Inborn Errors of Metabolism - Proteins Flashcards
Two main ways to test for PKU?
Guthrie heel blood spot
Tandem mass spec
Bayesian reasoning and pretest probability
Even with a very good test, post-test probability is still low if the pre-test probability is low
PKU due to
Phenylalanine hydroxylase deficiency
AR
Rare cause of PKU
Disorder of Tetrahydrobiopterin (BH4) cofactor
4 main manifestations of untreated PKU
Intellectual disability
Hypopigmentation
Eczema
Hypomyelination on brain MRI
Treatment of PKU
Dietary restriction of protein
supplement all non-Phe aa
life long
IF residual enzymatic acitivity can give Sapropterin - suuplemental BH4 cofactor
PKU and IQ
IQ is directly related to the age of initiation of therapy and the Phe levels achieved in childhood
Sapropterin
Treatment (BH4) for PKU with residual enzymatic activity
Maternal PKU
Phe is teratogenic
Should limit Phe well before conception and through gestation
Infants born to mother with unctontrolled PKU have growth restriction, microcephaly, IQ, and heart malformations
MSUD cause
deficiency in branched chain ketoacid dehydrogenase complex (BCKAD)
MOST manifestations are due to leucine accumulating in the brain
MSUD neonatal presentation
Irritable and poor feeding at 48 hours
Lethargy, opisthotonus, apnea
Cerebral edema, encephalopathy
REVERSIBLE with treatmetn
MSUD diagnostic findings
elevation of luecine
presence of allo-isoleucine
urine ketones in neonate
Low BCKAD activity
Can genetically sequence for 4 common genes
MSUD unique deficiency
DLD
assess lactate and alpha-ketoglutarate levels to ensure the child does not have combined enzyme deficiencies (DLD)
MSUD acute decompensation treatment
ABCD
remove offending agent (Dietary protein) supplement deficiencies
provide calories for anabolism to prevent mobilization of endogenous proteins (dextrose IVF/IV)
Consider dialysis in some
Slowly reintroduce proteins
MSUD chronic management
Trial thiamine supplement
Limit dietary protein
Leucine free formula
monitor isoluecine and valine levels
consider liver transplant (because they can give theirs)
Leucine is likely teratogen
Tyrosinemia Type I (hepatorenal type)
characteristic presentation?
acute liver failure in infancy
later hepatocellular carcinoma
hyperbilirubinemia / jaundice / ascites / all those things that go along with having a fucked up liver
rickets
acute neurological crisis with abdominal pain and neuropathy due to secondary porphyria
Tyrosinemia type I
cause
Results from fumarylacetoacetate hydrolase deficiency
Tyrosinemia type I diagnostic metabolite
succinylacetone in urine
Tyrosinemia type I management
Use medication (nitisinone - NTBC) to induce a different (milder) disease (Tyrosinemia type III) - Buildup of tyrosine but not subsequent hepatotoxic byproducts
monitor Tyr and Phe levels - tyrosine crystals can form on cornea :(
liver transplant may be necessary - monitor for HCC
Tyrosinemia type II (oculo-cutaneous type)
Results from 4-hydroxyphenypyruvic acid dehydrogenase deficiency (earlier)
Results in palmoplantar hyperkeratosis and keratitis
causes much higher Tyr
no acute decomp
manage by Tyr and Phe limitation and supplement other aa
Homocystinuria
Deficiency in cystathionine beta synthase
elevated homocysteine is toxic to skeleton - eye - vasculature
Homocystinuria - manifestation if untreated
lens dislocation / scoliosis / pectur carinatum / mild DD - marphenoid
elevated thrombotic risk
Homocystinuria - sequelae even if treated?
osteoperosis and vascular risk
Homocystinuria treatment?
restrict protein / methionine
folate / vitamin B12 supplementation
Pyridoxine (B6) trial
Betaine - alternative breakdown product
Diminish CV risk - avoid smoking and maybe anticoagulate
Acute consequences of hyperammonemia
encephalopathy / seizures / ataxia / visual loss / hallucinations / mania
vomiting / anorexia
in neonates temperature instability and hyperventilation
chronic consequences of hyperammonemia
DD
Nausea / FTT / protein avoidance
magrainse / anxiety / depression / disinhibition
hepatomegaly/ elevated liver enzymes
Triggers of hyperammonemic episode?
illness, fever, vomiting, fasting, surgery
postpardum, menarche
intense exercise
dietary protein load
medications - valproate / peg asparaginase
UTI
MOST common urea cycle disorder
OTC deficiency
ornithine transcarbamylase deficiency
X linked
Is there a newborn screen for OTC?
NO
OTC diagnosis?
orotic acid
low citrulline
high glutamine
OTC treatment?
ammonia scavengers
- sodium phenylacetate
- sodium benzoate - cheaper
Management of OTC
LOW protein diet (lowest of all IEMs) supplemnet citrulline or arginine ammonia scavengers close nut monitor dialysis liver tranplant future gene therapy
