Inborn Errors of Metabolism

Question 1

Phenylketonuria (PKU)

Answer 1

v phenylalanine hydroxyls or v tetrahydrobiopterin cofactor (malignant PKU).
Tyrosine becomes essential.
^ phenylalanine –> excess phenylketones (phenyl acetate, phenyllactate, phenylpyruvate) in urine.
Avoid aspartate bc contains phenylalanine.

Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor.

Autosomal recessive.
Normal first 2-3 days bc maternal enzyme.

Tx: v phenylalanine and ^ tyrosine in diet, tetrahydrobiopterin supplementation.

Question 2

Maple Syrup Urine Disease

Answer 2

Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) - I Love Vermont maple syrup.
Due to v branched chain a-ketoacid dehydrogenase (B1).
–> ^ a-ketoacida in the blood, esp leucine.

Severe CNS defects, intellectual disability, death.
Autosomal recessive.
Vomiting, poor feeding, urine smells like maple syrup.

Tx: restrict isoleucine, leucine, valine in diet; thiamine supplementation.

Question 3

Ornithine Transcarbamylase Deficiency

Answer 3

Most common urea cycle disorder.
X-linked recessive (NOT autosomal recessive!).
Interferes w body’s ability to eliminate ammonia.
Usu evident in first few days, but may present later.
Excess carbamoyl phosphate is converted to orotic acid (pyrimidine synthesis pathway).

^ orotic acid in blood and urine.
v BUN.
Symptoms of hyperammonemia.
NO megaloblastic anemia (vs orotic acuduria).

Question 4

Classic Galactosemia

Answer 4

Absence of galactose-1-phosphate uridyltransferase (G1P UDT). Loss of overall conversion galactose –> glucose.
Autosomal recessive.
Damage due to accumulation of toxic substances (e.g. galactitol accumulates in lens of eye).

Failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability, E coli sepsis in neonates.
Serious defects –> PO4 (3-) depletion.

Tx: exclude galactose and lactose from diet.

Question 5

Glycogen Storage Disease (general)

Answer 5

19 types, depending on the enzyme.
Most common = Type I, Von Gierke (glucose-6-phosphatase deficiency).
Autosomal recessive.
Can’t break down glycogen to glucose.

Protuberant abdomen (hepatomegaly), hypoglycemia w fast, lactic acidosis, growth failure, hypotonia (v muscle tone), delayed development, seizures.

Question 6

N-acetylglutamate synthase deficiency

Answer 6

Req’d cofactor for carbamoyl phosphate synthetase I.
Absence of N-acetylglutamate –> hyperammonemia.

Neonates w poorly regulated respiration and body temp, poor feeding, developmental delay, intellectual disability.

Identical presentation as carbonyl phosphate synthetase I deficiency.

Question 7

Hyperammonemia

Answer 7

Can be acquired (e.g. liver disease) or hereditary (e.g. urea cycle enzyme deficiencies).
–> excess NH3 –> depletes a-KG –> inhibition of TCA cycle.

Tremor, slurring speech, somnolence, vomiting, cerebral edema, blurring vision.

Tx: limit protein in diet.
Can v ammonia levels w: lactulose, rifaximin, benzoate, phenylacetate, or phenyl butyrate.