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PubMed1992

Plasma glutamine concentration: a guide in the management of urea cycle disorders.

Because increases in plasma glutamine concentrations are almost always associated with hyperammonemia in patients with urea cycle disorders, we determined the correlation between these two variables for 2 years in a child with ornithine transcarbamylase deficiency. A correlation coefficient of 0.77 (p less than 0.0001) was found. Hyperammonemia was rarely observed when plasma glutamine levels were near normal. These data suggest that one goal of therapy is the maintenance of plasma glutamine levels at or near normal values.

Amino Acid Metabolism, Inborn Errors↗

PubMed1991

Prospective treatment of urea cycle disorders.

We present a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period, and discuss the long-term developmental outcome of survivors. The families of 32 infants, among 43 identified prenatally as being at risk for a urea cycle disorder, chose to have their infants treated according to a diagnostic and therapeutic protocol, beginning at birth. The therapy was effective in avoiding neonatal hyperammonemic coma and death in seven patients with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency. When treated prospectively, five of eight patients with ornithine transcarbamylase deficiency avoided severe hyperammonemia and survived the neonatal period. Two patients with carbamoyl phosphate synthetase deficiency and two with ornithine transcarbamylase deficiency have subsequently died; three additional patients with the latter disorder have received orthotopic liver transplants. Our experience suggests that these surviving patients have had a more favorable neurologic outcome than patients rescued from neonatal hyperammonemic coma. However, all of them require a burdensome medical regimen and may have handicaps that include impairment of development and recurrent episodes of hyperammonemia. Further, those with deficiency of carbamoyl phosphate synthetase or ornithine transcarbamylase have a high mortality rate.

Amino Acid Metabolism, Inborn Errors↗

PubMed1977

Argininemia.

The clinical features of argininemia in two cousins included hyperactivity, spasticity, ataxia, retardation, and repeated attacks of hyperammonemia. Study of a large kindred suggests that arginase-deficiency is transmitted as a Mendelian recessive. Treatment with an essential amino acid mixture with the total nitrogen intake limited to the requirement, controlled the hyperammonemia, reduced the plasma arginine level, and permitted a marked clinical improvement. There has been a significant increase in intelligence levels; the previously retarded children are now approaching the normal range of function.

Amino Acid Metabolism, Inborn Errors↗

PubMed1995

Neonatal-onset propionic acidemia: neurologic and developmental profiles, and implications for management.

OBJECTIVES: To document the clinical and neurodevelopmental profiles of a cohort of patients with neonatal-onset propionic acidemia and to determine the efficacy of current therapy with respect to outcome. METHOD: The clinical, neurologic, and developmental status of six patients was prospectively evaluated during a 15-month period. Previous clinical and biochemical data were ascertained from hospital records to determine longitudinal nutritional status, number of episodes of hyperammonemia with ketoacidosis, and developmental performance with respect to age. RESULTS: No deaths resulted from propionic acidemia since the identification of the oldest patient in the series in 1980. Therapeutic intervention (e.g., gastrostomy tube feeding) resulted in improved nutritional status and possibly contributed to improved survival. All children had hypotonia, resulting in a significant effect on motor development; however, focal neurologic deficits and evidence of movement or seizure disorder were absent. Mild cortical atrophy was evident on cranial magnetic resonance imaging in four patients. All children, including two patients with no significant episodes of hyperammonemia and normal growth since the neonatal period, had a mild to moderate degree of intellectual impairment. CONCLUSIONS: The results of our study suggest that current therapy for neonatal-onset propionic acidemia is associated with improved survival and nutritional status, and an absence of focal neurologic deficits. However, hypotonia and cognitive delay were still present, even in children with "optimal" metabolic control. Additional therapeutic advances are required to improve the developmental and cognitive outcome.

Carboxy-Lyases↗

PubMed2003

Oral supplementation corrects plasma lysine concentrations in lysinuric protein intolerance.

