Disorders of urea cycle-II

• Deficiency of any of the urea cycle enzyme would result in hyperammonemia.
• All of the disorders are inhertted as autosomal recessive pattern, except hyperammonemia type II (ornithine transcarbamoylase deficiency) which is an X-linked disorder.

• Excessive amount of α-ketoglutarate from citric acid cycle is used to form glutamate to glutamine (to detoxify ammonia). 
• This results in decreased α-ketoglutarate available for TCA cycle leading to inhibition of TCA cycle and ATP production.

Hyperammonemia Type  ll  (OTG  Deficiency):

• Most common  Urea  Cycle  disorder.
• Urea cycle disorder with Orotic Aciduria, Marked elevations of plasma concentrations of glutamine and alanine with low levels of citrulline and arginine.
• Orotic aciduria in Hyperammonemia Type ll- Ornithine Transcarbamoylase defective hence Carbamoyl Phosphate accumulate in the mitochondria.
• Carbamoyl Phosphate reaches the cytoplasm enter into Pyrimidine Synthesis.
• Orotic Acid, an intermediate in the Pyrimidine synthesis accumulates which leads to Orotic Aciduria.

Hyperargininemia  (Argininemia),  A Distinct Urea  cycle Disorder:

• Hyperargininemia is the urea cycle disorder with least Hyperammonemia.
• 2 genetically distinct arginases in humans;-(ARGI) –>expressed in the liver and erythrocytes, and (ARG2) is found in renal and brain
  mitochondria.
• The compounds excreted in urine in hyperargininemia: Cystine, Ornithine, Lysine, Arginine COLA, Alpha ketoguanidinovaleric acid.

N-Acetyl Glutamate Synthase Deficiency:

• The sixth enzyme deficiency which lead to a urea cycle disorder, The condition is almost similar to Hyperammonemia Type I.
• Arginineo an allosteric activator of NAG Synthase improves CPS-I defect as N-Acetyl Glutamate activates CPS-I, But Arginine does not improve N-Acetyl Glutamate deficiency, as
  the enzyme itself is defective.

Hyperammonemia-Hyperornithinemia-Homocitrullinemia  (HHH)  Syndrome:

• Autosomal recessively inherited disorder,  Biochemical Defect is mutation in the ORNT 1 gene that encodes mitochondrial membrane Ornithine Permease.
• defect in the transport system of ornithine from the cytosol into the mitochondria.
• accumulation of ornithine in the cytosol causes hyperornithinemia.
• Homocitrulline is presumably formed from the reaction of mitochondrial carbamoyl phosphate with lysine.

Citrullinemia  Type  l

• caused by the deficiency of a mitochondrial transport protein named citrin.
• Citrin (aspartate-glutamate carrier protein) is a mitochondrial transporter encoded by a gene (SLC25A13) located on chromosome 7q.
• his protein’s functions is to transport aspartate from mitochondria into cytoplasm 
• Aspartate is required for converting citrulline to argininosuccinic acid So Citrulline accumulates.

Methods of estimation of blood ammonia:

1. Chemical Method: Berthelot Method
2. Enzymatic method: Glutamate Dehydrogenase Method
3. Using Ammonia selective Electrodes Methods of estimation of Urea 

Methods of estimation of Urea:

1. Chemical Method: Diacetyl MonoximeThiosemicarbazideMethod
2. Enzymatic Method: Using Urease

Tandem Mass Spectrometry is the most sensitive tool to detect metabolic Disorders.

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