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PubMed2002

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications.

Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the beta subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.

Adolescent↗

PubMedDate not supplied

Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency.

Systemic carnitine deficiency is a potentially lethal, autosomal recessive disorder characterized by cardiomyopathy, myopathy, recurrent episodes of hypoketotic hypoglycemia, hyperammonemia, and failure to thrive. This form of carnitine deficiency is caused by a defect in the active cellular uptake of carnitine, and the gene encoding the high affinity carnitine transporter OCTN2 has recently been shown to be mutated in patients suffering from this disorder. Here, we report the underlying molecular defect in three unrelated patients. Two patients were homozygous for the same missense mutation 632A-->G, which changes the tyrosine at amino acid position 211 into a cysteine (Y211C). The third patient was homozygous for a nonsense mutation, 844C-->T, which converts the arginine at amino acid position 282 into a stop codon (R282X). Reintroduction of wild-type OCTN2 cDNA into fibroblasts of the three patients by transient transfection restored the cellular carnitine uptake, confirming that mutations in OCTN2 are the cause of systemic carnitine deficiency.

Base Sequence↗

PubMed2001

Kidney transplantation in a girl with methylmalonic acidemia and end stage renal failure.

Methylmalonic acidemia (MMA) is an inborn error of organic acid metabolism that occurs in infancy with hypotonia, vomiting, dehydration, lethargy and failure to thrive and is biochemically characterized by metabolic ketoacidosis, hyperammonemia and sometimes hyperglycinemia. It results from deficiency of methylmalonyl-CoA mutase activity due to a defect in the mutase apoenzyme or to deficient function of one of the enzymes required for metabolism of its cofactor vitamin B12. Tubulointerstitial nephritis with progressive impairment of renal function is one of the most frequent long-term complications. We describe a case of a 17-year-old girl with methylmalonic acidemia unresponsive to vitamin B12 therapy. The clinical symptoms appeared at 4 months of life. She progressed into end stage renal disease and in January 1996 she started on hemodialytic treatment. In November 1996 we performed a kidney transplant. At present, urinary excretion of methylmalonic acid is normal and the renal function of the transplanted kidney is normal without any rejection episodes. We think that a kidney transplant could be a good therapeutic choice for the metabolic alterations in MMA with end stage renal disease. Indeed it would seem that the small methylmalonyl-CoA mutase activity present in the transplanted kidney could be sufficient to ensure normal metabolism of organic acids. Otherwise, the therapeutic goal can be achieved with a protein-restricted diet.

Adolescent↗

PubMed2006

Bridging to transplantation in acute liver failure in a 7-month-old infant.

BACKGROUND: Acute liver failure (ALF) in children is a rare but often fatal event. At present, liver transplantation is the only successful therapy in most cases. In the face of deteriorating hepatic encephalopathy in these children, some bridging therapy using artificial detoxification can be necessary to enable successful transplantation. In adults, albumin dialysis using the molecular absorbent recycling system (MARS) has been described as effective for bridging to liver transplantation. CASE REPORT: A previously healthy 7-month-old infant was admitted with ALF due to autoimmune hepatitis. King's College criteria for children with ALF indicated the need for transplantation (bilirubin 13.7 mg/dl, leukocytes 18,980/mm3, INR 5.83, age<2 years). Despite moderate hyperammonemia (75 microm/l) along with the development of pneumonia, the child deteriorated hemodynamically and neurologically, showing grade III encephalopathy proven by EEG. Albumin dialysis using MARS was used to bridge 36 hours to successful living-donor split-liver transplantation, and resulted in improvements in EEG, plasma levels of amino acids and hemodynamics. Twenty-four months after transplantation the child shows normal liver function and normal neuropsychological development. The explanted liver showed 80 % tissue destruction from autoimmune hepatitis. CONCLUSION: Albumin dialysis as described can be used successfully in infants < 1 year old for bridging to liver transplantation in cases of acute hepatic failure with deteriorating encephalopathy.

Albumins↗

PubMed2004

Operated hepatocellular carcinoma in two HIV- and HCV-positive hemophilic patients.

Some hemophilic patients in Japan suffer from infections with both human immunodeficiency virus (HIV) and hepatitis virus because they received contaminated nonheated blood products. Coinfection with HIV appears to accelerate the course of chronic hepatitis. Although powerful antiviral therapy was introduced as HIV treatment and the prognosis of HIV patients was dramatically improved, the risk of rapid progression of hepatitis and carcinogenesis remains for the patients. Recently, we performed surgery for hepatocellular carcinoma (HCC) in two hemophilic patients with HIV and hepatitis C virus (HCV) coinfection. Case 1 was a 52-years-old man who suffered from liver cirrhosis, hypersplenism, and hyperammonemia due to portosystemic shunt. A recent abdominal computed tomography (CT) scan had revealed a low-density area in segment VI of the liver. Splenectomy and partial resection of the liver were performed. Case 2 was a 66-year-old man who had been diagnosed with chronic hepatitis at age 50, and HIV infection at age 52 years. When his serum alpha-fetoprotein level was increased, CT scan of the liver revealed a mass in segment VIII. Subsegmentectmy of the liver was performed. Although the CD4 value in each patient was lower than 200 micro l, the operations were safely carried out and no major complication occurred. Because the chance of encountering HCC patients infected with HIV and HCV is increasing in Japan, we should consider the perioperative care of these patients, as well as the protection of medical workers against HIV infection.

Aged↗

PubMed1998

Expression analysis of two mutant human ornithine transcarbamylases in COS-7 cells.

Ornithine transcarbamylase (OTC) is located in the mitochondrial matrix of the liver and small intestine and catalyzes the second step of the urea cycle. OTC deficiency (OTCD) is an X-linked inborn error of metabolism and causes hyperammonemia. We reported in 1992 the A152V and G195R mutations in patients with OTCD. These mutant OTC cDNAs were prepared by site-directed mutagenesis using the polymerase chain reaction (PCR). The wild-type and mutant cDNAs were transiently expressed in COS-7 cells. The wild-type cDNA gave an OTC activity of 1180 +/- 47 nmol/min per mg protein. The OTC activities of the A152V and the G195R mutants were 3.7% and 2.5% of that of wild-type, respectively. Immunoblot analysis showed that the quantities of OTC proteins in the A152V and G195R mutants were 29% and 12% of that of wild-type, respectively. In pulse-labeling and pulse-chase experiments, the precursor form of OTC was synthesized and processed to the mature form. The A152V mutant OTC was processed to the mature form as rapidly as the wild-type precursor. However, the processed, mature form of the mutant OTC was rapidly degraded, presumably in the mitochondrial matrix. These results indicate that OTCD with the A152V mutation is due both to rapid degradation of the processed, mature form, and to a lower specific activity of the remaining protein.

Animals↗

PubMed2001

Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X.

Patients with mitochondrial ornithine transporter deficiency (or HHH syndrome) present with various neurological symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma due to hyperammonemia. We previously described three novel mutations in the ORNT1 gene in Japanese patients with HHH syndrome. In this article, we report a new patient with HHH syndrome, a 52-year-old woman, who had the typical clinical features, except for an absence of mental retardation. When we screened this patient, as well as a previously described Japanese patient, for mutations in the ORNT1 gene, we found that both were homozygous for a nonsense mutation (R179X). Furthermore, reverse transcription (RT)-polymerase chain reaction (PCR) of fibroblast RNA from one patient showed exon 4 skipping, as had been observed in a previously reported patient with R179X. These results, together with the findings in our previous report, show that, in three of our five reported Japanese HHH patients (six of ten alleles), R179X is present, suggesting that this is a common mutation in Japanese patients with HHH syndrome.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Large-animal models of fulminant hepatic failure.

For the development of an artificial liver support system, a clinically relevant large-animal model of fulminant hepatic failure (FHF) is indispensable. Although several large-animal models have been reported so far, they have not been entirely satisfactory. Recently, we have developed a new porcine model of FHF by means of intraportal administration of 0.1 mg/kg of alpha-amanitin and 1 microg/kg of lipopolysaccharide (LPS). This model has the following superior features: 100% mortality within 5 days along with a marked elevation of aspartate transaminase (AST) levels to around 10,000 IU/l, and severe metabolic disorders such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia; an onset of hepatic encephalopathy and a significant increase in intracranial pressure immediately before death; a reversal of FHF by orthotopic liver transplantation, proving that the toxicity is liver-specific and that the graft liver is unaffected; and the capability of the damaged liver to recover and achieve both morphological and functional regeneration in 1 week if supported by an efficient auxiliary graft. Because this porcine model satisfies many of the required criteria of an optimal FHF model, it is expected to provide a useful tool for the study of FHF and the development of new therapies.

Amanitins↗

PubMed2000

The first successful prenatal diagnosis on a Korean family with citrullinemia.

DNA prenatal diagnosis was successfully performed on a family with citrullinemia. The father carried the G324S mutation and the mother carried the IVS6-2A > G mutation in the argininosuccinate synthase gene. They had a previous child with citrullinemia who died in the week after birth owing to complicated hyperammonemia. The lost child turned out to be a compound heterozygote. DNA was extracted from the cultured amniotic cells after amniocentesis done at 18-week gestation. For the detection of the G324S mutation, the PCR and restriction fragment length polymorphism method was used, and for the IVS6-2A > G mutation, allele-specific PCR was performed. The fetus was found to carry G324S but not IVS6-2A > G, suggesting a heterozygote carrier. Pregnancy was continued and a healthy boy was born. Plasma amino acid analysis performed on the third day after birth was normal and the serial ammonia level was in the normal range. A molecular study on his genomic DNA after birth also agreed with the previous fetal DNA analysis. He is now 2-months old with normal growth and development.

Adult↗

PubMed2005

Dominantly inherited hyperinsulinaemic hypoglycaemia.

Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne et al 2004).

Exercise↗

PubMed2005

Recovery from parkinson syndrome and prolonged visually evoked potentials in hepatic encephalopathy.

The combination of Parkinson syndrome (PS) and prolonged visually evoked potentials (VEPs) in a single patient with hepatic encephalopathy (HE) has not been reported. A 52-year-old male with chronic HE developed PS in early 2001. Treatment with L-DOPA was only of minimal effect. In August 2001 he was admitted because of worsening PS and HE. There was anemia, hyperlipidaemia, markedly elevated liver-function-parameters, hyperammonemia, elevated resting-lactate, steatosis hepatis and hepatomegalia. VEPs showed markedly prolonged P100-latencies. Under L-DOPA, pramipexol, L-ornithin-L-aspartate, paromomycin-sulfate, and lactulose liver-function-parameters normalized and PS markedly improved. In February 2003, VEPs were normal. L-DOPA was discontinued by the patient in April 2003 and pramipexol in December 2003. Since then PS did not recur. This case shows that HE may go along with reversible PS and prolonged VEPs. Under adequate therapy liver-function-parameters and VEPs normalize and PS disappears.

Anti-Bacterial Agents↗

PubMed2005

Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide.

Chronic liver failure leads to hyperammonemia and consequently increased brain ammonia concentrations, resulting in hepatic encephalopathy. When the liver fails to regulate ammonia concentrations, the brain, devoid of a urea cycle, relies solely on the amidation of glutamate to glutamine through glutamine synthetase, to efficiently clear ammonia. Surprisingly, under hyperammonemic conditions, the brain is not capable of increasing its capacity to remove ammonia, which even decreases in some regions of the brain. This non-induction of glutamine synthetase in astrocytes could result from possible limiting substrates or cofactors for the enzyme, or an indirect effect of ammonia on glutamine synthetase expression. In addition, there is evidence that nitration of the enzyme resulting from exposure to nitric oxide could also be implicated. The present review summarizes these possible factors involved in limiting the increase in capacity of glutamine synthetase in brain, in chronic liver failure.

Ammonia↗

PubMed2005

Mechanisms of ammonia-induced astrocyte swelling.

Astrocyte swelling represents the major factor responsible for the brain edema associated with fulminant hepatic failure (FHF). The edema may be of such magnitude as to increase intracranial pressure leading to brain herniation and death. Of the various agents implicated in the generation of astrocyte swelling, ammonia has had the greatest amount of experimental support. This article reviews mechanisms of ammonia neurotoxicity that contribute to astrocyte swelling. These include oxidative stress and the mitochondrial permeability transition (MPT). The involvement of glutamine in the production of cell swelling will be highlighted. Evidence will be provided that glutamine induces oxidative stress as well as the MPT, and that these events are critical in the development of astrocyte swelling in hyperammonemia.

