Inborn Errors of Metabolism - Proteins

Question 1

Two main ways to test for PKU?

Answer 1

Guthrie heel blood spot

Tandem mass spec

Question 2

Bayesian reasoning and pretest probability

Answer 2

Even with a very good test, post-test probability is still low if the pre-test probability is low

Question 3

PKU due to

Answer 3

Phenylalanine hydroxylase deficiency

AR

Question 4

Rare cause of PKU

Answer 4

Disorder of Tetrahydrobiopterin (BH4) cofactor

Question 5

4 main manifestations of untreated PKU

Answer 5

Intellectual disability
Hypopigmentation
Eczema
Hypomyelination on brain MRI

Question 6

Treatment of PKU

Answer 6

Dietary restriction of protein

supplement all non-Phe aa

life long

IF residual enzymatic acitivity can give Sapropterin - suuplemental BH4 cofactor

Question 7

PKU and IQ

Answer 7

IQ is directly related to the age of initiation of therapy and the Phe levels achieved in childhood

Question 8

Sapropterin

Answer 8

Treatment (BH4) for PKU with residual enzymatic activity

Question 9

Maternal PKU

Answer 9

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

Question 10

MSUD cause

Answer 10

deficiency in branched chain ketoacid dehydrogenase complex (BCKAD)

MOST manifestations are due to leucine accumulating in the brain

Question 11

MSUD neonatal presentation

Answer 11

Irritable and poor feeding at 48 hours

Lethargy, opisthotonus, apnea

Cerebral edema, encephalopathy

REVERSIBLE with treatmetn

Question 12

MSUD diagnostic findings

Answer 12

elevation of luecine

presence of allo-isoleucine

urine ketones in neonate

Low BCKAD activity

Can genetically sequence for 4 common genes

Question 13

MSUD unique deficiency

Answer 13

DLD

assess lactate and alpha-ketoglutarate levels to ensure the child does not have combined enzyme deficiencies (DLD)

Question 14

MSUD acute decompensation treatment

Answer 14

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

Question 15

MSUD chronic management

Answer 15

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

Question 16

Tyrosinemia Type I (hepatorenal type)

characteristic presentation?

Answer 16

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

Question 17

Tyrosinemia type I

cause

Answer 17

Results from fumarylacetoacetate hydrolase deficiency

Question 18

Tyrosinemia type I diagnostic metabolite

Answer 18

succinylacetone in urine

Question 19

Tyrosinemia type I management

Answer 19

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

Question 20

Tyrosinemia type II (oculo-cutaneous type)

Answer 20

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

Question 21

Homocystinuria

Answer 21

Deficiency in cystathionine beta synthase

elevated homocysteine is toxic to skeleton - eye - vasculature

Question 22

Homocystinuria - manifestation if untreated

Answer 22

lens dislocation / scoliosis / pectur carinatum / mild DD - marphenoid

elevated thrombotic risk

Question 23

Homocystinuria - sequelae even if treated?

Answer 23

osteoperosis and vascular risk

Question 24

Homocystinuria treatment?

Answer 24

restrict protein / methionine

folate / vitamin B12 supplementation

Pyridoxine (B6) trial

Betaine - alternative breakdown product

Diminish CV risk - avoid smoking and maybe anticoagulate

Question 25

Acute consequences of hyperammonemia

Answer 25

encephalopathy / seizures / ataxia / visual loss / hallucinations / mania

vomiting / anorexia

in neonates temperature instability and hyperventilation

Question 26

chronic consequences of hyperammonemia

Answer 26

DD
Nausea / FTT / protein avoidance
magrainse / anxiety / depression / disinhibition
hepatomegaly/ elevated liver enzymes

Question 27

Triggers of hyperammonemic episode?

Answer 27

illness, fever, vomiting, fasting, surgery

postpardum, menarche

intense exercise

dietary protein load

medications - valproate / peg asparaginase

UTI

Question 28

MOST common urea cycle disorder

Answer 28

OTC deficiency
ornithine transcarbamylase deficiency
X linked

Question 29

Is there a newborn screen for OTC?

Answer 29

NO

Question 30

OTC diagnosis?

Answer 30

orotic acid
low citrulline
high glutamine

Question 31

OTC treatment?

Answer 31

ammonia scavengers

• sodium phenylacetate
• sodium benzoate - cheaper

Question 32

Management of OTC

Answer 32

LOW protein diet (lowest of all IEMs)
supplemnet citrulline or arginine
ammonia scavengers 
close nut monitor
dialysis
liver tranplant 
future gene therapy