In lysinuric protein intolerance (LPI), intestinal absorption and renal tubular reabsorption of arginine, ornithine, and lysine are impaired due to a defective cationic amino acid transporter. Deficiency of arginine and ornithine restricts the function of the urea cycle, leading to hyperammonemia after protein load, and to strong protein aversion. Mealtime supplements of citrulline, another urea cycle intermediate that uses other transport mechanisms, prevent postprandial hyperammonemia and improve protein tolerance. Deficiency of lysine, an essential amino acid, most probably also contributes to the symptoms of LPI. We investigated possibilities to improve the availability of lysine for tissues by increasing plasma lysine concentration. Six patients with LPI were started on short-term oral lysine supplementation that was administered with their regular citrulline doses and standard low-protein meals. L-Lysine in consecutive doses of 0.55 and 1.1 mmol/kg caused profuse diarrhea in first 3 patients. To avoid gastrointestinal side effects, the 3 other patients were started on smaller lysine supplements of only 0.05 mmol/kg per dose, given 3 times daily for 3 days. All pre- and postprandial plasma lysine concentrations remained within normal range in 2 of the 3 patients studied. Even after the larger doses, no significant effects on the urea cycle were seen. We conclude that low-dose oral lysine supplementation normalizes plasma lysine concentration in patients with LPI, and is safe and well tolerated at least in short-term use.

Absorption↗

PubMed2003

Acute postpartum mental status change and coma caused by previously undiagnosed ornithine transcarbamylase deficiency.

BACKGROUND: Acute postpartum mental status change usually represents postpartum blues or depression. Psychosis and coma are rare. This is a case report of a patient with previously undiagnosed ornithine transcarbamylase deficiency presenting as postpartum acute mental status change and coma. CASE: A 28-year-old multipara developed acute mental status change and coma 3 days after cesarean delivery. A metabolic profile and neurologic workup were unrevealing. An electroencephalogram revealed diffusely slow brain activity. She developed hyperammonemia and hyperglutaminemia and was diagnosed with ornithine transcarbamylase deficiency. Her newborn son was diagnosed with ornithine transcarbamylase deficiency on the previous day. Treatment with oral lactulose resulted in normalization of her ammonia level and resolution of her coma within 48 hours. She suffers no long-term sequelae. Dietary avoidance of protein was advised; outpatient treatment with sodium benzoate, sodium phenylacetate, and lactulose was initiated. A pedigree analysis is ongoing. CONCLUSION: Ornithine transcarbamylase deficiency should be included in the differential diagnosis of acute postpartum coma. Hyperammonemia, hyperglutaminemia, and orotic aciduria are diagnostic, facilitate early treatment, and mitigate the risk of permanent neurologic impairment or death.

Acute Disease↗

PubMed1984

Altered auditory brainstem evoked responses in the ferret model for Reye's syndrome.

The effects of influenza B, aspirin and hyperammonemia on the functional integrity of the cochlea were examined using the ferret model for Reye's syndrome. Auditory brainstem evoked responses (ABR) were recorded from treated ferrets and compared to those recorded from controls. Delayed latencies of all waves, as well as increased I-IV Interwave latencies were observed in recordings from treated ferrets. Importantly, the latencies of Wave I, nerve generator potential from the eighth nerve, and Wave IV, response potential from the brainstem nuclei, increased on Days 3 and 5 of the study. However, recorded ABR from treated ferrets on Day 10 showed that while the latencies of Wave IV were approximate to those of controls, Wave I remained delayed. These results suggest that systemic effects of influenza B, aspirin and hyperammonemia may lead acutely to both peripheral and central auditory dysfunction, and that the functional integrity of the central auditory system may recover more quickly than that of the peripheral system. Furthermore, these results suggest that such effects may lead to acute transient hearing impairment in patients with Reye's syndrome.

Ammonia↗

PubMed1994

Muscle ammonia and glutamine exchange during chronic liver insufficiency in the rat.