Ammonia↗

PubMed2003

Urea Cycle Disorders.

Urea cycle disorders comprise a group of inborn errors of metabolism that represent unique gene-nutrient interactions whose significant morbidity arises from acute and chronic neurotoxicity associated with often massive hyperammonemia. Current paradigms of treatment are focused on controlling the flux of nitrogen transfer through the hepatic urea cycle by a combination of dietary and pharmacologic approaches. Evolving paradigms include the development of cell and gene therapies. Current research is focused on understanding the pathophysiology of ammonia-mediated toxicity and prevention of neural injury.

Journal Article↗

PubMed1987

Transient visual loss in ornithine transcarbamoylase deficiency.

We examined a 32-year-old, previously healthy man who developed episodic bilateral visual impairment and confusion. Coincident hyperammonemia led to the diagnosis of ornithine transcarbamoylase deficiency, which was established by enzymatic analysis of a liver biopsy specimen. The available data were insufficient to determine if the metabolic derangement impaired vision at the level of the optic nerves or at the cerebral level.

Adult↗

PubMed1991

Animal model of systemic carnitine deficiency: analysis in C3H-H-2 degrees strain of mouse associated with juvenile visceral steatosis.

We analyzed carnitine profiles in C3H-H-2 degrees strain of mouse associated with fatty liver, hyperammonemia and hypoglycemia (Koizumi et al., 1988). Carnitine levels in serum, liver and muscle of mouse with fatty liver were markedly decreased in comparison with those of control mouse (littermates without fatty liver). This is a useful animal model to analyze the role of carnitine in lipid, amino acid and carbohydrate metabolism.

Aging↗

PubMed1985

Glycogen storage disease type IB: a new model of genetic disorders involving the transport system of intracellular membrane.

Our studies have revealed that the primary lesion of GSD type Ib exists in the G6P transport system in the microsomal membrane. Distinct evidence for the existence of a specific G6P transport system in microsomal membrane was obtained through these studies. This is the first example of a genetic disorder involving the transport system of an intracellular membrane. HHH syndrome (hyperornithinemia, hyperammonemia, and homocitrullinuria), in which the transport of ornithine to the mitochondria is presumed to be defective, may be another example belonging to this category of genetic disorders (18-20). A possibility exists that there are many other disorders due to defects in the membrane transport of intracellular organelles.

Adult↗

PubMed1986

Liver carbonic anhydrase and urea synthesis. The effect of diuretics.

In isolated perfused rat liver, urea synthesis is rapid and reversibly inhibited not only by the well-known carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide, but also by diuretics, like xipamide, mefruside, chlortalidone, and chlorothiazide. Furosemide was without effect. Similar to findings with isolated perfused rat liver, acetazolamide inhibits urea synthesis from ammonium ions in normal and cirrhotic human liver slices. Inhibition of urea synthesis by xipamide and acetazolamide is accompanied by a 70% decrease of the cellular citrulline content and the tissue levels of 2-oxoglutarate and citrate, suggesting a block of urea synthesis at a step prior to citrulline formation. At a constant extracellular pH (7.4), inhibition of urea synthesis by xipamide, mefruside and acetazolamide was overcome by increasing the extracellular concentrations of HCO3- and CO2 to above twice the normal values. This shows that inhibition of urea synthesis by these diuretics is not due to an unspecific inhibition of one of the urea cycle enzymes but is due to an inhibition of mitochondrial carbonic anhydrase and therefore due to an impaired HCO3- provision for mitochondrial carbamoylphosphate synthesis. It is concluded that the activity of mitochondrial carbonic anhydrase is required for urea synthesis also in human liver and that several diuretics impair urea synthesis by inhibition of mitochondrial carbonic anhydrase. The pathophysiological significance of these data is discussed with respect to the development of diuretics-induced hyperammonemia and alkalosis in liver disease.

Acetazolamide↗