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1.
Am J Med Genet A ; 185(7): 2026-2036, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33851512

RESUMEN

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia with variable clinical manifestations. Using data from a nationwide study, we investigated the onset time, gene variants, clinical manifestations, and treatment of patients with UCDs in Japan. Of the 229 patients with UCDs diagnosed and/or treated between January 2000 and March 2018, identified gene variants and clinical information were available for 102 patients, including 62 patients with ornithine transcarbamylase (OTC) deficiency, 18 patients with carbamoyl phosphate synthetase 1 (CPS1) deficiency, 16 patients with argininosuccinate synthetase (ASS) deficiency, and 6 patients with argininosuccinate lyase (ASL) deficiency. A total of 13, 10, 4, and 5 variants in the OTC, CPS1, ASS, and ASL genes were respectively identified as novel variants, which were neither registered in ClinVar databases nor previously reported. The onset time and severity in patients with UCD could be predicted based on the identified gene variants in each patient from this nationwide study and previous studies. This genetic information may help in predicting the long-term outcome and determining specific treatment strategies such as liver transplantation in patients with UCDs.


Asunto(s)
Argininosuccinatoliasa/genética , Argininosuccinato Sintasa/genética , Carbamoil-Fosfato Sintasa (Amoniaco)/genética , Ornitina Carbamoiltransferasa/genética , Trastornos Innatos del Ciclo de la Urea/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Variación Genética/genética , Humanos , Hiperamonemia/enzimología , Hiperamonemia/genética , Hiperamonemia/patología , Lactante , Masculino , Enfermedades Metabólicas/enzimología , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/patología , Trastornos Innatos del Ciclo de la Urea/enzimología , Trastornos Innatos del Ciclo de la Urea/patología , Adulto Joven
2.
J Pediatr Endocrinol Metab ; 33(10): 1349-1352, 2020 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-32809955

RESUMEN

Objectives Carbonic anhydrase VA (CAVA) deficiency is a rare autosomal recessive inborn error of metabolism that leads to acute metabolic crises, especially in the neonatal or infantile period. It is caused by a deficiency of the enzyme CAVA, which is encoded by the CA5A gene. Case presentation Fifteen patients with homozygous pathogenic CA5A mutations involving 10 different lesions have been reported in the literature up to date. Main clinical and biochemical features of CAVA deficiency include lethargy, hyperammonemic encephalopathy, metabolic acidosis, elevated lactate and hypoglycemia. In most patients reported so far, a single metabolic decompensation attack has been reported, and they have remained stable thereafter with no further crisis. Conclusions We report the 16th case of CAVA deficiency, who was diagnosed by whole-exome sequencing and showed a typical course of the disease with normal development at 18 months.


Asunto(s)
Encefalopatías/patología , Anhidrasa Carbónica V/deficiencia , Anhidrasa Carbónica V/genética , Hiperamonemia/patología , Mutación , Encefalopatías/enzimología , Encefalopatías/genética , Femenino , Humanos , Hiperamonemia/enzimología , Hiperamonemia/genética , Recién Nacido , Pronóstico
3.
J Physiol Biochem ; 74(4): 523-530, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30058052

RESUMEN

The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-14C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group. We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.


Asunto(s)
Aminoácidos de Cadena Ramificada/metabolismo , Hiperamonemia/metabolismo , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Amoníaco/envenenamiento , Animales , Radioisótopos de Carbono , Ciclo del Ácido Cítrico/efectos de los fármacos , Glutamina/agonistas , Glutamina/metabolismo , Hiperamonemia/enzimología , Hiperamonemia/fisiopatología , Técnicas In Vitro , Ácidos Cetoglutáricos/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Metilhistidinas/metabolismo , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/enzimología , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/enzimología , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Especificidad de Órganos , Concentración Osmolar , Oxidación-Reducción , Biosíntesis de Proteínas/efectos de los fármacos , Proteolisis/efectos de los fármacos , Ratas Wistar
4.
Am J Transplant ; 17(5): 1405-1408, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27997078

RESUMEN

Ornithine transcarbamylase deficiency represents the most common inherited defect of the urea cycle. This enzyme, predominantly found in the liver, plays a crucial role in recycling free ammonia, with deficiencies often leading to fatal complications. Here, we present the case of a 63-year-old man with alcoholic cirrhosis who underwent orthotopic liver transplantation, gradual worsening of his mental status, and progressive elevation of ammonia levels. Liver allograft function was deemed normal, raising concern for a donor-derived metabolic disorder of the urea cycle. Evaluation of the donor patient's blood revealed that the donor was heterozygous for the OTC gene. Posttransplantation changes in mental status should prompt a clinician to consider the most likely causes; however, once these have been ruled out, it is important to consider the less common causes of metabolic derangements. The rarity of these disorders makes expertise of diagnosis, standardization of evaluation, and treatment strategies challenging.


Asunto(s)
Edema Encefálico/etiología , Hiperamonemia/etiología , Trasplante de Hígado/efectos adversos , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/complicaciones , Ornitina Carbamoiltransferasa/metabolismo , Donantes de Tejidos , Edema Encefálico/enzimología , Humanos , Hiperamonemia/enzimología , Masculino , Persona de Mediana Edad , Pronóstico , Trasplante Homólogo
5.
Amino Acids ; 48(1): 1-20, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26259930

RESUMEN

In mammals, two major routes exist for the metabolic conversion of L-glutamine to α-ketoglutarate. The most widely studied pathway involves the hydrolysis of L-glutamine to L-glutamate catalyzed by glutaminases, followed by the conversion of L-glutamate to α-ketoglutarate by the action of an L-glutamate-linked aminotransferase or via the glutamate dehydrogenase reaction. However, another major pathway exists in mammals for the conversion of L-glutamine to α-ketoglutarate (the glutaminase II pathway) in which L-glutamine is first transaminated to α-ketoglutaramate (KGM) followed by hydrolysis of KGM to α-ketoglutarate and ammonia catalyzed by an amidase known as ω-amidase. In mammals, the glutaminase II pathway is present in both cytosolic and mitochondrial compartments and is most prominent in liver and kidney. Similarly, two routes exist for the conversion of L-asparagine to oxaloacetate. In the most extensively studied pathway, L-asparagine is hydrolyzed to L-aspartate by the action of asparaginase, followed by transamination of L-aspartate to oxaloacetate. However, another pathway also exists for the conversion of L-asparagine to oxaloacetate (the asparaginase II pathway). In this pathway, L-asparagine is first transaminated to α-ketosuccinamate (KSM), followed by hydrolysis of KSM to oxaloacetate by the action of ω-amidase. One advantage of both the glutaminase II and the asparaginase II pathways is that they are irreversible, and thus are important in anaplerosis by shuttling 5-C (α-ketoglutarate) and 4-C (oxaloacetate) units into the TCA cycle. In this review, we briefly mention the importance of the glutaminase II and asparaginase II pathways in microorganisms and plants. However, the major emphasis of the review is related to the importance of these pathways (especially the common enzyme component of both pathways--ω-amidase) in nitrogen and sulfur metabolism in mammals and as a source of anaplerotic carbon moieties in rapidly dividing cells. The review also discusses a potential dichotomous function of ω-amidase as having a role in tumor progression. Finally, the possible role of KGM as a biomarker for hyperammonemic diseases is discussed.


Asunto(s)
Amidohidrolasas/metabolismo , Asparagina/metabolismo , Glutamina/metabolismo , Hiperamonemia/enzimología , Neoplasias/enzimología , Nitrógeno/metabolismo , Azufre/metabolismo , Amidohidrolasas/genética , Animales , Asparagina/química , Glutamina/química , Humanos , Hiperamonemia/genética , Hiperamonemia/metabolismo , Neoplasias/genética , Neoplasias/metabolismo
6.
Biochimie ; 119: 146-65, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26542286

RESUMEN

Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures.


Asunto(s)
Amidinotransferasas/metabolismo , Creatina/metabolismo , Guanidinoacetato N-Metiltransferasa/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Amidinotransferasas/deficiencia , Amidinotransferasas/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/deficiencia , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Animales , Transporte Biológico Activo , Encefalopatías Metabólicas Innatas/diagnóstico , Encefalopatías Metabólicas Innatas/enzimología , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Creatina/biosíntesis , Creatina/deficiencia , Creatina/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/metabolismo , Metabolismo Energético , Guanidinoacetato N-Metiltransferasa/deficiencia , Guanidinoacetato N-Metiltransferasa/genética , Atrofia Girata/diagnóstico , Atrofia Girata/enzimología , Atrofia Girata/genética , Atrofia Girata/metabolismo , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/enzimología , Hiperamonemia/genética , Hiperamonemia/metabolismo , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Trastornos del Desarrollo del Lenguaje/diagnóstico , Trastornos del Desarrollo del Lenguaje/enzimología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/enzimología , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Metilación , Proteínas de Transporte de Membrana Mitocondrial , Trastornos del Movimiento/congénito
7.
Proc Natl Acad Sci U S A ; 112(17): 5521-6, 2015 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-25870278

RESUMEN

Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.