The aim of this study was to investigate the role of skeletal muscle in ammonia and glutamine metabolism during chronic hyperammonemia induced by liver insufficiency. The hindquarter ammonia and amino acid fluxes and muscle tissue concentrations were studied in two rat models of chronic liver insufficiency, portacaval shunting and portacaval shunting plus bile-duct ligation, as well as in sham-operated animals, 7 and 14 days after surgery, and in normal, unoperated rats. To reduce nutritional influences, portacaval-shunted rats and sham-operated rats were pair-fed to portacaval shunt biliary obstruction rats. Arterial ammonia levels were elevated in both liver insufficiency groups. In the portacaval shunting plus bile-duct ligation group, arterial glutamine levels were elevated compared with sham-operated controls. No net hind-quarter ammonia uptake was observed in any of the groups, despite hyperammonemia in the chronic liver insufficiency groups. Hindquarter glutamine release was always increased in the liver insufficiency groups compared with sham-operated controls, despite similar muscle glutamine levels in the sham-operated and hyperammonemic groups, suggesting enhanced muscle glutamine synthesis in the latter groups. Muscle ammonia levels were always increased and muscle glutamate decreased in the hyperammonemic groups, probably indicating glutamate consumption by enhanced glutamine synthesis. The increased phenylalanine tissue concentrations and efflux in portacaval shunt/biliary obstruction rats suggest that enhanced net muscle protein breakdown, amino acid catabolism and transamination, rather than ammonia uptake from the blood furnish amino acids and ammonia for enhanced glutamine synthesis. These experiments suggest that nutritional factors are important in explaining altered muscle metabolism during chronic liver insufficiency.

Amino Acids↗

PubMed1998

Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study.

BACKGROUND/AIMS: In the current state of knowledge of the pathophysiology of hepatic encephalopathy, a reduction in hyperammonemia is the most important evidence of effective treatment. Therefore, the therapeutic efficacy of oral L-ornithine-L-aspartate, which improves impaired ammonia detoxification, was investigated in patients with cirrhosis, hyperammonemia and stable, overt, chronic hepatic encephalopathy, and in subclinical hepatic encephalopathy in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Oral L-ornithine-L-aspartate was administered three times daily at fixed times for 14 consecutive days in a total dose of 18 g per day. The design was chosen to prevent an increase in ammonia induced by a protein meal of 0.25 g/kg body weight, given at the start of the daily treatment period. Efficacy variables were: fasting and postprandial ammonia concentration, Number-Connection-Test time, mental state grades, and a Portosystemic Encephalopathy Index. Analyses were based on the total study sample of 32 placebo- and 34 L-ornithine-L-aspartate-treated patients as well as on the subgroup samples in the overt (20 placebo- and 23 L-ornithine-L-aspartate-treated) and subclinical hepatic encephalopathy (12 placebo- and 11 L-ornithine-L-aspartate-treated) patients. RESULTS: Number Connection Test performance times (p<0.01) as well as fasting (p<0.01) and postprandial (p<0.05) venous blood ammonia concentrations in the L-ornithine-L-aspartate-treated group showed improvement in comparison to placebo. Also, the mental state grade (p<0.05) and the Portosystemic Encephalopathy Index (p<0.01), improved to a much greater degree in the L-ornithine-L-aspartate group than in the placebo group. Adverse events were observed in neither the placebo nor the L-ornithine-L-aspartate-treated patients. CONCLUSION: Oral L-ornithine-L-aspartate is a safe, well-tolerated treatment with a good compliance rate and a beneficial therapeutic effect in patients with cirrhosis and stable, overt, chronic hepatic encephalopathy.

Administration, Oral↗

PubMedDate not supplied

Cell-selective effects of ammonia on glutamate transporter and receptor function in the mammalian brain.

Increased brain ammonia concentrations are a hallmark feature of several neurological disorders including congenital urea cycle disorders, Reye's syndrome and hepatic encephalopathy (HE) associated with liver failure. Over the last decade, increasing evidence suggests that hyperammonemia leads to alterations in the glutamatergic neurotransmitter system. Studies utilizing in vivo and in vitro models of hyperammonemia reveal significant changes in brain glutamate levels, glutamate uptake and glutamate receptor function. Extracellular brain glutamate levels are consistently increased in rat models of acute liver failure. Furthermore, glutamate transport studies in both cultured neurons and astrocytes demonstrate a significant suppression in the high affinity uptake of glutamate following exposure to ammonia. Reductions in NMDA and non-NMDA glutamate receptor sites in animal models of acute liver failure suggest a compensatory decrease in receptor levels in the wake of rising extracellular levels of glutamate. Ammonia exposure also has significant effects on metabotropic glutamate receptor activation with implications, although less clear, that may relate to the brain edema and seizures associated with clinical hyperammonemic pathologies. Therapeutic measures aimed at these targets could result in effective measures for the prevention of CNS consequences in hyperammonemic syndromes.

Amino Acid Transport System X-AG↗

PubMed1999

Ammonia downregulates GLAST mRNA glutamate transporter in rat astrocyte cultures.

