Inborn Errors: Urea Cycle Flashcards
List three symptoms of hyperammonemia
Coma
Encephalopathy
Irreversible neurological damage
What is the clinical presentation of urea cycle disorders?
Some may present with poor feeding, lethargy, coma, hypotonia
Others may be asymptomatic but have abnormal plasma test results.
What are the general precipitating factors for urea cycle disorders?
The urea cycle functions to remove waste ammonia from the body and consists of a series of amino acids and enzymes that transfer ammonia to urea, which is then excreted. The urea cycle may by interrupted due to primary failure of intermediates, secondary inhibition of the process, or through liver failure. All pathways result in increased ammonia which is toxic to the CNS.
What are the common enzymes that cause urea cycle disorders?
OTC - Ornithine Transcarbamylase Deficiency
most common deficiency, X-linked, females do much better than males
CBS - Cystathione B-Synthatase Deficiency
Homocystinuria, Autosomal recessive, 50% are B6 (pyridoxine) responsive
BCKD - Branched Chain Ketoacid Dehydrogenase Def.
Maple Syrup Urine Disease, leucine metabolites accumulate in urine,
Fumarylacetoacetate Hydrolase Deficiency
Tyrosenemia Type 1, Liver disease (early infancy), Rickets (late infancy), Porphyria-like syndrome (any age)
What are the metabolite changes seen in OTC deficiency?
Ornithine Transcarbamylase deficiency results in: High plasma ammonia High plasma glutamine Low plasma citrulline High urinary orotic acid
What are the metabolite changes seen in Fumarylacetoacetate Hydrolase Deficiency?
FH Deficiency/Tyrosinemia Type 1:
Plasma Tyrosine = 10x normal (440 uM)
Plasma Methionine = 10x normal (160 uM)
Urine organic acids including succinylacetone and d-aminolevulinic acid.
(Succinylacetone inhibits d-ALA, causes porphyria-like syndrome)
What are the metabolite changes seen in CBS deficiency?
Cystathione B-Synthase Deficiency result in:
Plasma Homocysteine ~ 2uM (normally not detectable)
Plasma Methionine = 10x normal (180uM)
Urine Homocysteine = 20 mmol/mg creatinine
Total Homocysteine = 150 uM
What are the metabolite changes seen in BCKD deficiency?
Plasma Leucine»Valine (norm: Valine>Leucine)
Leucine 20x greater than normal
2-hydroxyisoleucine is responsible for the Maple Syrup urine odor
What are three categories of disorders of Amino Acid metabolism?
Aminoacidopathies
Urea Cycle Disorders
Disorders of Organic Acid Metabolism
What is the general treatment strategy for urea cycle defects?
Dietary protein restriction
Ammonia scavenging medications
Glutamine, Glycine, Na Phenylacetate, Na Benzoate
L-arginine or L-citrulline supplementation
Hemodialysis or IV scavengers for severe acute hyperammonemia
What are the three presentations of fumarylacetoacetate hydrolase deficiency?
Early infancy:
1-6 months
Liver disease (hepatic failure, jaundice, cirrhosis with renal tabulopathy)
Late infancy:
Rickets due to renal tubulopathy
No obvious liver failure
Porphyria:
Accumulation of porphyrins in blood
At any age
Succinylacetone inhibits d-ALA dehydratase
Abdominal pain crisis
Peripheral neuropathy
Tyrosine is only moderately elevatedWhat are the common presentations and treatment for homocystenuria?
Marfanoid habitus (tall, thin, very long arms) Osteoporosis Scoliosis Autosomal Recessive Often missed on newborn screens 50% of CBS mutations are pyridoxine (Vitamin B6) responsive Thromboembolisms common Atherosclerotic disease Eye abnormalities Ectopic lentis Myopia Developmental disabilities Neuropsychiatric Symptoms
Treatment
Pyridoxine challenge (750mg/day) monitor plasma methionine and total homocysteine
Protein restriction
Methionine free medical foods
Supplementation with B12, folate, cysteine
What are the three common presentations of BCKD deficiency and what is the treatment?
Severe neonatal form
