylalanine cannot be converted –> Tyrosine
Phenylalanine Hydroxylase
Mental Retardation, Behavioral Problesm, Seizures, Hyperactivity, stunted growth (microcephaly) and skin rashes
Maple Syrup Urine Disease (MSUD)
leucine, isoleucine, valine
Bracnched Chain Amino Acids are Trans-aminated, but not carboxylated
Urine Smells like Maple Syrup
Damage to the Brain can occur during times of high physical exertion (exercise, fever, infection)
tyrosinemia
tyrosine
Delayed Enzyme maturation in the catabolic tyrosine
Homocysteinemia
methionine synthase, N5-N10TF reductase, B-Cystathionien synthase
Also from B12, Folate and B6
atherosclerosis – promotes plaques (increases smooth muscle growth, while decreasing epithelial tissueg rwoth)
Thrombosis (because homocysteine interfers with the clotting cascade)
pallegra
Missing nicotinomide (niacin)
No NAD+; 4 D’s: dermatitis, dementia, diarhea, death
Cholera
Toxin blocks Gs
constant activation of the G-protein cascade
Diarrhea
Pertussis
toxin blocks Gi
no Inhibition of G-protein cascade
BerBeri (Overview) – frequent in alcoholics as they do not absorb Thiamine well
B1 deficiency, no Thiamine; problems with TK, PDH, aKGDH
enzymes don’t work –n o decraboxylation (E3)
Wet: heart, edema, cofusion, nystagmus
Dry: peropherial neuropathy
Wernicke Korsacoff (Dry BeriBeri)
Thiamine deficient from alcohol
Neural disfunction: nystagmus, edema, confusion, ataxia (random movememnts)
Drug Tolerance
Increased cycP450 activity
Drugs clear faster
Aspirin Over Dose
run out of NADPH to reduce glutathione to neutralize the toxin
Barbituate toxic
ethanol mixed will inhibited cycP450
Familial Lou Gherig’s (ALS)
no superoxide dis mutase – radical O2 species destroy tissues, genetic origin
slow break down of nerves/muscles
MODY (maturity onset diabetes of the young)
no glucokinase in pancreaseb eta-cells; no ATP;potassium channel does not stop, therefore calcium does not enter the cells, no insulin is produced by the pancreatic Beta-Cells.
B6 deficiency (pyridoxyl phosphate)
no phosphorylase, no glycogen breakdown, no homocysteine breakdown
Arsenic Poisoning
Arsenic targets lipoic Acid
no PDH, aKGDH, garlic breath, rice water stool and vomiting
no activity of: phosphoglycerate kinase or glyceraldehyde-3-phosphate dehydrogenase
Malonate
competes with succinate for succinate dehydrogenase interfering with fumurate production
Low fumarate
Fluoroacetate
blocks aconitase
low isocitrate (citrate build-up, slowing glycolysis and promoting FA production)
Oligomycin
blocks F0 channel of ATP synthse
DCCD
DCCD
thermogenin (natural for heat in babies and some animals)
Uncoupler, destroys the hydrogen ion gradient
weight loss, warmth, no energy, death if great amount
weight loss, warmth, no energy, death if great amount
Uncoupler, moves potassium ions, destroys the gradient
dinitrophenol (diet pill)
Uncoupler
Rotenone
No Fe-S to CoQ in complex 1
Antimycin A
Cytochrome C can’ta ccept electron, complex 3
Cyanide/C=O
no Fe binding in complex 4`no Energy
Atractyloside
no ATP leave, no ADP
Kearns Sayre Syndrome (KSS)
Mitochondrial DNA deletion
muscle/nervous system problems – eyes
Pearson Syndrome
Mitochondrial DNA deletion
marrow (bone)/pancreas problems + KSS problems
MERRF (myoclonic epilepsy and ragged red fiber)
epilepsy and red, jagged muscles
MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis + storke-like symptoms
muslce weakness, headaches, seizures, strokes,\, keto acidosis
Leigh Syndrome
missence in mitochondrial DNA, ATP synthase (basically can’t make ATP synthase because of mutation, so you can’t make ATP. Resulting in decreased energy production
SEVERE neurol effects, early death (1-2 years), lactic acidosis
LHON (leber hereditary optic neuropathy)
missence in mitochondrial DNA –> complex1
eye nerves stop working ==> blindness
ETF deficiency
fatal. Can’t get energy from FADH2 produced upon FA oxidation
Symptoms are exagerated during fasting
ETF:CoQ oxidoreductase
fatal. Can’t get energy from FADH2 produced upon FA oxidation
Zellwegaers syndrome
defect inperoxisome biogenesis ==> no peroxisomes
No peroxisomes
