Non-Existent
18th December 2008, 11:53 PM
Introduction
Background
Normal enzyme function of N -acetylglutamate synthetase (NAGS) deficiency is confined to the hepatic mitochondria and mediates the reaction acetyl-coenzyme A (CoA) + glutamate ® N -acetylglutamate + CoA. As a mitochondrial reaction, each of the substrates is normally omnipresent. Acetyl-CoA is a cofactor in many mitochondrial reactions, and glutamate is the transamination product of a -ketoglutarate and alanine; a -ketoglutarate is produced by the Krebs cycle.
The normal function of N -acetylglutamate (NAG), the reaction product, is to act as an activator of carbamyl phosphate synthetase (CPS) (see Media file 1), which is also a mitochondrial enzyme. The activation process requires physical binding of NAG to the CPS enzyme, in turn, causing the inactive form of CPS to convert to an active state. Thus, CPS activity is regulated by the relationship of available NAG to inactive CPS enzyme protein.
The biochemical effect of NAGS deficiency is an inability to form adequate NAG; this results in failure to activate the enzyme responsible for the reaction NH4 + + CO2 + ATP ® H2 N-CO-PO3 2- + ADP, which is the entry step into the urea cycle (see Carbamyl Phosphate Synthetase Deficiency).
Clinical signs and symptoms of NAGS deficiency occur when ammonia fails to fix into carbamoyl phosphate (CP) effectively, thus disabling the urea cycle. This leads to accumulation of alanine and glutamine (transamination products of pyruvate and glutamate, respectively) and, finally, of ammonia. The condition is progressive without intervention.
Pathophysiology
Overall, the hepatic urea cycle is the major route for waste nitrogen disposal, generation of which is chiefly from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal as well. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in Hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of NAG, the enzyme activator that initiates incorporation of ammonia into the cycle.
Frequency
United States
Too few cases have been reported to cite any incidence figures. However, recognition of affected patients is increasing. Because the clinical presentation is indistinguishable from that of CPS deficiency and because the diagnosis is difficult, requiring an open liver biopsy, the true incidence may be underestimated. This is further emphasized by the fact that genetically affected individuals may remain asymptomatic for many years.
International
Only a handful of cases have been reported worldwide.
Mortality/Morbidity
NAGS deficiency is associated with significant morbidity and mortality. Patients who present with hyperammonemia are at risk for cerebral edema and death if treatment is not immediately begun. Survivors of hyperammonemic coma are likely to suffer brain damage and resulting developmental delays, learning disabilities, and/or mental retardation.
Sex
Case reports of NAGS deficiency have shown the condition to occur in both sexes; because the mutation is inherited as an autosomal recessive trait, this is to be expected.
Age
NAGS deficiency can present at any age. As with many inherited metabolic diseases, the most likely time of presentation is in the newborn period.
Clinical
History
The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, somewhat vary in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually in this article; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following:
Anorexia
Irritability
Heavy or rapid breathing
Lethargy
Vomiting
Disorientation
Somnolence
Asterixis (rare)
Combativeness
Obtundation
Coma
Cerebral edema
Death, if treatment is not forthcoming or effective
As a consequence, the most striking clinical findings of each urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.
Physical
General
Signs of severe hyperammonemia may be present.
Poor growth may be evident.
Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
Pulmonary
Tachypnea or hyperpnea may be present.
Apnea and respiratory failure may occur in later stages.
Abdominal: Hepatomegaly may be present and is usually mild.
Neurologic
Poor coordination
Dysdiadochokinesia
Hypotonia or hypertonia
Ataxia
Tremor
Seizures and hypothermia
Lethargy progressing to combativeness to obtundation to coma
Decorticate or decerebrate posturing
Causes
The pedigree distribution of reported cases supports an autosomal recessive inheritance pattern, and the growing numbers of reported cases confirm that this is the case.
The NAGS gene was the last one of the urea cycle to be cloned. The gene locus is 17q21.31, spans 4.5 kb, and contains 6 introns and 7 exons. The 534 amino acid residues contained in the ribosomal protein are reduced to 486 by cleavage at the N -terminus upon import to the mitochondrion. A total of 21 mutations have been reported, 10 of which were associated with acute neonatal presentation.1 Interestingly, no mutations were found in exon 1, which is believed to code for the 50 amino acid mitochondrial-targeting segment that is cleaved.
Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms.
Background
Normal enzyme function of N -acetylglutamate synthetase (NAGS) deficiency is confined to the hepatic mitochondria and mediates the reaction acetyl-coenzyme A (CoA) + glutamate ® N -acetylglutamate + CoA. As a mitochondrial reaction, each of the substrates is normally omnipresent. Acetyl-CoA is a cofactor in many mitochondrial reactions, and glutamate is the transamination product of a -ketoglutarate and alanine; a -ketoglutarate is produced by the Krebs cycle.
The normal function of N -acetylglutamate (NAG), the reaction product, is to act as an activator of carbamyl phosphate synthetase (CPS) (see Media file 1), which is also a mitochondrial enzyme. The activation process requires physical binding of NAG to the CPS enzyme, in turn, causing the inactive form of CPS to convert to an active state. Thus, CPS activity is regulated by the relationship of available NAG to inactive CPS enzyme protein.
The biochemical effect of NAGS deficiency is an inability to form adequate NAG; this results in failure to activate the enzyme responsible for the reaction NH4 + + CO2 + ATP ® H2 N-CO-PO3 2- + ADP, which is the entry step into the urea cycle (see Carbamyl Phosphate Synthetase Deficiency).
Clinical signs and symptoms of NAGS deficiency occur when ammonia fails to fix into carbamoyl phosphate (CP) effectively, thus disabling the urea cycle. This leads to accumulation of alanine and glutamine (transamination products of pyruvate and glutamate, respectively) and, finally, of ammonia. The condition is progressive without intervention.
Pathophysiology
Overall, the hepatic urea cycle is the major route for waste nitrogen disposal, generation of which is chiefly from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal as well. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in Hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of NAG, the enzyme activator that initiates incorporation of ammonia into the cycle.
Frequency
United States
Too few cases have been reported to cite any incidence figures. However, recognition of affected patients is increasing. Because the clinical presentation is indistinguishable from that of CPS deficiency and because the diagnosis is difficult, requiring an open liver biopsy, the true incidence may be underestimated. This is further emphasized by the fact that genetically affected individuals may remain asymptomatic for many years.
International
Only a handful of cases have been reported worldwide.
Mortality/Morbidity
NAGS deficiency is associated with significant morbidity and mortality. Patients who present with hyperammonemia are at risk for cerebral edema and death if treatment is not immediately begun. Survivors of hyperammonemic coma are likely to suffer brain damage and resulting developmental delays, learning disabilities, and/or mental retardation.
Sex
Case reports of NAGS deficiency have shown the condition to occur in both sexes; because the mutation is inherited as an autosomal recessive trait, this is to be expected.
Age
NAGS deficiency can present at any age. As with many inherited metabolic diseases, the most likely time of presentation is in the newborn period.
Clinical
History
The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, somewhat vary in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually in this article; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following:
Anorexia
Irritability
Heavy or rapid breathing
Lethargy
Vomiting
Disorientation
Somnolence
Asterixis (rare)
Combativeness
Obtundation
Coma
Cerebral edema
Death, if treatment is not forthcoming or effective
As a consequence, the most striking clinical findings of each urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.
Physical
General
Signs of severe hyperammonemia may be present.
Poor growth may be evident.
Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
Pulmonary
Tachypnea or hyperpnea may be present.
Apnea and respiratory failure may occur in later stages.
Abdominal: Hepatomegaly may be present and is usually mild.
Neurologic
Poor coordination
Dysdiadochokinesia
Hypotonia or hypertonia
Ataxia
Tremor
Seizures and hypothermia
Lethargy progressing to combativeness to obtundation to coma
Decorticate or decerebrate posturing
Causes
The pedigree distribution of reported cases supports an autosomal recessive inheritance pattern, and the growing numbers of reported cases confirm that this is the case.
The NAGS gene was the last one of the urea cycle to be cloned. The gene locus is 17q21.31, spans 4.5 kb, and contains 6 introns and 7 exons. The 534 amino acid residues contained in the ribosomal protein are reduced to 486 by cleavage at the N -terminus upon import to the mitochondrion. A total of 21 mutations have been reported, 10 of which were associated with acute neonatal presentation.1 Interestingly, no mutations were found in exon 1, which is believed to code for the 50 amino acid mitochondrial-targeting segment that is cleaved.
Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms.