Inborn Errors of Urea Cycle Trans I.

The Urea Cycle Step 1 2 Enzyme Carbamoyl phosphate synthetase I Ornithine transcarbamoylase Arginosuccinate synthetase Location Mitochondria Mitochondria Substrate NH3 + CO2 + 2 ATP Carbamoyl phosphate + Ornithine Citrulline + aspartate + MgATP Arginosuccinate L-arginine + H2O Product Carbamoyl phosphate Citrulline Deficiency Hyperammonemia type I Hyperammonemia type II Citrullinemia

Cytosol

Arginosuccinate + AMP + Mg-PPi L-arginine + fumarate L-ornithine + urea

4 5

Arginosuccinase Arginase

Cytosol Cytosol

Arginosuccinuria Arginemia

Creators: D2.Grp 1 Alejado, Ruby Joy; Ramos, Voltaire; Sagle, Maria Josefina; Soriano, Ellison; Tandayu, Nicolle Ann 2012

II. Inborn Errors of Urea Cycle > deficiencies of the enzymes involved in urea cycle > common symptoms are due to hyperammonemia and ammonia intoxication is characterized by: a. tremors b. slurring of speech Enzyme Deficient CPS I Deficiency Hyperammonemia type I c. blurring of vision d. vomiting Unique S/S - clinical manifestation indistinguishable with OTC deficiency - severe: onset can be seen in neonatal period - Male patients usually show clinically severe symptoms at younger ages than female patients - most severe: increase of NH3 13 days after birth - frequent elevation of NH3 blood level = occasionally elevate to lifethreatening level e. irritability f. hepatic coma Transmission Autosomal recessive Dx -gene analysis for pre-natal diagnosis Tx - nutritional restriction of protein - administration of ARGININE/CITRULLINE and SODIUM BENZOATE/SODIUM PHENYLACETATE g. death

OTC

Hyperammonemia type II

X-linked

- amino acid analysis - High levels: > NH3 > GLN/GLU > ORNITHINE (not essential) - LOW levels: > Citrulline > Arginine

Mild

> nutritional restriction of protein > oral

administration of citrulline and arginine

Severe > acute attack in adult > NH3 reach lifethreatening > infusion of effective amino acid (arginine) > drugs to employ alternative pathways of eliminating nitrogen (SODIUM BENZOATE and

Creators: D2.Grp 1 Alejado, Ruby Joy; Ramos, Voltaire; Sagle, Maria Josefina; Soriano, Ellison; Tandayu, Nicolle Ann 2012

SODIUM PHENYLACETATE) > liver transplant

Arginosuccinate syntethase

Citrullinemia

Arginosuccinase Arginosuccinuria

Arginase

Arginemia

- extremely high citrulline blood level - very low arginine blood level - increased arginosuccinate in blood and urine - hepatomegaly - kinky hair - spastic paraplegia - accumulation of arginine - intractable mental retardation

Autosomal recessive

- amino acid analysis

- nutritional restriction of

protein intake - administration of arginine

- restriction of arginine and

Autosomal recessive

- amino acid analysis

protein is effective

Autosomal recessive

- amino acid analysis of plasma

- protein restriction

Creators: D2.Grp 1 Alejado, Ruby Joy; Ramos, Voltaire; Sagle, Maria Josefina; Soriano, Ellison; Tandayu, Nicolle Ann 2012