no VLCFA or BCF breakdown, therefore VLCFA and BCFA are incorporated into the membranes of cells, causing disruption and leaky membranes ==> this results in multiple organ failure (nervous system, too) in addition to plasmalogen deficiencies
Refsum disease
no phytanic acid (branched chain) oxidase –> no alpha oxidation or branched chain fatty acids metabolism
BCFA accumulation
accumulation of phytanic acid in myelin sheath disrupts neuronal conductance
Adrenoleukodystrophy (ALD)
mutated ABCD1 VLCFA transporter into the peroxisome –> accumulation of VLCFA in the cytosol
disrupting adrenal and nervous function — major cause is X-linked disorder ==== Noted: there are infantile, young child and late-onset forms
Jamaican Vomiting Disease
hypoglycin toxin from unrip ackee fruit, block short and medium chain acyl-CoA dehydrogenase activity causing severe hypoglycemia due to lack of FA oxication, resulting in elevated serum FA and dicarboxylic acid levels, this can also result in a carintine deficiency because all of the carnitine is bound to SCFAs, MCFAs, therfore the peroxisome is unable to transport in LCFAs for oxidation
Sphingolipidoses
all are lysosomal storage diseases
generalized gangliosidosis
no GM1-beta-galactosidase;
causes mental retardation, hepatomegaly, skeletal deformities, accumulation of gangliosides & mucopolysaccharides
fatal, autosomal recessive – keep it mind that GM1 is the first one we break down in the series
Tay-Sachs disease
no hexosaminidase A; causes mental retardation, blindness, muscular weakness, seizures; accumulation of GM2 (300x) and GA2 (20x, asialo derivative), cherry-red spot in normally yellow/white macula of eye – mutation in the alpha subunit affects the Hex A (doesn’t affect Hex B)
fatal, autosomal recessive, higher incidence in Ashkenazi Jewish Eastern European community
Fabry’s disease
no alpha-galactosidase; reddish-purple skin rash, kidney failure, lower extremity pain, accumulation of galactolactosylceramide
only X-linked recessive lysosomal storage disease, not fatal
Fabry’s disease
no alpha-galactosidase; reddish-purple skin rash, kidney failure, lower extremity pain, accumulation of galactolactosylceramide
only X-linked recessive lysosomal storage disease, not fatal
lactosyl ceramidosis (ceramide lactoside lipidosis)
no lactosylceramide beta-galactosidase; brain damage, heptaosplenomegaly, accumulation of lactosylceramide
lactosyl ceramidosis (ceramide lactoside lipidosis)
no lactosylceramide beta-galactosidase; brain damage, heptaosplenomegaly, accumulation of lactosylceramide
Gaucher’s disease
no glucocerebroside beta-glucosidase; hepatosplenomegaly, erosion of long bones/pelvis, infantile form has mental retardation, accumulation of glucosylceramide
autosomal recessive, some forms are fatal; has genotype-phenotype correlation where expression of symptoms/severity depends on where mutation is in protein (or in activating proteins)
Gaucher’s disease
no glucocerebroside beta-glucosidase; hepatosplenomegaly, erosion of long bones/pelvis, infantile form has mental retardation, accumulation of glucosylceramide
autosomal recessive, some forms are fatal; has genotype-phenotype correlation where expression of symptoms/severity depends on where mutation is in protein (or in activating proteins)
metachromatic leukodystrophy
no aryl-sulfatase A; mental retardation, demyelination, progressive paralysis & dementia, accumulation of galactosylceramide-sulfate
metachromatic leukodystrophy
no aryl-sulfatase A; mental retardation, demyelination, progressive paralysis & dementia, accumulation of galactosylceramide-sulfate
Krabbe disease
no galactoceramide beta-galactosidase; mental retardation, total absence of myelin, particle accumulation in brain, accumulation of galactosylceramide
Krabbe disease
no galactoceramide beta-galactosidase; mental retardation, total absence of myelin, particle accumulation in brain, accumulation of galactosylceramide
Niemann-Pick disease
no sphingomyelinase; mental retardation, hepatosplenomegaly, accumulation of sphingomyelin
, fatal early in life
Niemann-Pick disease
no sphingomyelinase; mental retardation, hepatosplenomegaly, accumulation of sphingomyelin
, fatal early in life
Farber’s disease
no ceramidase; painful deformed joints, accumulation of ceramide