Abnormalities in glutamate metabolism and glutamatergic neurotransmission appear to play an important role in the pathogenesis of hyperammonemia and hepatic encephalopathy. Previous studies from our laboratory have shown that treatment of cultured astrocytes with NH4Cl result in decreased glutamate uptake. To extend these observations, we performed a Northern blot analysis of the astroglial glutamate transporter GLAST (EAAT1) in NH4Cl-treated primary rat astrocyte cultures. Following treatment with 2, 5, 10 mM NH4Cl for 3 days, cortical astrocytes showed a 22, 29, 36% decrease in GLAST mRNA, respectively. Striatal astrocytes showed 25, 51, 50% reduction, while cerebellar cultures showed decrements of 18, 37, 38%. Similar decreases in GLAST mRNA were also observed after 1 day of ammonia treatment. These findings, together with recent reports on the reduction of the GLT-1 glutamate transporter in in vivo models of acute liver failure and hyperammonemia, strongly suggest that an abnormality in astroglial glutamate uptake constitutes a critical aspect in the pathogenesis of hepatic encephalopathy and other hyperammonemic conditions.

ATP-Binding Cassette Transporters↗

PubMed1983

Hyperargininemia: clinical course and treatment with sodium benzoate and phenylacetic acid.

In a patient with hyperargininemia, oral administration of sodium benzoate or phenylacetic acid together with an essential amino acid mixture was used to prevent hyperammonemia and to decrease plasma and CSF concentrations of arginine. Sodium benzoate reduced the plasma ammonia levels, which was confirmed by the increase of urinary excretion of hippuric acid. Phenylacetic acid also controlled hyperammonemia, and EEG findings also improved. By these treatments, plasma and CSF concentrations of arginine showed a slight decrease, but were far above the normal range. There was no clinical improvement, and spasticity of the lower and upper extremities was progressive with mental deterioration.

Amino Acid Metabolism, Inborn Errors↗

PubMed1984

Citrullinemia presenting as uncontrollable epilepsy.

We report the case of a 16-year-old girl with a variant form of citrullinemia who had been treated with anticonvulsants for uncontrolled epilepsy during the last 4 years. The diagnosis of citrullinemia was made because she had elevated values for serum citrulline (about 10 times control levels), elevated blood ammonia (over 400 micrograms/dl) and reduced activity of argininosuccinate synthetase in the biopsied liver tissue. Her EEG showed high voltage slow activity, but not triphasic waves, when she had high concentrations of blood ammonia. Treatment with a low-protein diet and sodium benzoate resulted in a normalized blood ammonia level, but her plasma citrulline levels remained unchanged. After the therapy she had neither convulsions nor seizure discharges on EEG, even when all anticonvulsant drug therapy was stopped. Thus it is suggested that hyperammonemia may account for the observed abnormal EEG findings, and triphasic waves on EEG are not always recorded in cases of hyperammonemia.

Adolescent↗

PubMed1999

Subclinical portal-systemic encephalopathy in a child with congenital absence of the portal vein.

A 6-year-old girl with congenital absence of the portal vein (CAPV) who had persistent hyperammonemia due to a congenital portosystemic shunt is reported. The patient only exhibited mild intention tremor, without any apparent neurological manifestations of portal-systemic encephalopathy. However, magnetic resonance imaging of the head showed white matter atrophy with ventricular dilatation, which is thought to represent subclinical brain damage caused by chronic hyperammonemia. This is the first report of subclinical portal-systemic encephalopathy in a patient with CAPV. The present case suggests that the effect of a congenital portosystemic shunt on the central nervous system is serious, but can be clinically latent in children with CAPV.

Angiography↗

PubMed2003

Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease.

Case 1 is a 37-year-old Japanese man who was admitted to this hospital with a disturbance of consciousness. A diagnosis of adult-onset type II citrullinemia was made by DNA analysis of SLC25A13 (851del4/851del4) and measurement of hepatic ASS activity (2% of control value). After regaining consciousness, Case 1 was started on a dietary therapy, revealing that hypertriglyceridemia and ketogenesis impairment deteriorated on a low-protein diet and ameliorated on a carbohydrate-restricted (high-protein) diet. Case 1 could tolerate 70 g/day of protein while using arginine granules and developed hyperammonemia only after discontinuation of the administration. Case 2 (an elder brother of Case 1) is also homozygote for the same SLC25A13 mutation. The hepatic activity of argininosuccinate synthetase was about 20% of the control value. However, Case 2 exhibited neither hyperammonemia nor lipid metabolism abnormalities. These results suggest that, although adult-onset type II citrullinemia is caused by a deficiency of citrin, which plays key roles in carbohydrates, amino acids and even lipid metabolism, some other environmental or genetic factors are required for the onset of the disease, and from the authors' clinical experience, a carbohydrate-restricted (relatively high-protein) diet is advocated as a benefit to the patients, and that arginine granules are indispensable to this new dietary therapy.

