Inborn errors 2: Urea cycle defects

Question 1

1. List three symptoms of hyperammonemia.

Answer 1

unexplained vomiting, seizures, progressive obtundation)

Question 2

2. Describe the clinical presentation of urea cycle disorders including the precipitating factors.

Answer 2

precipitating factors- infections, fever, vomiting, GI bleeding, decreased energy or protein intake, chemo, high dose corticosteroids, prolonged or intense physical activity, surgery under general anesthesia, high protein load, Valproate and L-asparaginase/pegaspargase

Question 3

3. List the common enzyme defects that cause urea cycle disorders.

Answer 3

OTC, NAGS, carbamoyl phoshphate synthase (CBS), arginase, arginosuccinate lyase, argininosuccinate synthase

Question 4

4. List the metabolites that are increased with the common urea cycle disorders especially OTC deficiency.

Answer 4

OTC- low citrulline, high glutamine in blood

- high orotic acid in urine

Question 5

5. Describe the approach to treating urea cycle defects including the use of ammonia scavenging medications.

Answer 5

glutamine and glycine are ammonia scavenging agents

sodium phenylacetate and sodium benzoate grab glycine and glutamine and allow them to be excreted

Question 6

Phenylketonuria signs and symptoms

Answer 6

due to a deficiency in phenylalanine hydroxylase.
this reaction also requires BH4
–> phenylalanine tox, tyrosine and Tyrosine based neurotransmitter deficiency

blond hair, mental disability, musty body odor
deficiency in phenylalanine hydroxylase

Question 7

Tyrosemia type 1

Answer 7

deficiency in fumarylacetoacetate hydrolase deficiency
causes accumulation of fumarylacetoacetatewhich leads to succinylacetone (liver toxic)—> inhibits delta aminolevulinic acid dehydratase—>abdominal pain

carcinogenic, cirrhosis

AR, french canadian, and finland
 3 different presentations
-early infancy liver disease
-late infancy- rickets (renal tubular disease
-porphyria-like attack at any age

Question 8

Alkaptonuria

Answer 8

congenital deficiency of homogentosate oxidase in the degradative pathway of tyrosine to fumarate
AR
black urine, black pigment of cartilege and collagen, degenerative arthritis from fourth decade

Question 9

homocysteinuria

Answer 9

AR- all forms result in excess homocysteine

look for increased *methionine on screens cuz homcyst is unstable

increased homocysteine in the urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis/scoliosis, lens subluxation, thrombosis and atherosclerosis

Cystathionine synthase deficiency
-Tx- decrease met, increase cyst, increase b12 and folate in diet

decreased affinity of cystathionine synthase for pyridoxal phospate
-Tx-increase B6 and cysteine in diet

Homocysteine methyltransferasedeficiency
-Tx- methionine in diet

Question 10

2. Describe three approaches to treating a patient with PKU/hyperphenyalaninemia.

Answer 10

diagnose before symptomatic by NBS
restrict phenylalanine in the diet for life,
provide adequate calories and protein-need special medical drink
maintain normal growth and development

Newer tx
BH4 tx
LNAA tx (large neutral amino acid)
PHE ammonia Lyase
Macroglyoprotein
Liver cell transplant

especially manage in pregnancy

keep PKU below 300-400uM

Question 11

3. Define maternal PKU syndrome.

Answer 11

mother has uncontrolled PKU puts baby at risk for PKU phenotype without genetics

Question 12

4. Describe the original rationale for newborn screening.

Answer 12

as a society we decided that certain conditions are worth knowing about from birth prior to development of symptoms.

disease needs to be a legitimate public health concern
treatable?
infratructure?
is screening test invasive
is screening economical
understanding of natural history of degree
is there an agreed policy on whom to treat

Question 13

5. List the amino acids that are elevated in maple syrup urine disease.

Answer 13

toxic accumulation of Leucine, Isoleucine and valine
AR, E1 alpha mennonite
E2 thiamine responsive

mitochondrial Branched Chain ketoacid dehydrogenase complex

Leucine causes cerebral edema.
supplement valine and isoleucine in certin patients
medical foods- no branched amino acids

Question 14

6. Describe the changes in biochemical intermediates that occur with classic homosystinuria.

Answer 14

homocysteine and methionine

Question 15

7. Describe the signs and symptoms of classic homocystinuria.

Answer 15

increased homocysteine in the urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis/scoliosis, lens subluxation, thrombosis and atherosclerosis

Question 16

8. Describe the approach to treating a patient with classic homocystinuria.

Answer 16

Cystathionine synthase deficiency
-Tx- decrease met, increase cyst, increase b12 and folate in diet

decreased affinity of cystathionine synthase for pyridoxal phospate
-Tx-increase B6( pyridoxine) and cysteine in diet

Homocysteine methyltransferase deficiency
-Tx- methionine in diet

Question 17

9. Describe the clinical symptoms of tyrosinemia type 1.

Answer 17

failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes

Question 18

10. Name the pathognomonic compound of tyrosinemia type 1.

Answer 18

1

Question 19

effects of an enzyme/co-factor defect

A–/–>B—->C—->D
—> E—> F

Answer 19

disease phenotype may result from

• Accumulation of Metabolite A
• Overflow to alternative toxic pathway
• reduced formation of metabolite D
• a combination of all

Question 20

3 types of MSUD

Answer 20

severe neonatal (no residual enzyme activity)

• maple syrup odor in urine,
• few abnormalities on routine lab tests,

Acute intermittent form (with residual activity)
•Late onset
•Ataxia
•Ketoacidotic coma sometimes with hypoglycemia
•Amino acids and keto acids can be normal between attacks

Subacute chronic form (with residual activity)
•Hypotonia and developmental delay
•Failure to thrive
•Spastic paraplegia

Question 21

Tx of Tyrosemia type 1

Answer 21

NTBC- inhibits production of FAA and succinylacetone

-does increase tyrosine! so we restrict dietary tyrosine

Question 22

Ornithine Transcarbamylase (OTC) Deficiency

Answer 22

most common urea cycle disorder
x linked recessive
interferes with bodies ability to eliminate ammonia
excess carbamoyl phosphate is is converted to orotic acid

increased orotic acid in the blood and urine, decreased BUN, sx’s of hyperammonemia,
no megaloblastic anemia

Question 23

UCD TX-

Answer 23

dietary restriction of protein
lactulose to acidify Gi tract and trap NH4+ for excretion
ammonia scavengers, L arginine or L citrulline supplemntation

hemodialysis, IV scavengers
consider liver tranplan for severe patients