Inborn errors 2: Urea cycle defects Flashcards
- List three symptoms of hyperammonemia.
unexplained vomiting, seizures, progressive obtundation)
- Describe the clinical presentation of urea cycle disorders including the precipitating factors.
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
- List the common enzyme defects that cause urea cycle disorders.
OTC, NAGS, carbamoyl phoshphate synthase (CBS), arginase, arginosuccinate lyase, argininosuccinate synthase
- List the metabolites that are increased with the common urea cycle disorders especially OTC deficiency.
OTC- low citrulline, high glutamine in blood
- high orotic acid in urine
- Describe the approach to treating urea cycle defects including the use of ammonia scavenging medications.
glutamine and glycine are ammonia scavenging agents
sodium phenylacetate and sodium benzoate grab glycine and glutamine and allow them to be excreted
Phenylketonuria signs and symptoms
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
Tyrosemia type 1
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
Alkaptonuria
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
homocysteinuria
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
- Describe three approaches to treating a patient with PKU/hyperphenyalaninemia.
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
- Define maternal PKU syndrome.
mother has uncontrolled PKU puts baby at risk for PKU phenotype without genetics
- Describe the original rationale for newborn screening.
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
- List the amino acids that are elevated in maple syrup urine disease.
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
- Describe the changes in biochemical intermediates that occur with classic homosystinuria.
homocysteine and methionine
- Describe the signs and symptoms of classic homocystinuria.
increased homocysteine in the urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis/scoliosis, lens subluxation, thrombosis and atherosclerosis
- Describe the approach to treating a patient with classic homocystinuria.
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
- Describe the clinical symptoms of tyrosinemia type 1.
failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes
- Name the pathognomonic compound of tyrosinemia type 1.
1
effects of an enzyme/co-factor defect
A–/–>B—->C—->D
—> E—> F
disease phenotype may result from
- Accumulation of Metabolite A
- Overflow to alternative toxic pathway
- reduced formation of metabolite D
- a combination of all
3 types of MSUD
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
Tx of Tyrosemia type 1
NTBC- inhibits production of FAA and succinylacetone
-does increase tyrosine! so we restrict dietary tyrosine
Ornithine Transcarbamylase (OTC) Deficiency
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
UCD TX-
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
