Biochem 744 - Urea Cycle Disorders

NAGS, N-acetylglutamate synthase deficiency

o   Inheritance: Autosomal recessive, 1 in 2,000,000 incidence

o   MOA: Dysfunctional enzyme leads to ↑glutamine and alanine, ↑↑↑ammonia, normal orotic acid

  Leads to: profound hyperammonemia, lethargy, poor feeding, loss of thermoregulation, seizure, cerebral edema, coma, death

§  Diagnosed via: variant testing. Urine analytes are all unstable

§  Treated via : carbaglu, which is essentially a supplement of the missing end product N-acetylglutamate.

-            CPS1, Carbamoylphosphate synthetase deficiency (Proximal UCD)

o   Inheritance: Autosomal recessive, 1 in 1,200,000 incidence

o   MOA: Dysfunctional enzyme leads to ↑glutamine and alanine, ↑↑↑ammonia, normal orotic acid, ↓ citrulline and arginine

§  Leads to: profound hyperammonemia, lethargy, poor feeding, loss of thermoregulation, seizure, cerebral edema, coma, death

§  Diagnosed via: variant testing. Urine analytes are all unstable

§  Treated via : supportive. Since enzyme is the first step in the urea cycle, this one is really hard to treat. Prognosis is exceedingly poor. N-acetylgultamate supplementation is ineffective since the enzyme in question must be functional to kick off Urea cycle

-            OTC, Ornithine transcarbamylase deficiency (Proximal UCD)

o   Inheritance: X-linked, 1in 56,000 incidence

o   MOA: Dysfunctional enzyme leads to ↑glutamine and alanine, ↑↑↑ammonia, ↑↑↑orotic acid, ↓ citrulline and arginine

§  Leads to: infantile onset : severe neonate hyperammonemia à acute encephalopathy >50% hyperammonemia. Late-onset : may present with life threatening hyperammonemia episodes, altered mental status, learning disabilities, liver disease, unexplained cerebral palsy

§  Diagnosed via: Orotic acid elevation

§  Treated via : avoidance of hyperammonemia, ammonia scavengers, low protein diet liver transplant

-            Citrullinemia T1 (Distal UCD)

o   Inheritance: Autosomal, 1in 250,000 incidence

o   MOA: Dysfunctional enzyme leads to ↑glutamine and alanine, ↑↑ammonia, ↑orotic acid, ↑ citrulline and arginine

§  Leads to: infantile onset : elevated ammonia with initial hyperammonemic episodes leading to developmental delay, seizure

§  Diagnosed via: ↑ citrulline, ↓arginine

§  Treated via : avoidance of catabolism, ammonia scavengers, low protein, possible liver transplant

-            Arginosuccinic Aciduria (ASA) (ASL Deficiency) (Distal UCD)

o   Inheritance: Autosomal, 1in 220,000 incidence

o   MOA: Dysfunctional enzyme leads to ↑citrulline and Arginosuccinic acid, ↓arginine

§  Leads to: hyperammonemia in neonates, neurocognitive delay, seizures, liver disease, trichorrhexis nodosa (brittle hair), hypertension

§  Diagnosed via: ↑ ammonia, ↑ citrulline, ↓arginine

§  Treated via : avoidance of catabolism, ammonia scavengers, low protein, arginine supplementation

-            Arginase Deficiency (ARG1) (Distal UCD)

o   Inheritance: Autosomal, 1in 950,000 incidence

o   MOA: Dysfunctional enzyme leads ↓arginine

§  Leads to: life threatening hyperammonemic episodes rare, poor growth and feeding, microcephaly, developmental delay, seizures, chronic liver disease

§  Diagnosed via: ↓arginine

§  Treated via : avoidance of catabolism, ammonia scavengers, low protein