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MCG > Inborn Errors of Metabolism > Flashcards

Inborn Errors of Metabolism Flashcards

1
Q

defn of inborn errors of metabolism

A

an inherited defect in 1 of the critical components of a basic metabolic pathway resulting in clinical disease

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2
Q

what occurs to cause an IEM?

A
  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
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3
Q

principles of treatment of IEM?

A
  1. restrict substrate
  2. provide cofactors
  3. provide product
  4. replace enzyme
  5. provide alternate route of elimination
  6. treat secondary effects
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4
Q

types of IEM?

A

disorders of:

protein metabolism

carb metabolism

fat metabolism

lysosomal metabolism

mitochondrial metabolism

vitamins & cofactors

purine & pyrimidine metabolism

peroxisomal metabolism

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5
Q

where can IEMS cause effect?

A

protein

carbs

fats

lysosomal storage

mitocohndrial disease

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6
Q

what is PKU example of?

A

amino acid metabolism inborn error

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7
Q

what occurs to cause PKU?

A

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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8
Q

treatment of PKU?

A
  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
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9
Q

what is typical diet for a pku patient?

A
  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

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10
Q

how long is PKU treated for

A

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

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11
Q

what is maternal PKU? treatment?

A

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

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12
Q

what happens if there’s a cofactor defect, i.e in PKU?

A

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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13
Q

organic acidemia is

A

inborn error of aa metabolism in which pathway intermediate that’s elevated is a non-amino organic acid

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14
Q

what type of IEM is maple syrup urine disease

A

aminoacidopathy

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15
Q

aminoacidopathy vs organic acidemia?

A

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)

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16
Q

cause of propionic acidemia?

A

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

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17
Q

treatment of propionic acidemia?

A
  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
18
Q

long term outcomes of propionic acidemia

A

mental retardation

recurrent metabolic decompensation

end organ failure

19
Q

OTC deficiency is what kind of IEM

A

urea cycle defect, a protein IEM

20
Q

what happens in OTC deficiency

A

cannot metabolize ornithine -> citrulline

extremely high ammonia levels

21
Q

treatment of OTC?

A
  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
22
Q

galactosemia is an ex of what

A

disorder of galactose metabolism, carbohydrate IEM

23
Q

what most commonly causes galactosemia

A

deficiency in Gal-1-P uridylyltransferase

cannot make galactose-1-P -> glucose-1-P

24
Q

symptoms of galactosemia

A

very sick

25
Q

treatment of galactosemia?

A
26
Q

what does a GSD cause?

A

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

thus get build up of G6P in liver

27
Q

how to treat GSD 1a?

A

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

treat gout

28
Q

long term outcomes of GSD 1 a?

A
29
Q

function of b-oxidation

A

make energy once glycogen is depleted - break down fats

30
Q

MCAD ?

A

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

31
Q

treatment of MCAD ?

A
  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
32
Q

gaucher disease cause?

A

spingolipid metabolism issue

signs/symptoms are consequence of accumulation of storage material -> massive liver, spleen filled w/ sphingolipid due to gaucher disease; blood abnormalities

33
Q

characteristics of gaucher disease

A
34
Q

diff types of gaucher disease?

A
35
Q

treatment of gaucher disease?

A

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

36
Q

what are resp chain defects caused by

A

mitochondrial dna disease which encodes components of the chain

37
Q

what is concept of heteroplasmy and threshold effect

A

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

38
Q

what is replicative segregation

A

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

39
Q

cause of mito diseases?

A

can be caused by mitochondrial dna mutations, maternal inheritance, and/or nuclear dna mutations, autosomaml recessive inheritance

40
Q

where do mito diseases most commonly manifest

A

high energy organs

may have 2 symptoms in 2 diff organs - ie deafness and diabetes together

41
Q

examples of “classical” mito disease?

A

MELAS, NARP, MERRF, LEIGH’s disease

MCG (77 decks)

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