fatal early in life
Farber’s disease
no ceramidase; painful deformed joints, accumulation of ceramide
fatal early in life
Sandhoff’s Activator disease
missing activator protein required for hexosaminidase A function, causes accumulation of GM2 (Tay-Sachs-like)–
Sandhoff’s Activator disease
missing activator protein required for hexosaminidase A function, causes accumulation of GM2 (Tay-Sachs-like)–
Respiratory Distress Syndrome
in premature newborns with lack of surfactant
treated with injection of lung surfactant (contains di-palmitoyl-PC)
Respiratory Distress Syndrome
in premature newborns with lack of surfactant
treated with injection of lung surfactant (contains di-palmitoyl-PC)
alcohol dehydrogenase variations
isozyme of aldehyde dehydrogenase with low Vmax -> slower ethanol metabolism -> bigger hangover sooner
alcohol dehydrogenase variations
isozyme of aldehyde dehydrogenase with low Vmax -> slower ethanol metabolism -> bigger hangover sooner
Wernicke-Korsakoff/Beriberi
B1
Wernicke-Korsakoff/Beriberi
B1
Rickets
Vitamin D
Rickets
Vitamin D
Bleeding Disorder
Vitamin K
Bleeding Disorder
Vitamin K
Megaloblastic Anemia
Vitamin B12 ro Folate
Megaloblastic Anemia
Vitamin B12 ro Folate
Vit A deficiency
vit A/carotenoid def; bad retina pigment, epithelials
night blind, dry skin
Vit A deficiency
vit A/carotenoid def; bad retina pigment, epithelials
night blind, dry skin
Cystinuria
bad C,K,R, ornithine transport, cystines in urine
kidney stones
Blood in Urine
Flank Pain
Cystinuria
bad C,K,R, ornithine transport, cystines in urine
kidney stones
Blood in Urine
Flank Pain
Hartnups
impaired transport of neutral amino acids on the apical brush border.
bad neutral transporter; low Trp, low NAD
impaired transport of neutral amino acids on the apical brush border.
bad neutral transporter; low Trp, low NAD
Hartnups
impaired transport of neutral amino acids on the apical brush border.
bad neutral transporter; low Trp, low NAD
impaired transport of neutral amino acids on the apical brush border.
bad neutral transporter; low Trp, low NAD
Pellagra
Niacin defficient
4D’s dementia, diarrhea, dermatitis, death
Pellagra
Niacin defficient
4D’s dementia, diarrhea, dermatitis, death
Alcaptonuria
no split of homogentisic acid in phenylalanine degrade
black urine, arthritis
Alcaptonuria
no split of homogentisic acid in phenylalanine degrade
black urine, arthritis
PKU (phenyl-ketonuria)
no Phenylalanine hydroxylase or THB (no F to Y) F and Phenylalanine-pyruvate builds up; block LNHA transport to CNS
retardation
PKU (phenyl-ketonuria)
no Phenylalanine hydroxylase or THB (no F to Y) F and Phenylalanine-pyruvate builds up; block LNHA transport to CNS
retardation
Tyrosinemia Type 1
cabbage odor, vomit, no thrive, liver fail, death
Tyrosinemia Type 1
cabbage odor, vomit, no thrive, liver fail, death
Tyrosinemia Type 2
neuro, eye/skin lesions
Tyrosinemia Type 2
neuro, eye/skin lesions
Homocystinuria
no Cystathione B Synth, Methionine Synth or Methylene THF reductase; inc smooth musc growth, dec endothelial growth
inc atherosclerosis and heart prob risk, retardation, osteoporosis, optic lens detach
Homocystinuria
no Cystathione B Synth, Methionine Synth or Methylene THF reductase; inc smooth musc growth, dec endothelial growth
inc atherosclerosis and heart prob risk, retardation, osteoporosis, optic lens detach
Folate Def. (B9)
low folate, no THF, no purine/pyrimidine synth
megaloblastic anemia, neural tube defect
Folate Def. (B9)
low folate, no THF, no purine/pyrimidine synth
megaloblastic anemia, neural tube defect
PNP deficiency
no Purine Nucleoside Pase, inc dGTP, no T cell
partial immuno deficiency, hypouricemia
PNP deficiency
no Purine Nucleoside Pase, inc dGTP, no T cell
partial immuno deficiency, hypouricemia
Porphyria
photophobic, skin damage, anemic, intermitant mental status changes
Porphyria
photophobic, skin damage, anemic, intermitant mental status changes
no Ornithine Transcarboxylase
hyperammonemia and orotic aciduria
no Ornithine Transcarboxylase
hyperammonemia and orotic aciduria
no N acetylglutamate
no active CPS-1
no urea cycle, inc ammonia, early death
no N acetylglutamate
no active CPS-1
no urea cycle, inc ammonia, early death