Journal Article↗

PubMed2002

Diagnosis and monitoring of inborn errors of metabolism using urease-pretreatment of urine, isotope dilution, and gas chromatography-mass spectrometry.

To diagnose inborn errors of metabolism, it would be desirable to simultaneously analyze and quantify organic acids, purines, pyrimidines, amino acids, sugars, polyols, and other compounds using a single-step fractionation; unfortunately, no such method currently exists. The present article will be concerned primarily with a practical yet comprehensive diagnostic procedure of inborn errors of metabolism (IEM). This procedure involves the use of urine or eluates from urine on filter paper, stable isotope dilution, and gas chromatography-mass spectrometry (GC-MS). This procedure not only offers reliable and quantitative evidence for diagnosing, understanding and monitoring the diseases, but also provides evidence for the diagnosis of new kinds of IEM. In this review, the differential diagnosis for hyperammonemia are described; deficiencies of ornithine carbamoyl transferase, argininosuccinate synthase (citrullinemia), argininosuccinate lyase and arginase, lysinuric protein intolerance, hyperammonemia-hyperornithinemia-homocitrullinemia syndrome, and citrullinemia type II. The diagnosis of IEM of purine and pyrimidine such as deficiencies of hypoxanthine-guanine phosphoribosyl transferase, adenine phosphoribosyl transferase, dihydropyrimidine dehydrogenase, dihydropyrimidinase and beta-ureidopropionase are described. During the pilot study for newborn screening, we found neonates with diseases at a rate of 1 per 1,400 including propionic acidemia, methylmalonic acidemia, orotic aciduria, beta-ureidopropionase deficiency, lactic aciduria and neuroblastoma. A rapid and reliable prenatal diagnosis for propionic acidemia is also described.

Adult↗

PubMed1998

Oral supplementation with branched-chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis.

We investigated whether supplementation with branched-chain amino acids (BCAA) improves survival of rats with carbon tetrachloride (CCl4) -induced cirrhosis. Liver cirrhosis was induced in 40 male Sprague-Dawley rats by administering CCl4 for 15 weeks. Twenty rats each were then assigned to the control and BCAA group and fed a casein diet or a BCAA-supplemented casein diet, respectively, for an additional 17 weeks with repeated injections of CCl4. No significant difference occurred in either mean energy or nitrogen intake or in body or liver weight between the two groups. BCAA-supplementation significantly preserved plasma albumin concentrations (P < 0.05) and inhibited significantly the occurrence of ascites and hyperammonemia (P < 0.05). The survival rate was significantly higher in the BCAA group (P=0.03), while no significant difference was found in liver histology between the groups. These results suggest that BCAA improved survival of rats with CCl4-induced cirrhosis by preventing hypoalbuminemia and hyperammonemia without directly reducing hepatic necrosis and fibrosis.

Administration, Oral↗

PubMed1998

X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency.

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. It is X-linked and hemizygous new-born males usually suffer fatal hyperammonemia. In contrast, carrier females manifest variable phenotypes, ranging from asymptomatic carriers to those with severe hyperammonemia. In order to understand the correlation between X-inactivation status and the clinical phenotype of carrier females with this disorder, we analyzed the X-inactivation pattern of peripheral blood leukocytes in a family consisting of a clinically normal mother and two daughters with severe manifestation. In addition, we obtained tissue samples from various parts of the liver of one of these daughters and analyzed X-inactivation patterns and the residual OTC activities. The X-inactivation of peripheral blood leukocytes was nearly random in these carrier females and showed no correlation with the disease phenotype. However, the X-inactivation of the liver was much more skewed and correlated well with the OTC activity of all samples. Interestingly, the degree of X-inactivation varied considerably, even within the same liver.

Child↗