Amino Acid Disorders

Question 1

Deficiency of hepatic phenylalanine hydroxylase (PAH, which converts Phe Tyrosine with help of BH4 cofactor)

Answer 1

PKU

Question 2

Branched chain ketoacid dehydrogenase (BCKAD) deficiency

Answer 2

Maple Syrup Urine Disease

Question 3

Autosomal Recessive; fumarylacetoacetate hydrolase (FAH) deficiency

Answer 3

Tyrosinemia Type I

Question 4

Defect in CBS enzyme (which normally converts homocysteine cystathionine)

Answer 4

Homocysteinuria

Question 5

Newborn Screening in 2014

Answer 5

> 40 disorders screened for in Colorado
Minimum screen of ‘mandated disorders’ signed into federal law 2008
ex: PKU, MSUD, galactosemia, etc

Question 6

PKU Pathophysiology

Answer 6

Due to elevated total body phenylalanine

No direct pathologic effect on the liver

Question 7

Mental retardation and autistic behaviors
White matter hyperintensities (pseudoleukodystrophy)
Seizures

Answer 7

PKU

Question 8

therapy for PKU

Answer 8

Restrict dietary protein – Phe tolerance depends on residual enzyme activity

Supplement with phenylalanine-free medical beverage

Strict rx in prego mommy w/ pku

Question 9

Branched chain ketoacid dehydrogenase (BCKD) deficiency

Answer 9

Maple syrup urine disease

Autosomal recessive inheritance

Incidence 1/185,000 births

Question 10

Few abnormalities on routine lab tests

Maple syrup odor in urine (2-hydroxyisoleucine)

Answer 10

Severe neonatal form MSUD

Question 11

Late onset
Ataxia
Ketoacidotic coma sometimes with hypoglycemia
Amino acids and keto acids can be normal between attacks

Answer 11

Acute intermittent form MSUD

-with residual activity

Question 12

Hypotonia and developmental delay
Failure to thrive
Spastic paraplegia

Answer 12

Subacute chronic form MSUD

Question 13

Acute treatment of MSUD

Answer 13

• Eliminate dietary protein
• Supplement val and isoleucine
• Provide adequate non-protein energy source and amino acids that are not BCAA
• Avoid hypotonic fluids
• Treat cerebral edema if symptoms develop

Question 14

Fumarylacetoacetate hydrolase (FAH) deficiency
Autosomal recessive inheritance

Answer 14

Tyrosinemia type 1

Question 15

Early in infancy– Liver disease (hepatic failure or cholestatic jaundice or cirrhosis with renal tubulopathy)

Answer 15

Tyrosinemia type 1

Porphyria-like attack at any age (can be presenting sign)

Question 16

• Ketonuria, irritability, poor feeding
• Encephalopathy (lethargy, intermittent apnea, opisthotonus, stereotyped mvmts i.e. “fencing” or “bicycling”) progressing to coma and resp failure within 10 days

Answer 16

MSUD

Question 17

• -Developmental delay, autistic behaviors, seizures
• Musty odor to urine
• Decreased hair/skin pigmentation (from tyrosinase inhibition)
• Later in life: exaggerated DTRs tremor, para/hemiplegia

Answer 17

untreated PKU

Question 18

Late infancy: Rickets due to renal tubulopathy (Fanconi syndrome) with no obvious liver failure

Answer 18

Tyrosinemia type 1

Porphyria-like attack at any age (can be presenting sign)

Question 19

Tyrosinemia type 1: Treatment

Answer 19

Phe and Tyr restriction==> avoid excessive hypertyrosinemia (risk of keratitis,or Palmoplantar keratosis )

Liver transplant if hepatocellular carcinoma develops

Question 20

Eye abnormalities

Skeletal defects (Marfanoid habitus, osetoporosis, scoliosis; most common in B6 non-responsive)
*looks like marfan 

Developmental disability and neuropyschiatric s/s

Answer 20

Homocysteinuria

• B6 responsive: usually milder
• B6 non-responsive

Question 21

If untreated: repeated neurologic crises and death before age 10

Type 1: hepatorenal–> nitisinone
Type 2: oculocutaneous; tyrosine crystals in eyes, hyperkeratosis of palms and soles
Type 3: may be asymptomatic, some developmental delay

Answer 21

Tyrosinemia Type I

Autosomal Recessive; fumarylacetoacetate hydrolase (FAH) deficiency

Question 22

Cystathionine β-synthase deficiency

Autosomal recessive inheritance

Answer 22

Classical homocystinuria

Question 23

Homocystinuria treatment

Answer 23

Pyridoxine (B6) challenge
750 mg orally per day for one week

Restrict dietary protein
Supplemented with methionine free medical foods
Oral betaine
Consider supplementation with B12, folate, and/or cysteine

Question 24

50% of CBS (Cystathionine β-synthase) mutations are __________ responsive

Answer 24

pyridoxine (vitamin B6)

Question 25

Elevated methionine and homocysteine

Low CBS activity

Answer 25

Homocysteinuria

Question 26

Serum: high succinylacetone, Tyr, Met, and Phe
Urine: high succinylacetone, Tyr metabolites, ALA

Answer 26

Tyrosinemia Type I

Question 27

Elevated serum BCAAs (leu, isoleu, val)
Ketouria
Low BCKAD activity (mutation detected on molecular analysis

Answer 27

Maple Syrup Urine Disease

Question 28

Guthrie card bacterial inhibition assay (BIA)
Fluorometric analysis (fewer false positives than BIA)
Tandem mass spectrometry (can diagnose many disorders at once, but more expensive)

*Serum Phe >120 umol/L

Answer 28

Phenylketonuria

PKU