Hyperammonemias

Hyperammonemias are caused by inborn errors of ureagenesis and organic acidemias, liver immaturity (transient hyperammonemia of the newborn), and liver failure (hepatic encephalopathy). Neonatal hyperammonemias are characterized by vomiting, lethargy, lack of appetite, seizures, and coma. The underlying defects can be identified by appropriate laboratory measurements (e.g., assessment of metabolic acidosis if present and characterization of organic acids, urea cycle intermediates, and glycine). 

Inborn errors of the six enzymes of ureagenesis and NAG synthase have been described. The inheritance pattern of the last is not known, but five of the urea cycle defects are autosomal recessive and ornithine carbamoyl-transferase (OCT) deficiency is X-linked. 

The sensitivity of this test is increased by increasing the flux in the pyrimidine biosynthetic pathway. The enhanced flux is accomplished by allopurinol, which by way of oxypurinol ribonucleotide inhibits the formation of final product uridine 5 -phosphate (UMP) in the pyrimidine biosynthesis (Chapter 27). 

Antenatal diagnosis for fetuses at risk for the urea cycle enzyme disorders can be made by appropriate enzyme assays and DNA analysis in the cultured amniocytes. 

Acute neonatal hyperammonemia, irrespective of cause, is a medical emergency and requires immediate and rapid lowering of ammonia levels to prevent serious effects on the brain. Useful measures include hemodialysis, exchange transfusion, peritoneal dialysis, and administration of arginine hydrochloride. The general goals of management are to 

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Hyperammonemia Type 1. A consequence of carbamoyl phosphate synthase I deficiency (reaction 1, Figure 29-9), this relatively infrequent condition (estimated frequency 1 62,000) probably is familial. 

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Figure 30-14. Catabolism of i-lysine. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals indicate the probable sites of the metabolic defects in periodic hyperlysinemia with associated hyperammonemia and persistent hyperlysinemia without associated hyperammonemia.

Although rum ammonia levels are not routinely measured, it is a useful indicator of Reye s syndrome and should be monitored in newborns at risk of developing hyperammonemia Ammonia is produced in many analytically useful enzyme reactions and the ammonium ISE has been used as the base sensor in several enzyme electrodes (see next section). In addition to valinomycin, other antibiotics such as the nonactin homalogs and gramicidins also behave as ionophores. The nonactin homolo were originally studied for their ability to selectively bind potassiiun ions It was then discovered that ammonium ions were preferred over potassium ions, and the selectivity coefficient Knh+ = 0.12 was reported. Since ammonia is present at fairly low levels in serum, this selectivity is not sufficient to to accurately measure NH4 in the presence of K. An extra measure of selectivity can be gained by using a gas permeable membrane to separate the ammonia gas from the sample matrix... 

Ferenci P, Pappas SC, Munson PJ, Jones AE Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit. Hepatology 1984 4 25-29. 

Urea cycle defects Failure to convert ammonia to urea via urea cycle (Fig. 40-5). Coma, convulsions, vomiting, respiratoryfailure in neonate. Often mistaken for sepsis of the newborn. Mental retardation, failure to thrive, lethargy, ataxia and coma in the older child. Associated with hyperammonemia and abnormalities of blood aminogram Low protein diet Acylation therapy (sodium benzoate, sodium phenylacetate) Arginine therapy in selected syndromes Hepatic transplantation... 

Severe urea cycle defects become manifest in infants with a severe syndrome of coma, convulsions and vomiting during the first few days of life. Clinical confusion with septicemia is common, and many infants are treated futilely with antibiotics. Hyperammonemia is usually severe, even in excess of 1 mmol/1 (normal in term infants <100 xmol/l). 

Diagnosis of CPS or OTC deficiency may not be apparent from the blood aminogram. Ornithine levels typically are normal. The presence of hyperammonemia, hyperglu-taminemia, hyperalaninemia and orotic aciduria in a critically ill infant affords presumptive evidence for OTC deficiency. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. 

Diagnosis of a urea cycle defect in the older child can be elusive. Patients may present with psychomotor retardation, growth failure, vomiting, behavioral abnormalities, perceptual difficulties, recurrent cerebellar ataxia and headache. It is therefore essential to monitor the blood ammonia in any patient with unexplained neurological symptoms, but hyperammonemia is inconstant with partial enzymatic defects. Measurement of blood amino acids and urinary orotic acid is indicated. 

Hyperammonemia also occurs in some organic acidurias, particularly those that affect neonates. Therefore, the urine organic acids should be quantitated in all patients with significant hyperammonemia. 

