Amino Acid Disorders

Question 1

PKU (cause/genetics)

Answer 1

deficiency of hepatic PAH (converts Phe to Tyr with BH4 cofactor)
AR

Question 2

PKU (leads to …)

Answer 2

1) classic PKU (complete or near complete PAH defic)
2) Non-PKU HPU (hyperphenylalaninemia) Much less severe cognitive effects
3) Variant PKU

Question 3

PKU: Phe levels should be …

… and why?

Answer 3

in Mom: 120-360 umol/L prior to conception and during preg

Phe is a TERATOGEN - elevated levels can cause birth defects

Question 4

PKU pres/phenotypes

Answer 4

Rare to pres no as caught by newborn screen
Severe: >1200
Moderate: 600-1200
Mild/benign:

Question 5

PKU: labs/diagnx

Answer 5

Newborn screen (24-72 hours after birth):
1) GUTHRIE CARD BIA
2) Flurometric analysis (fewer false positives)
3) Tandem mass spectormetry (more expensive but can diagnx many dz at once)
Looking for serum Phe >120 umol/L

Question 6

PKU treat (classic)

Answer 6

Classic: RESTRICTED NATURAL PROTEIN diet for life (Phe-free formula)
PHE INTAKE 240-350 mg/day to maintain 120-360 mmol.L serum Phe
Adjuvant 6R-BH

Question 7

PKU treat (non-PKU HPA, and women with PAH defic)

Answer 7

non-PKU HPA: treatment maybe not nec if Phe

Question 8

MSUD (genetics)

And increased risk for?

Answer 8

AR, BCKAD defic (branched chain ketoacid dehydrogenase)
INCREASED RISK for ADHD, depression, anxiety
BCKDHA E1a: MSUD 1A
BCKDHB E1b: MSUD 1B
DBT (E2): MSUD 2

Question 9

MSUD pres

Answer 9

Maple syrup odor in cerumen at 12-24 hrs
KETONURIA, irritiability, poor feeding
ENCEPHALOPATHY (lethargy, apnea, fencing and bicycling odd movements –>coma and resp failure (in 10 days)

Question 10

MSUD diagnx

Answer 10

Elveated srum BCAA (leu, isoleu, val)
Ketonuria
Low BCKAD activity

Question 11

MSUD treat

Answer 11

Eliminate dietary protein with judicious isoleu an val (400-600)
Poss dialysis to remove BCAA but insufficient
Liver transplant!!

Question 12

Tyrosinemia (genetics and types)

Answer 12

AR, FAH defic (fumarylacetoacetate hydrolase)
Type 1: hepatorenal –> pitisinone
Type 2: oculocutaneous: tyr crystals in eyes, keratosis on palms and soles
Type 3: may be asymptomatic, some dev delay

Question 13

Tyrosinemia (pres)

Answer 13

Can be:
1) 1-6 mos
2) Later in 1st year with liver and renal dysfxn WITH FAILURE TO GROW AND RICKETS
Type 2: risk of keratitis
Type 1: HEPATOCELLULAR CARCINMOA
If untreated: neuro crises then death before 10 yo

Question 14

Tyrosinemia Diagnx (serum and urine)

Answer 14

Decreased FAH activity
Serum: high succinylacetone, Tyr, Met, Phe
Urine: high succinylacetine, Tyr metabolites, ALA

Question 15

Tyrosinemia Treat

Answer 15

Nitisinone, NTBC (decreases succinylacetone), Phe and Tyr dietary restriction
Liver transplant if carcinoma

Question 16

Homocysteinuria (genetics/phenotypes)

Answer 16

AR, variable expressivity
Defect in CBS enzyme (that converts homocysteine –> cystathionine)
2 phenotypes: B6 responsive (milder) and non-responsive

Question 17

Homocysteinuria (pres)

Answer 17

Skeletal defects
Myopia or ectopio lentis
Recurrent thromboembolism (major cause of early death)
Dev disability and neuropsych symptoms

Question 18

Homocysteinuria (diagnx/labs)

Answer 18

Elev methionine and homocysteine
Low CBS activity
Often MISSED on newborn screen

Question 19

Homocysteinuria treat

Answer 19

B6 aka pyroxidine (if responsive)
Betaine, folate, B12 supplement
PROTEIN RESTRICTED DIET (serum HC

Question 20

Cornerstone of tx

Answer 20

dietary therapy +/- pharmacologic doses of enzyme cofactors
Some amount of the a.a. is necessary for normal growth/development
AND remember: not all inborn errors and reliably detected on the newborn screen