Hyperammonemia

urea cycle disorders#hyperammonemia

1. Hyperammonemia

2. Contents Introduction Causes Types Diagnosis Management Summary

3. Introduction Increase ammonia in blood Normal level of ammonia (10-40μmol/L)very low, compared to BUN. Medical emergency-neurotoxic Biochemical sign of failure of liver & defects in urea cycle enzymes. Symptoms- tremors, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision. Leads to loss of consciousness,coma and convulsions, and may be fatal

4. Explanation for ammonia toxicity Withdrawal of Alpha ketoglutarate to form glutamate ( catalyzed by glutamate dehydrogenase) and then glutamine (catalyzed by glutamine synthetase) Leads to lower concentrations of all citric acid cycle intermediates Reduced generation of ATP Ammonia also inhibits oxidative decarboxylation of Alpha ketoglutarate

5. Causes Enzyme defects in urea cycle Organic acidurias Congenital lactic acidosis Hepatic encephalopathy; liver failure Cor pulmonale Pulmonary emphysema Renal failure

6. Types Acquired Hyperammonemia (Hepatic Coma) Liver disease is the common cause in adults # Hyperammonemia – characteristic feature of liver failure. #The condition known as – portal systemic encephalopathy Cirrhosis of Liver – collateral circulation – Portal blood shunted into Systemic circulation Ammonia Urea It may also be due to viral hepatitis or hepatotoxins(alcohol)

7. Types 2.Congenital hyperammonemia G enetic deficiencies of enzymes of urea cycle – overall incidence- 1:25,000 live births X linked OTC deficiency – most common All other urea cycle disorders - autosomal recessive Urea cycle disorders are characterized by hyperammonemia, encephalopathy and respiratory alkalosis.

8. Four of five metabolic diseases, results in accumulation of precursors of urea principally ammonia and glutamine. Ammonia intoxification is most severe when the metabolic block occurs at reactions 1 and 2 . #note Hyperammonemia seen with arginase deficiency is less severe .

9. Carbomyl Phosphate Synthetase I deficiency Hyperammonemia type I Comparatively rare Incidence is 1 in 100000 Severe Hyperammonemia ; very high ammonia levels in blood. Autosomal recessive Mental retardation.

10. N- Acetylglutamate Synthetase deficiency N acetyl glutamate synthetase catalyzes the formation of N Acetylglutamate from glutamate and acetyl CoA Note: clinical and biochemical features of of NAGS deficiency are indistinguishable from those arising from a defect in carbamoyl phosphate synthase 1.

11. Ornithine transporter deficiency Hyperornithinemia, hyper ammonemia and homocitrullinuria HHH Syndrome Mutation of ORNT1 gene – ornithine permease Failure to import ornithine from cytoplasm to mitochondria Decreased urea in blood Autosomal recessive condition

12. Ornithine Transcarbomylase deficiency Hyperammonemia type II Most common and X linked trait. High ammonia level in blood Levels of glutamine are elevated in blood ,cerebrospinal fluid and urine. Orotic aciduria – channeling of carbomyl phosphate into pyrimidine synthesis. Glutamate+NH3 glutamine synthetase. Glutamine

13. Arginosuccinate synthetase deficiency Citrullinemia Characterized by hyperammonemia ,citrullinuria and citrullinemia High blood levels of ammonia and citrulline 1-2 g of citrulline are excreted daily. Autosomal recessive Incidence is 1 in 70000

14. Arginosuccinate lyase deficiency Arginosuccinic aciduria leads to arginosuccinic aciduria and therefore metabolic acidosis. Hyperammonemia less severe. Arginosuccinate is elevated in CSF and excreted in urine. lncidence is 1:75000 Typical clinical feature : friable tufted hair ( trichorrhexis nodosa)

15. Arginase deficiency Hyperargininemia Mild variety with accumulation and excretion of arginine Hyperargininemia and argininuria are seen Symptoms like other urea cycle disorders do not appear until age 2 to 4 years. Incidence is 1 in 100000

16. Signs and Symptoms Early onset hyperammonemia(neonates) Normal appearance at birth Hypothermia Lethargy Irritability feeding disruption ( increases catabolism) Vomitting Seizures Hyperventillation; grunting respiration

17. Signs and Symptoms Late onset hyperammonemia(later in life) Intermittent ataxia Intellectual impairment Gait abnormality Recurrent reye syndrome Tend to avoid protein in their food Epilepsy

18. Diagnosis *Family history *Physical examination : No findings *Lab tests: Arterial blood gas analysis Serum aminoacid levels Urinary orotic acid levels Urinary ketone tests Plasma and urinary organic acid levels Enzyme assays

19. Diagnosis *Molecular genetic testing *Tandem Mass Spectrometry- even small amounts of metabolic intermediates accumulated in the blood of newborn infants can b e detected *Liver function tests

20. Management Restrict protein intake and supplement with Alpha ketoacids. Administration of compounds that bind covalently to non essential amino acids producing nitrogen containing molecules that are excreated in the urine example :phenyl acetate can conjugate with glutamine and glycine forming Phenylacetatylglutamine and hippurate Gene therapy

21. Summary

22. References D M Vasudevan Harper’s illustrated biochemistry Lippincott NCBI