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PubMed1976

Histochemical studies in experimental portal-systemic encephalopathy.

Results of a histochemical study of glutamic dehydrogenase in experimental portal-systemic encephalopathy with hyperammonemia indicate that the enzyme's activity in brain was increased in all stages of the encephalopathy, and this increase appeared to be localized exclusively in astrocytes. The results are consistent with the view that the astrocyte has a critical role in ammonia metabolism in brain, probably in ammonia detoxification. The findings, moreover, indicate that one pool of glutamate, possibly the small pool, is located in the astrocyte.

Alzheimer Disease↗
PubMed1984

Cerebellar hemorrhage complicating methylmalonic and propionic acidemia.

Methylmalonic (MMA) and propionic (PPA) acidemias are inherited disorders characterized by a wide spectrum of clinical and biochemical findings. We report the neuropathologic findings in two young infants with MMA and PPA in which death probably resulted from cerebellar hemorrhage. When combined with a previous report of isovaleric acidemia complicated by diffuse subarachnoid and parenchymal cerebellar hemorrhage, it is apparent that cerebellar hemorrhage must be considered in any infant with a fulminating organic acidemia. Rapid neurologic deterioration despite an improvement in acidosis and hyperammonemia is an indication for computed tomography of brain. Surgical evacuation of the blood may improve the chance for survival in this catastrophic illness.

Acidosis↗
PubMed1989

Pontine myelinolysis and delayed encephalopathy following the rapid correction of acute hyponatremia.

We describe a case of pontine myelinolysis associated with hyponatremia and hyperammonemia resulting from bladder irrigation during a transurethral prostatic resection. Following the procedure the patient exhibited seizurelike activity. He underwent rapid correction of the hyponatremia, he initially recovered but developed encephalopathy 19 days later. Magnetic resonance images showed symmetrical lesions in the white matter of the cerebellar peduncles. A relatively small pontine lesion was also noted. The patient later recovered. This case demonstrates that myelinolysis associated with rapid correction of hyponatremia may be greater in the cerebellar peduncles than in the central pons.

Aged↗
PubMed1982

Encephalopathy and fatal myopathy in two siblings. Their association with partial deficiency of muscle carnitine.

Two brothers had intermittent episodes of muscle weakness, lethargy, hyperammonemia, rhabdomyolysis, and elevated activities of creatine phosphokinase (CPK), lactic dehydrogenase, and SGOT in serum associated with low muscle carnitine but normal serum carnitine concentrations. These siblings represent a "mixed" form of carnitine deficiency with the elements of both systemic and myopathic carnitine deficiency. The older sibling died suddenly after a 24-hour fast. The younger boy has received carnitine for three years. During this period, serum CPK activity has remained elevated and increased further during illnesses, but no clinical symptoms of encephalopathy or myopathy have appeared.

Carnitine↗
PubMed1997

Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency.

A Leu148Phe substitution of the ornithine transcarbamylase (OTC) gene was identified in a 2-year-old girl with OTC deficiency (14% of control). Her two elder sisters died in childhood of hyperammonemia, and the patient also died of OTC deficiency. Enzyme activity in Cos1 cells transfected by the mutant cDNA was undetectable, thereby indicating a definite pathogenic mutation. Familial gene analysis showed that the mother had wild-type OTC alleles on both X-chromosomes and the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. This clinical case shows that a somatic and germline mosaicism for a single-gene disorder led to an unusual pattern of X-linked inheritance in the family, and all three daughters in the family died of OTC deficiency. The possibility that inherited factors will lead to skewed X-inactivation needs to be considered.

Fatal Outcome↗
PubMed1999

Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency (McKusick 311250), an X-linked inherited disorder, often presents in males with severe neonatal onset of hyperammonemia. Maternal gonadal mosaicism in OTC deficiency was postulated previously, but no cases have been reported. We report on a family in which two consecutive males were affected with OTC deficiency, which was proven biochemically with characteristic metabolites and absent enzyme activity in liver. OTC genotyping in both brothers showed a new mutation in exon 6 (Met206Arg: ATG-->AGG), which encodes part of the equatorial H6 alpha-helix. Biochemical investigations confirmed normal results in the mother and grandmother and the absence of OTC activity in the affected males. Genotyping of the mother and grandmother was performed on peripheral blood leukocytes and skin fibroblasts and showed no mutation in the somatic cells. The recurrence of OTC deficiency in offsprings of a woman with normal genotype strongly suggests gonadal mosaicism. Gonadal mosaicism needs to be considered when counseling couples in which the mother has had a previously affected child with OTC deficiency but apparently is not a carrier.

