defn of inborn errors of metabolism
an inherited defect in 1 of the critical components of a basic metabolic pathway resulting in clinical disease
what occurs to cause an IEM?
1. substrate is overactive
2. product is not produced enough or at all
3. enzyme or cofactor is deficient or inactive
4. substrate forms secondary abnormal metabolites which can also result in clinical symptoms
5. substrate can cause secondary inhibition of other pathways
principles of treatment of IEM?
1. restrict substrate
2. provide cofactors
3. provide product
4. replace enzyme
5. provide alternate route of elimination
6. treat secondary effects
types of IEM?
vitamins & cofactors
purine & pyrimidine metabolism
where can IEMS cause effect?
what is PKU example of?
amino acid metabolism inborn error
what occurs to cause PKU?
if the enzyme phenylalanine hydroxylase or the cofactor THB is deficient, then phenylalanine does not -> tyrosine
tyrosine is thus not metabolized -> dopamine -> melanin
treatment of PKU?
1. restrict Phe in diet, as it's an essential aa
2. provide cofactors - use Kuvan, which replenishes THB, stabilizes enzyme, enhances its activity, modifies phenotype
3. provide Tyrosine supplment to diet
4. enzyme substitution therapy to imitate action of Phenylalanine hydroxylase w/ alternate enzyme, phenylalanine ammonium lyase
what is typical diet for a pku patient?
1. phenylalanine-free formula which contains all other aa except phenylalanine
2. 3g natural protein
3. unlimited protein-free fruits and veggies, snacks
4. forbid all high protein foods - egg, milk, meat
how long is PKU treated for
used to be, only first 6 yrs of life, monitored Phe amount
however poor control in later years -> neurocognitive difficulties
thus monitor longer now b/c unknown what neuro consequences of high blood Phe over decades is
what is maternal PKU? treatment?
if mom has PKU, impacts baby, as Phe is a teratogen
baby can have birth defects - microcephaly, congenital heart disease, craniofacial abnormalities, small for gestational age
fetus will certainly be a carrier, but odds of mom finding a carrier partner is rare so only problem here's the exposed fetus, will not have PKU itself
what happens if there's a cofactor defect, i.e in PKU?
will impact all metabolic processes that use that cofactor
so not only Phenylalanine -> Tyr is messed up, but also get decreased dopamine and serotonin because other metabolic processes that use THB are impacted
this is malignant PKU - all 3 pathways are affected
treat w/ cofactor + deficient neurotransmitters
organic acidemia is
inborn error of aa metabolism in which pathway intermediate that's elevated is a non-amino organic acid
what type of IEM is maple syrup urine disease
aminoacidopathy vs organic acidemia?
organic acidemia occurs when aa has been converted to an organic acid, later in the chain, and organic acid is elevated in level (ie accumulation of methyl malonyl CoA)
amino acidopathy is an elevated amt of the aa itself (ie PKU, have accumulation of phenylalanine)
cause of propionic acidemia?
disorder of propionyl CoA carboxylase, which catalyzes propionyl CoA -> D-methylmalonyl CoA
caused by aa issue in VOMIT: Valine, OCFA, Met, Isoleucine, Threonine, Cholesterol, Thymine, Uracil
treatment of propionic acidemia?
1. restrict substrate, VOMIT aa - w/ formula w/o VOMIT aa; use anibiotics to decrease gut bacteria
2. provide cofactor(s), biotin
3. alternate pathways of elimination by providing extra carnitine so eliminate propionic acid in the urine
4. treat secondary effects - high ammonia so detoxify it; add bicarb to neutralize acid in the pH of blood
long term outcomes of propionic acidemia
recurrent metabolic decompensation
end organ failure
OTC deficiency is what kind of IEM
urea cycle defect, a protein IEM
what happens in OTC deficiency
cannot metabolize ornithine -> citrulline
extremely high ammonia levels
treatment of OTC?
1. restrict all proteins! as this is the subtrate for urea cycle. give formula w/ only essential amino acids
2. provide product - citrulline. also arginine, b/c that isn't made if no urea cycle is occuring
3. replace the enzyme - here, liver transplant
4. alternate pathway of elimination - dialysis to remove ammonia, or ammonia scavenging medication
galactosemia is an ex of what
disorder of galactose metabolism, carbohydrate IEM
what most commonly causes galactosemia
deficiency in Gal-1-P uridylyltransferase
cannot make galactose-1-P -> glucose-1-P
symptoms of galactosemia
treatment of galactosemia?
what does a GSD cause?
deficiency in enzyme that converts glucose-6-p -> glucose
thus get build up of G6P in liver
how to treat GSD 1a?
avoid fasting - feed all the time - so don't attemp gluconeogenesis
long term outcomes of GSD 1 a?
function of b-oxidation
make energy once glycogen is depleted - break down fats
medium chain acyl CoA dehydrogenase deficiency
most common fatty acid oxidation defect
1/5 patietns have sudden death
if this pathway's broken, don't make ketones; if fasting and no ketone produced, could be a fatty acid oxidation issue b/c not making acetyl CoA -> acetoacetate -> B-OH-butarate
treatment of MCAD ?
1. restruct substarte, avoid fasting; lower fat higher carb diet
2. alternate pathways of elimination - add carnitine to bind to and elminiate fatty acid intermediates
3. treat secondary effects - hypoglycemia, hyperammonemia, liver failure
gaucher disease cause?
spingolipid metabolism issue
signs/symptoms are consequence of accumulation of storage material -> massive liver, spleen filled w/ sphingolipid due to gaucher disease; blood abnormalities
characteristics of gaucher disease
diff types of gaucher disease?
treatment of gaucher disease?
cannot restrict sphingolipids, so treat by treating w/ the enzyme - do enzyme replacement threapy
or inhibit sphingolipids by inhibiting many steps above in metabolic pathway
what are resp chain defects caused by
mitochondrial dna disease which encodes components of the chain
what is concept of heteroplasmy and threshold effect
each of your cells in the mito has thousands of kinds of mitochondria, some w/ mutations and others without
someone w/ a mito disease will have some mito w/ mutations and some without, and phenotype expression will depend on how many of those mito have defects
expression of disease phenotype differs
what is replicative segregation
random allotment of daughter cells during cellular replication
mitochondria populations may change in the same tissue over time w/ cellular divisions
get drifting of mito populations, some cells improve, some worsen in daughter cells
very hard to predict what might happen because things can change as cells replicate, even with the same person
cause of mito diseases?
can be caused by mitochondrial dna mutations, maternal inheritance, and/or nuclear dna mutations, autosomaml recessive inheritance
where do mito diseases most commonly manifest
high energy organs
may have 2 symptoms in 2 diff organs - ie deafness and diabetes together
examples of "classical" mito disease?
MELAS, NARP, MERRF, LEIGH's disease