Inborn Errors: Urea Cycle Defects

Question 1

Old phenotype of PKU

Answer 1

1. ID plateauing during the first year of life. Irreversible after this
2. Blond
3. Blue eyes
4. Musty odor

Question 2

PKU

Answer 2

1. Deficiency of PAH (Requires BH4 as cofactor)
2. Removal of Phe allows it to diminish and halt further degradation of mental status (more normal mental status)
3. Newborn screening of bacterial inhibition assay to screen for PKU (Guthrie)

Question 3

Which criteria are used to determine if newborn screening is warranted for disease?

Answer 3

Wilson-Junger Criteria

Question 4

How do you treat Krabbe Disease?

Answer 4

Umbilical-Cord Blood Transplant…. very high mortality

Question 5

Minimum mandatory screen

Answer 5

1. Aminoacidopathies
2. Organic acidemias
3. Dx of carbohydrate metabolism
4. FA oxidation disorders
5. Urea cycle disorders
6. Some non-metabolic disorders

Question 6

Maternal PKU

Answer 6

Leads to the following in the child:

1. microcephaly
2. cardiac lesion
3. mental retardation

Question 7

Tyrosine is a precursor of

Answer 7

1. Dopamine and L-DOPA

2. Melanin

Question 8

** Disease phenotypes may result from: ***

Answer 8

1. accumulation of a metabolite (precursor toxicity)
2. overflow to alternative products (potentially toxic)
3. Reduced formation of desired metabolite (product deficiency)
4. A combo of all of the above

Question 9

PKU incidence etc

Answer 9

1. AR inheritance
2. 1:16,000 live births in US
3. Rare variants of biopterin synthesis or recycling are also seen

Question 10

Hyperphenylalaninemia

Answer 10

Severe: Plasma Phe > 1200 microM
Moderate: 600-1200
Mild:

Question 11

Long term therapy for PKU

Answer 11

• restrict Phe but not eliminate it
• provide adequate calories, protein, vit and minerals
• maintain normal growth and development
  “Tx for life”
• new form of biopterin available
• LNAA to compete for Phe
• Liver cell transplant?

Question 12

Metabolic encephalopathies - management

Answer 12

1. Remove offending agent (NPO, STOP cataboism, dialysis)
2. Clinical phenotypes depend upon enzyme activity - lots of variables
3. Vitamins and nutrition

Question 13

Are ketones normal in newborns?

Answer 13

Nope!

Question 14

MSUD and plasma AA profile

Answer 14

1. Massive Leu
2. Elevated Val
3. Elevated Ile
4. • DNPH test

Question 15

MSUD

Answer 15

1. Defects in branched chain ketoacid dehydrogenase
2. AR Inheritance; P.Y391N in E1alpha protein
3. Penn amish and mennonite population

Question 16

3 presentations of MSUD

Answer 16

1. Severe neonatal form
   - few abnormalities on lab tests
   - maple syrup odor in urine
2. Acute intermittent form
   - late onset
   - ataxia
   - ketoacidotic coma with normal AA and keto acids between attacks
3. Subacute chronic form
   - hypotonia and dev delay
   - failure to thrive
   - spastic paraplegia

Question 17

Acute Tx of MSUD

Answer 17

1. Eliminate dietary protein intake
2. Supplement Val and Ile
3. Avoid hypotonic fluids
4. Treat cerebral edema

Question 18

Chronic Tx of MSUD

Answer 18

• protein restricted diet
• Leucine intake about 400-600 mg then 600-800 after adolescence
• supplement Val and Ile
• Thiamine supplementation in E2 deficiency