Carbamyl phosphate synthetase deficiency. Carbamyl phosphate synthetase deficiency is rare. Neonates quickly develop lethargy, hypothermia, vomiting and irritability. The hyperammonemia typically is severe, even exceeding 1 mmol/1. Occasional patients with a partial enzyme deficiency have had a relapsing syndrome of lethargy and irritability upon exposure to protein. Brain damage can occur in both neonatal and late-onset groups. 

Animal models for OTC deficiency include the sparse fur (spf) mouse (15% control enzyme activity) and the sparse fur-abnormal skin and hair (spf-ash) mouse (5% of control). Both kinds of mutant mouse manifest hyperammonemia, orotic aciduria, growth failure and sparse fur. 

OTC deficiency must be suspected in any patient, male or female, with unexplained neurological symptoms. The absence of hyperammonemia should not rule out the diagnosis, especially with a history of protein intolerance, a suggestive family history or an untoward reaction... 

Citrullinemia. Neonates with AS deficiency usually die, and most survivors suffer major brain injury. Patients with a partial deficiency may have a milder course, and a few individuals with citrullinemia have been phenotypi-cally normal. The diagnosis usually is apparent from the hyperammonemia and the extreme hypercitrullinemia. The activity of AS can be determined in both fibroblasts and chorionic villus samples, thus simplifying the problem of antenatal diagnosis. 

The underlying biochemical defect is a failure of mitochondrial uptake of ornithine. This results in a failure of citrulline synthesis and a consequent hyperammonemia. Urinary orotic acid is high, presumably because of underutilization of carbamyl phosphate. In contrast, excretion of creatine is low, reflecting the inhibition of glycine trans-amidinase by excessive levels of ornithine. 

The cause is defective transport of dibasic amino acids by the proximal tubule and intestine. The transport defect occurs at the basolateral rather than the luminal membrane. Hyperammonemia reflects a deficiency of intra-mitochondrial ornithine. An effective treatment is oral citrulline supplementation, which corrects the hyperammonemia by allowing replenishment of the mitochondrial pool of ornithine. 

Dialysis, including hemodialysis and peritoneal dialysis, relieves acute toxicity during fulminant hyperammonemia. Exchange transfusions also have been performed, but this technique has not been equally useful in removing ammonia. 

Sixteen patients had an associated hyperammonemia, citrullinemia and hyperlysinemia. This presentation is the most malignant, with death in early infancy. This French phenotype is commonly associated with the absence of any immunological cross-reacting material (CRM) corresponding to the pyruvate carboxylase apoenzyme protein. 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

KCN, 10 mg/kg BW Loss of consciousness in 100% blood ammonia levels increased 2.5X brain amino acid levels (i.e., leucine, isoleucine, tyrosine, phenylalanine) increased by 1.5-3.0X. Alpha ketoglutarate, at 500 mg/kg BW by intraperitoneal injection, completely blocked the development of cyanide-induced loss of consciousness and hyperammonemia 19... 

Wu, X.Z., M. Yamada, T. Hobo, and S. Suzuki. 1989. Uranine sensitized chemiluminescence for alternative determinations of copper (II) and free cyanide by the flow injection method. Anal. Chem. 61 1505-1510. Yamamoto, H.A. 1989. Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice. Toxicol. Appl. Pharmacol. 99 415 120. 

Although carnitine administration may partially ameliorate hyperammonemia, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid. 

Yamamoto H. 1989. Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice. Toxicol Appl Pharmacol 99 415-420. 

Amino groups released by deamination reactions form ammonium ion (NH " ), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. Figure I-17-1 summarizes the flow of nitrogen from tissues to either the liver or kidney for excretion. The reactions catalyzed by four major enzymes or classes of enzymes involved in this process are summarized in Table T17-1. 

Mdst result in hyperammonemia and cerebral edema, decreased BUN, increased blood glutamine... 

Hyperammonemia Hyperammonemia has been reported and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, measure an ammonia level. 

Hyperammonemia and encephalopathy associated with concomitant valproic acid use Administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. 

CPT-II deficiency is more common and mainly manifests as muscle weakness, myoglobinemia, and myoglobinuria upon exercise severe cases lead to hyperketotic hypoglycemia, hyperammonemia, and death. 

Chiidren affiicted with MCAD deficiency experience muscie weakness, iethargy, fasting hypo-giycemia, and hyperammonemia, which mayiead to seizures, coma and, potentiaiiy, brain damage and death. 

Symptoms of hereditary hyperammonemia include many of the neurologic manifestations of acquired hyperammonemia, but they are seen mainly in infants and frequently lead to mental retardation. 

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