Amino acids hyperammonemia

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. 

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. 

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. 

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. 

Hyperammonemia has occurred during parenteral nutrition as a component of therapy for renal insufficiency (905). The hyperammonemia presented as a change in mental status, developing about 3 weeks after initiation of parenteral nutrition therapy in most cases the episodes are of increasing duration and paroxysmal. In three of the patients, serum amino acid analysis in the acute phase showed reduced concentrations of ornithine and citrulline (the respective substrate and product of condensation with carbamyl phosphate at its entry into the urea cycle). Concentrations of arginine, the precursor to ornithine, were raised. 

A number of amino acid transport disorders may be associated with one or several of the systems described in Table 20.4. These are characterized by the excretion of amino acids in the urine but no increase in amino acid levels in the bloodstream. They are usually of hereditary origin. The most common disorder is cystinuria, characterized by the excretion of cystine. Because cystine is only slightly water soluble, cystinuria is often accompanied by the deposition of cystine-containing stones in the genitourinary tract. Cystinuria is apparently caused by a defect in the cationic amino acid transport system. Another disease that affects this system is lysinuric protein intolerance, which is associated with a failure to transport lysine, ornithine, arginine, and citrulline across membranes. Citrulline and ornithine are urea cycle intermediates (see later), and a disruption of their interorgan traffic results in hyperammonemia. 

Consideration of other plasma amino acids also informs the diagnosis of inborn errors of urea synthesis. The plasma concentrations of glutamine and alanine are often elevated in parallel with or prior to the ammonium concentration as they act as a nitrogen buffer. Plasma arginine concentrations are low since the only synthetic route for arginine in humans is via the urea cycle. In contrast, the arginine concentration is elevated in ARG-1 deficiency. Hyperornithinemia and homocitrullinuria are the characteristic features of the hyperammonemia, hyperornithinemia, and homocitrullinuria (HHH) syndrome caused by a defect in the ornithine transporter (ORNT-1). 

The accumulation of any of these amino acids could be due to reduced activity of their respective enzymes in the urea cycle (Sec. 15.5), resulting in decreased overall activity of the cycle. Inborn errors of metabolism are known for deficiencies in these enzymes. Decreased activity of the urea cycle results in elevated levels of ammonia in the blood, a condition known as hyperammonemia that causes nausea, vomiting and even coma. 

Animal and human studies have shown that an elevated concentration of ammonia (hyperammonemia) exerts toxic effects on the central nervous system. There are several causes, both inherited and acquired, of hyperammonemia. The inherited deficiencies of urea cycle enzymes are the major cause of hyperammonemia in infants. The two major inherited disorders are those involving the metabolism of the dibasic amino acids lysine and ornithine and those involving the metabolism of organic acids, such as propionic acid, methylmalonic acid, isovaleric acid, and others (see Chapter 55). 

In hyperammonemia, however, there is no single large preponderant ninhydrin-positive band of amino acid visible after paper chromatography and the pattern of urinary amino acid found on chromatography may appear to be normal or nearly so. However, the glutamine band is usually more than normally prominent. Confirmation is by a quantitative ion exchange chromatography as below, which will also reveal the increased excretion of alanine. 

None of these cases can be considered as established examples of an isolated carbamyl phosphate synthetase deficiency. Although in the first the clinical history and the presence of severe hyperammonemia support the diagnosis of a defect of urea synthesis, the normal finding of levels of plasma amino acids, apart from glycine, is against it. No actual numerical data on the level of activity of the urea cycle enzymes are given. 

The blood alanine level is also always increased, sometimes markedly to about 2-4 times the normal value (L3, L6). This is presumably because the normal transamination of alanine to pyruvate, which requires a-ketoglutarate, is inhibited both by the excess of glutamine in the blood and by the drain on a-ketoglutarate. One other amino acid, camosine, has been found to be present in the plasma or in raised amounts in the urine, in those cases of hyperammonemia where it has been sought (LIO). There are no consistent changes in any of the other amino acids, including lysine, in the blood. 

The changes in levels of amino acids other than glutamine in the cerebrospinal fluid in hyperammonemia are variable. In two reported instances (L3, L6), the arginine level was low, 30-50% of the normal. This could be a reflection of the decreased plasma arginine level or possibly of the block in the urea cycle in the brain itself. On the other hand, in another instance (LIO), the arginine level was normal. The changes in the other amino acids are also not consistent. In any case, the cerebrospinal fluid levels of amino acids are so low that such changes as were found are difiicult to interpret with certainty (Table 6). 

This condition has been described by Rett (RIO, Rll) and Rett and Stockl (R12) in 22 children, all girls, the oldest of them 13 years of age, from a survey of 6000 mentally subnormal children. In all 22, the blood ammonia was raised from 2 to 5 times the normal the highest being 165 /ig/100 ml. The blood urea was said to be normal in all cases, as was the plasma amino acids. Where liver biopsy was obtained, this was also normal. The brain was examined in 5 children who died. They showed cerebral atrophy but no Alzheimer Type II cells. A relationship between hyperammonemia and the cerebral changes of the syndrome was postulated and attention drawn to the similarity with some of the neurological manifestations of children with urea cycle defects. However, the cause of the hyperammonemia was unexplained, and it seems unlikely that these were examples of primary urea cycle disorders. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

Protein degradation and the inflammatory response (p. 664) Inherited defects of the urea cycle (hyperammonemia) (p. 664) Inborn errors of amino acid degradation (p. 672)... 

A newborn becomes progressively lethargic after feeding and increases his respiratory rate. He becomes virtually comatose, responding only to painful stimuli, and exhibits mild respiratory alkalosis. Suspicion of a urea cycle disorder is aroused and evaluation of serum amino acid levels is initiated. In the presence of hyperammonemia, production of which of the following amino acids is always increased ... 

Laboratory tests on a sick child reveal a low white blood cell count, metabolic acidosis, increased anion gap, and mild hyperammonemia. Measurement of plasma amino acids reveals elevated levels of glycine, and measurement of urinary organic acids reveals increased amounts of propionic acid and methyl citrate. Which of the following processes is most likely ... 

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