Inborn Errors

Question 1

phenylalanine hydroxylase deficiency
Autosomal Recessive
Phenylalanine cannot get converted to tyrosine

Answer 1

PKU

Question 2

Intellectual Disability
Hypopigmentation
Eczema
Hypomyelination on brain MR

Answer 2

PKU

Question 3

PKU Treatment

Answer 3

Restrict protein
Sapropterin (BH4 cofactor)
Supplement non-PHE amino acids

Question 4

Deficiency of the branched chain ketoacid dehydrogenase complex
4 different mutations that are causative
Most manifestations are due to leucine accumulation in the brain

Answer 4

Maple Syrup Urine Disease

Question 5

Irritability and poor feeding at 48 hours
Lethargy, opisthotonus, apnea
Cerebral edema, encephalopathy
Reversible with treatment

Answer 5

Severe Neonatal presentation of Maple Syrup Urine Disease

Question 6

Diagnosis of MSUD

Answer 6

Elevation of leucine
Presence of allo-isoleucine
Presence of urine ketones in a neonate
Assessment of lactate, alpha-ketoglutarate for combined enzyme deficiencies (DLD)
Branched chain ketoacid dehydrogenase complex enzyme activity

Question 7

Treatment of MSUD

Answer 7

Trial thiamine supplementation (specific genotypes)
Limit dietary protein
Leucine-free formula, regular serum leucine levels
Close monitoring of nutritional status, especially isoleucine and valine
Consider liver transplant
Liver can be given to another person on the transplant list for a different indication
Leucine is likely a teratogen, though data are sparse in comparison to PKU

Question 8

Fumaryl Acetoacetate Hydrolase

Answer 8

Tyrosinemia type 1 (hepatorenal tyrosinemia)

Question 9

Typically presents as acute liver failure in infancy, later hepatocellular carcinoma
Hyperbilirubinemia, jaundice, ascites, coagulopathy, hepatomegaly, rickets
Acute neurologic crisis with abd pain and neuropathy due to secondary porphyria

Answer 9

Tyrosinemia type 1 (hepatorenal tyrosinemia)

Question 10

Diagnosis of Tyrosinemia type 1 (hepatorenal tyrosinemia

Answer 10

succinylacetone in urine

Question 11

Treatment of Tyrosinemia type 1 (hepatorenal tyrosinemia

Answer 11

An unusual treatment paradigm - use medication (NTBC) to induce a different (milder) metabolic disease (tyrosinemia III)

Question 12

Considerations with NTBC therapy for Tyrosinemia type 1

Answer 12

Still need monitoring for hepatocellular carcinoma (HCC)

On NTBC need dietary therapy (avoid phenylalanine and tyrosine) to prevent oculo-cutaneous manifestations

Question 13

Results from 4-OH phenylpyruvic acid dehydrogenase deficiency
Causes much higher tyrosine elevations

Answer 13

Tyrosinemia Type 2, AKA oculocutaneous tyrosinemia

Question 14

Results in palmoplantar hyperkeratosis and keratitis

Answer 14

Tyrosinemia Type 2, AKA oculocutaneous tyrosinemia

Question 15

cystathionine beta synthase deficiency

Answer 15

Homocystinuria

Question 16

toxic effect on several tissues - skeleton, eye, vasculature

Untreated patients will have lens dislocation, scoliosis, pectus carinatum, mild developmental delays

Answer 16

Homocystinuria

Question 17

Similar to Marfans

Answer 17

Homocystinuria

Question 18

Treatment of homcystinuria

Answer 18

Mainstay of treatment is methionine restricted diet and betaine
B12 and folate supplementation are also often needed
Patients are often on coumadin or other anticoagulants

Question 19

Encephalopathy, seizures, ataxia, visual loss, hallucinations, mania
Vomiting and loss of appetite
In neonates: temperature instability, hyperventilation

Answer 19

Acute Hyperammonemia

Question 20

Developmental delay
Nausea, failure to thrive, protein avoidance
Migraines
Anxiety, depression, disinhibition
Hepatomegaly, elevated liver enzymes

Answer 20

Chronic Hyperammonemia

Question 21

Triggers for Hyperammonemia

Answer 21

Illness, fever, vomiting, fasting, surgery
Postpartum period, menarche
Intense exercise
Dietary protein load
Medications - valproate, peg asparaginase
UTI

Question 22

Most common deficiency in hyperammonemia

Answer 22

Ornithine transcarbamylase deficiency- gene only

X-linked

Question 23

Diagnosis of Ornithine transcarbamylase deficiency

Answer 23

Diagnostic metabolite is orotic acid; also with low citrulline, high glutamine

Question 24

Treatment of OTC

Answer 24

Very low protein diet (lowest of all IEMs)
Supplement citrulline or arginine
Ammonia scavenging medications (sodium phenylacetate and sodium benzoate)
Close nutritional monitoring
Aggressive support during illness
Dialysis
Liver transplantation