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Flashcards in Inborn Errors of Metabolism Deck (41):

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? 

disorders of: 

protein metabolism 

carb metabolism 

fat metabolism 

lysosomal metabolism 

mitochondrial metabolism 

vitamins & cofactors 

purine & pyrimidine metabolism 

peroxisomal metabolism 


where can IEMS cause effect? 




lysosomal storage 

mitocohndrial disease


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 

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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 


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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

mental retardation 

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


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symptoms of galactosemia 

very sick 

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treatment of galactosemia? 

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what does a GSD cause?

deficiency in enzyme that converts glucose-6-p -> glucose 

thus get build up of G6P in liver 


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how to treat GSD 1a? 

avoid fasting - feed all the time - so don't attemp gluconeogenesis 

treat gout 


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long term outcomes of GSD 1 a? 

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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 

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diff types of gaucher disease? 

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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 


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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 


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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? 



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