Abortion, Induced↗
PubMed1999

Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.

A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.

Amino Acids↗
PubMed2000

Pegaspargase-induced pancreatitis.

BACKGROUND: The purpose of this study is to report the incidence of pancreatitis in patients treated with pegaspargase in our hospital during a 2-year period. PROCEDURE: We identified episodes of pancreatitis related to the intramuscular administration of pegaspargase 2,500 IU/m(2) for the treatment of childhood hematological malignancies during a 2-year period (May 1996-April 1998). Patients were evaluated clinically and by sequential serum amylase and lipase determinations and radiographic examinations. For comparison, episodes of pancreatitis in patients who only received native Escherichia coli L-asparaginase were examined during the same time period. RESULTS: Nine children with acute lymphoblastic leukemia (ALL) of 50 (18%) patients who received pegaspargase were diagnosed to have pancreatitis. All had prior therapy with native L-asparaginase. These children developed symptoms consisting of abdominal pain, nausea, vomiting, and decreased appetite within a median of 15 days from the onset of pegaspargase administration. Six patients became symptomatic after their initial dose. Seven patients developed severe or unacceptable toxicity (grades 3 and 4), measured by increased amylase (>2 times normal) and lipase levels or radiographic evidence of pancreatic inflammation or pseudocyst. One patient also developed hyperammonemia and encephalopathy. In contrast, only one out of 52 (1.9%) ALL patients who received native E. coli L-asparaginase during the same time period developed pancreatitis (P= 0.007). CONCLUSION: Clinicians should be aware of a possible higher incidence of pancreatitis associated with pegaspargase.

Adolescent↗
PubMed1998

Roles of neuroactive amino acids in ammonia neurotoxicity.

Many neurologic disorders are related to congenital or acquired hyperammonemia (HA). Advanced symptoms of HA range from seizures in acute stages to stupor and coma in more chronic conditions, manifesting variable imbalance between the inhibitory and excitatory neurotransmission. Evidence obtained with the use of experimental HA models suggests that acute neurotoxic effects of ammonia are mediated by overactivation of ionotropic glutamate (GLU) receptors, mainly the N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree the KA/AMPA receptors. NMDA receptor-mediated neurotoxicity may be potentiated by impaired control of their function by metabotropic GLU receptors, which are inactivated by ammonia. Prolonged overactivation of the NMDA receptors upon extended ammonia exposure causes their downregulation. The GLU receptor changes may be related to their excessive exposure to extrasynaptic GLU. Ammonia promotes GLU accumulation in the extrasynaptic space by enhancing its release from neurons, and/or by decreasing its reuptake to the nerve endings and astrocytes, where the effect results from inactivation (downregulation) of the astrocytic glutamate transporter GLT1. Excitotoxic effects of ammonia are augmented by increased synthesis of nitric oxide (NO), which is associated with NMDA receptor activation and/or increased synaptic transport of arginine (ARG). A shift toward neural inhibition is promoted by positive modulation of the gamma-aminobutyric acid (GABA)ergic tone resulting from excessive accumulation in the brain of endogenous central benzodiazepine receptor agonists, and from upregulation of astrocytic peripheral benzodiazepine receptors leading to elevated levels of prognenelone-derived neurosteroids, which positively modulate the GABA(A) receptor complex. Inhibitory neurotransmission may also be favored by enhanced release from astrocytes of an inhibitory amino acid, taurine.

Ammonia↗
PubMed1996

Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms.

We identified three new and three known mutations in male patients with OTC deficiency using PCR amplification of all the individual exons, including the adjacent intron sequences, followed by direct sequencing of the amplimers. Two mutations were found in males presenting with neonatal fatal hyperammonemia and no detectable enzyme activity in their livers. The H302Y mutation found in one patient affects the putative binding site for ornithine. The second patient had an R141X mutation, which is one of the few recurrent mutations in the OTC gene. Four different missense mutations were identified in male patients with late onset of the disease and residual OTC activities between 14% and 35%. The mutations are Y176C and P220A and the known mutations K88N and T343K, respectively. Four of the patients' mothers were identified as carriers. In two cases, the mutations had occurred spontaneously. In addition, the frequency of four polymorphisms of the OTC gene was studied. The K46R polymorphism in exon 2 and the Q27OR polymorphism in exon 8 were found in 36% and 4% of screened alleles, respectively. Two questionable polymorphisms in exon 4, F101L and L111P, were not present in any of the screened alleles.

