Amino Acid Disorders

Question 1

Alkaptonuria: Genetics

Answer 1

Inheritance: Autosomal recessive
Amino acid pathway: Tyrosine breakdown
Deficient enzyme: Homogentisate 1,2-dioxygenase (leads to buildup of homogentisic acid)

Labs:
•24-hour urinalysis for homogentisic acid elevation

Question 2

Alkaptonuria: Features and Treatment

Answer 2

Major features:
•Black urine
•Bone/cartilage necrosis
•Height loss secondary to spinal changes
•Aortic/mitral valve calcification

Treatment:
•Dietary Phe and Tyr restriction
•Nitisone can inhibit enzyme responsible for buildup of homogentisic acid

Question 3

Homocystinuria: Genetics

Answer 3

Inheritance: Autosomal recessive
Amino acid pathway: Methionine synthesis
Deficient enzyme: Cystathionine Beta-Synthase
•Catalyzes the first step in the breakdown of homocysteine into methionine

Labs: Plasma amino acids, also on NBS

Question 4

Homocystinuria: Features and Treatment

Answer 4

•Marfanoid habitus/features (including pectus deformities and ectopia lentis)
•Distinguishable from Marfan by:
oPresence of intellectual disability (not seen in Marfan)
oThromboembolitic events (strokes) (Vessel/aortic dilation seen in Marfan)
oJoint contractures (Joint laxity seen in Marfan)
•Hypopigmentation
•Seizures
•Risk for MI + MVP
•Psychiatric problems

Treatment:
•Vitamin B6 (pyridoxine) is effective for 50% of patients
•Protein restricted diet
•Betaine provides alternate pathway for breakdown of homocysteine
oRisk for excess methionine with this treatment
•If residual enzyme activity is present, folate and vitamin B12 can optimize enzyme activity

Question 5

Maple Syrup Urine Disease (MSUD)

Answer 5

Inheritance: Autosomal recessive
Amino Acid Pathway: Branched-chain amino acids (isoleucine, leucine, valine)
•“I Love Vermont’s Maple Syrup”
Deficient enzyme: Branched-chain alpha-ketoacid dehydrogenase complex

Labs:
•Plasma Amino Acids
Also on NBS (isoleucine/leucine ratios)

Question 6

Maple Syrup Urine Disease (MSUD): Features

Answer 6

Major features:
•Urine smells like maple syrup
•Developmental delay
•Poor feeding
•Lethargy
•Opisthotonic posturing
•Respiratory failure
•Encephalopathy with illness

Treatment:
•AVOID LEUCINE
•Dietary leucine restriction/high calorie leucine free formulas

Question 7

Phenylketonuria (PKU)

Answer 7

Inheritance: Autosomal recessive
Amino acid pathway: Phenylalanine  Tyrosine
•Tyrosine is involved in pigmentation, inability to convert Phe to Tyr results in the characteristic pale hair/skin of individuals with PKU
Deficient enzyme: Phenylalanine hydroxylase

Labs:
•Plasma amino acids
•Mass spec on NBS
•Biopterin (BH4) is a cofactor for phe hydroxylase – R/O biopterin deficiency

Question 8

Phenylketonuria (PKU): Features (Untreated)

Answer 8

Major features (untreated):
•Severe intellectual disability
•Microcephaly
•“Musty odor”
•Seizures 
•Behavioral problems
•Exaggerated neurologic reflexes

Question 9

Phenylketonuria (PKU): Features (Treated)

Answer 9

Major features (treated):
•Dependent on how well treatment is maintained
•Psychiatric problems
•Learning difficulties/lower IQ
Treatment:
•Dietary Phe restriction
•Special low Phe foods/formulas
•If an individual has residual enzyme activity, biopterin supplementation may help improve enzyme activity

Question 10

Maternal PKU:

Answer 10

•High Phe levels are a teratogen
•Mother’s with PKU who do not maintain treatment will expose their fetuses to high Phe levels
•Fetal features:
   o Microcephaly
   o IUGR
   o Intellectual disability
   o Increased risk for CHDs

Question 11

Tyrosinemia: Genetics

Answer 11

Inheritance: Autosomal recessive
Amino acid pathway: Tyrosine breakdown
Deficient enzyme: 4-fumarylacteoacetase (Type I), Tyrosine transaminase (Type II), p-Hydroxyphenyl pyruvate dioxygenase (Type III)
PATIENTS SMELL LIKE CABBAGE

Question 12

Tyrosinemia, Type I

Answer 12

Type I:
•MOST SEVERE
•HSM
•Acute liver failure/jaundice
•Renal failure
•Rickets – leg bone deformity
•Failure to thrive
•Chronic weakness

Treatment:
•Orfadin – blocks 2nd step in enzyme pathway to prevent buildup of toxic metabolite

Question 13

Tyrosinemia, Type II

Answer 13

Type II:
•Keratosis palmoplantaris (hyperkeratosis of hands and feet)
•Intellectual disability (~50%)
•Ocular and cutaneous findings
•Growth retardation

Treatment:
•Dietary restriction of Phe and Tyr

Question 14

Tyrosinemia, Type III

Answer 14

Type III:
•Rarest
•Normal liver function
•Mild intellectual disability
•Seizures

Treatment:
•Dietary restriction of Phe, Tyr, and Met