Ammonia↗
PubMed1999

Congenital hyperinsulinism: molecular basis of a heterogeneous disease.

Congenital hyperinsulinism (CHI) is a disease phenotype characterized by increased, usually irregular, insulin secretion leading to hypoglycemia, coma, and severe brain damage, left untreated. Hyperinsulinism may be caused by a range of biochemical disturbances and molecular defects. In pancreatic beta cells, insulin secretion is stimulated by closure of the ATP-dependent potassium channel (K(ATP) channel). K(ATP) channel is a complex composed of at least two subunits: the sulfonylurea receptor SUR1 and Kir6.2, an inward rectifier K+ channel member. Mutations in both subunits have been identified in patients with the autosomal recessive form of hyperinsulinism, including 28 different mutations in the SUR1 gene and two mutations in the Kir6.2 gene. These mutations co-segregated with disease phenotype, also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and with attenuated K(ATP) channel function. Inadequately high insulin secretion in one family with an autosomal dominant mode of inheritance is caused by a mutation in the glucokinase gene, resulting in increased affinity of the enzyme for glucose. Five different mutations have been identified in the glutamate dehydrogenase gene, resulting in overactivity of this enzyme and causing a syndrome of hyperinsulinism and hyperammonemia. In 13 cases, hyperinsulinism was caused by one or more focal pancreatic lesions with specific loss of maternal alleles of the imprinted chromosome region 11p15. In five patients, this loss of heterozygosity unmasked a paternally inherited recessive SUR1 mutation. The new molecular approaches in PHHI give further insight into the mechanism of pancreatic beta cell insulin secretion. The heterogeneous group of patients with CHI may now be classified according to their basic defects in the four different genes, with potential implications for a more specific treatment.

Diabetes Mellitus, Type 2↗
PubMed2000

SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families.

Lysinuric protein intolerance (LPI) is a rare inherited disease caused by defective transport of the dibasic amino acids at the basolateral membranes of epithelial cells in the renal tubules and small intestine. The metabolic defect leads to brain dysfunction caused by hyperammonemia with a functional impairment of the urea cycle. Recently, mutations in the human SLC7A7 cDNA coding for y(+)LAT-1, which express dibasic amino acid transport activity, were reported to be responsible for LPI. In the present study, we examined the genomic structure of SLC7A7 by DNA sequencing of PCR products, and determined that the gene had 11 exons and 10 introns spanning about 18 kb of genomic DNA. We also identified an alternative RNA splicing at the 5' untranslated region of the SLC7A7 mRNA in human peripheral blood leukocytes, cultured lymphoblasts, and fibroblasts. As a result of mutational analysis of SLC7A7 in three Japanese LPI families, we found a nonsense mutation (R410X), a splicing mutation(911+1G>A) in intron 4, and four silent polymorphisms (201C/T, 445A/G, 784C/T, 946T/C). Identification of the genomic structure of SLC7A7 may provide a molecular basis for a genetic survey for LPI.

5' Untranslated Regions↗
PubMed1993

Pathologic characterization of short-chain acyl-CoA dehydrogenase deficiency in BALB/cByJ mice.

BALB/cByJ mice have a deficiency of short-chain acyl-CoA dehydrogenase (SCAD) and are a useful model for studying the inborn errors of fatty acid metabolism which affect humans. Patients with some of these disorders present with hypoglycemia, hyperammonemia, and microvesicular fatty change of hepatocytes. In the present study we examined pathogen-free, SCAD deficient BALB/cByJ mice and control BALB/cBy mice for biochemical and tissue changes following fasting or salicylate challenge. We observed mitochondrial swelling and microvesicular fatty changes in hepatocytes in mutant mice, especially severe following a fast. However, fasting did not alter their blood ammonia and there was no apparent clinical disease. Similarly, salicylates did not produce disease in the BALB/cByJ mice. We did detect in mice an alternative pathway for salicylate metabolism, by-passing glycine conjugation which is the principal metabolic pathway in humans.

Acyl-CoA Dehydrogenase↗
PubMed1995

Central pontine myelinolysis as a complication of partial ornithine carbamoyl transferase deficiency.

Central pontine myelinolysis (CPM) is a demyelinating condition of the central pons with or without associated foci of demyelination in extrapontine areas. We present a case of partial ornithine carbamoyl transferase deficiency in a 5-year-old girl which was complicated by CPM. The patient was a previously undiagnosed girl who presented with mild hyperammonemic encephalopathy with a maximum plasma ammonia level of 376 microM on admission. Laboratory testing established the diagnosis of OCT deficiency, and therapy with hydration and protein restriction was successful in returning the plasma ammonia levels to normal. Five days after correction of her hyperammonemia, the patient developed intractable seizures and coma. Serial MRI scans of the brain revealed the evolution of the characteristic findings of CPM. Plasma ammonia and electrolyte concentrations were well controlled throughout this time. This represents the first description of CPM in a patient with a urea cycle defect.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Disorders of carnitine transport and the carnitine cycle.

Carnitine plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane. This transfer requires enzymes and transporters that accumulate carnitine within the cell (OCTN2 carnitine transporter), conjugate it with long chain fatty acids (carnitine palmitoyl transferase 1, CPT1), transfer the acylcarnitine across the inner plasma membrane (carnitine-acylcarnitine translocase, CACT), and conjugate the fatty acid back to Coenzyme A for subsequent beta oxidation (carnitine palmitoyl transferase 2, CPT2). Deficiency of the OCTN2 carnitine transporter causes primary carnitine deficiency, characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues. Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy, or with skeletal and cardiac myopathy. This disease responds to carnitine supplementation. Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia. The heart and the muscle, which express a genetically distinct form of CPT1, are usually unaffected. These patients can have elevated levels of plasma carnitine. CACT deficiency presents in most cases in the neonatal period with hypoglycemia, hyperammonemia, and cardiomyopathy with arrhythmia leading to cardiac arrest. Plasma carnitine levels are extremely low. Deficiency of CPT2 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise. More severe variants of CPT2 deficiency present in the neonatal period similarly to CACT deficiency associated or not with multiple congenital anomalies. Treatment for deficiency of CPT1, CPT2, and CACT consists in a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine, carnitine supplements, and avoidance of fasting and sustained exercise.

Animals↗
PubMed1978

Cerebral blood flow and metabolism in chronically hyperammonemic rats: effect of an acute ammonia challenge.

The effects of chronic hyperammonemia on cerebral metabolism were studied in rats four and eight weeks after the construction of a portacaval shunt. Compared to sham-operated controls, shunted animals had increased arterial concentrations of ammonia and glutamine and decreased glutamate. Cerebral blood flow, measured by xenon 133 washout in animals lightly anesthetized with nitrous oxide, increased from a control of 91 +/- 5 (mean +/- SEM) to 139 +/- 20 ml per 100 gm tissue per minute after shunting for eight weeks; however, the cerebral metabolic rate for oxygen was not different from control four or eight weeks after the shunting procedure. Following intraperitoneal administration of a small ammonium acetate load (2.6 mmol/kg), eight-week portacaval animals consistently underwent a fall in cerebral blood flow and cerebral oxygen consumption and developed high-voltage slow waves in the electroencephalogram. Glutamine was produced by the brains of all groups of animals; the cerebral metabolic rate for glutamine was greater than control in eight-week portacaval rats, the only animals to show a net uptake of ammonia into brain. The findings suggest that increased cerebral sensitivity to ammonia, along with nonspecific effects of chronic portal-systemic shunting, may lead to uncoupling of cerebral blood flow and oxidative metabolism.

Ammonia↗
PubMed1986

Atypical presentation and neuropathological studies in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

A 6 1/2-month-old male offspring of consanguineous Egyptian parents was first seen because of fever, somnolence, vomiting, right focal motor seizures, right hemiparesis, elevated transaminase levels, hyperammonemia, and acidosis. A computed tomographic scan of the head suggested swelling of the left cerebral hemisphere, and an electroencephalogram indicated left frontotemporal abnormalities, but brain biopsy demonstrated diffuse white matter spongiosis and gliosis. Subsequently, urine organic acid analysis and enzyme assays were diagnostic of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

Brain↗