Asunto(s)
Glutamato-Amoníaco Ligasa/metabolismo , Hiperamonemia/enzimología , Hígado/enzimología , Animales , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Marcación de Gen , Glutamato-Amoníaco Ligasa/genética , Hiperamonemia/genética , Hiperamonemia/patología , Hiperamonemia/fisiopatología , Hígado/metabolismo , Hígado/fisiopatología , Locomoción , Memoria , Ratones , Ratones Noqueados , Estrés Oxidativo/genética
8.
Mol Cell Biochem ; 381(1-2): 157-61, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23703029

RESUMEN

Rapid metabolism of lactate is an important aspect of bioenergetic adaptation in the brain during non-physiological conditions. The low grade hyperammonemia (HA) is a common condition in the patients with chronic hepatic encephalopathy (HE); however, biochemistry of lactate turnover during low grade HA remains poorly defined. The present article describes profile of lactate dehydrogenase (LDH) isozymes vis-a-vis lactate level in the brain slices exposed with 0.1-0.5 mM ammonia, found to exist in the brain during chronic HE. A significant increment in LDH activity coincided with a similar increase in lactate level in the brain slices exposed with 0.5 mM ammonia. This was consistent with a selective increment of LDH-4 that synthesizes lactate from pyruvate with a concomitant decline in LDH-1 which catalyzes conversion of lactate to pyruvate; resulting into ~3-fold increase in LDH-4/LDH-1 ratio in those brain slices. The PFK2 domain of PFK2/FBPase2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) regulates glycolysis to maintain the pyruvate pool for lactate synthesis. The PFK2 expression was also observed to be increased ~2-fold (P < 0.001) in 0.5 mM ammonia treated brain slices. These findings provide enzymatic regulation of increased lactate turnover in the brain exposed with moderate HA.


Asunto(s)
Encéfalo/enzimología , Hiperamonemia/enzimología , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Fosfofructoquinasa-2/metabolismo , Amoníaco/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Activación Enzimática/efectos de los fármacos , Femenino , Isoenzimas/metabolismo , Especificidad de Órganos/efectos de los fármacos , Ratas
9.
Arch Biochem Biophys ; 536(2): 101-8, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23628343

RESUMEN

An increased concentration of ammonia is a non-specific laboratory sign indicating the presence of potentially toxic free ammonia that is not normally removed. This does occur in many different conditions for which hyperammonemia is a surrogate marker. Hyperammonemia can occur due to increased production or impaired detoxification of ammonia and should, if associated with clinical symptoms, be regarded as an emergency. The conditions can be classified into primary or secondary hyperammonemias depending on the underlying pathophysiology. If the urea cycle is directly affected by a defect of any of the involved enzymes or transporters, this results in primary hyperammonemia. If however the function of the urea cycle is inhibited by toxic metabolites or by substrate deficiencies, the situation is described as secondary hyperammonemia. For removal of ammonia, mammals require the action of glutamine synthetase in addition to the urea cycle, in order to ensure lowering of plasma ammonia concentrations to the normal range. Independent of its etiology, hyperammonemia may result in irreversible brain damage if not treated early and thoroughly. Thus, early recognition of a hyperammonemic state and immediate initiation of the specific management are of utmost importance. The main prognostic factors are, irrespective of the underlying cause, the duration of the hyperammonemic coma and the extent of ammonia accumulation. This paper will discuss the biochemical background of primary and secondary hyperammonemia and will give an overview of the various underlying conditions including a brief clinical outline and information on the genetic backgrounds.


Asunto(s)
Amoníaco/metabolismo , Hiperamonemia/metabolismo , Hiperamonemia/fisiopatología , Urea/metabolismo , N-Acetiltransferasa de Aminoácidos/metabolismo , Animales , Glutamato-Amoníaco Ligasa/metabolismo , Humanos , Hiperamonemia/enzimología , Hiperamonemia/etiología
10.
Anal Bioanal Chem ; 405(4): 1345-51, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23143007

RESUMEN

Mitochondrial fatty acid oxidation (FAO) disorders are caused by defects in one of the FAO enzymes that regulates cellular uptake of fatty acids and free carnitine. An in vitro probe acylcarnitine (IVP) assay using cultured cells and tandem mass spectrometry is a tool to diagnose enzyme defects linked to most FAO disorders. Extracellular acylcarnitine (AC) profiling detects carnitine palmitoyltransferase-2, carnitine acylcarnitine translocase, and other FAO deficiencies. However, the diagnosis of primary carnitine deficiency (PCD) or carnitine palmitoyltransferase-1 (CPT1) deficiency using the conventional IVP assay has been hampered by the presence of a large amount of free carnitine (C0), a key molecule deregulated by these deficiencies. In the present study, we developed a novel IVP assay for the diagnosis of PCD and CPT1 deficiency by analyzing intracellular ACs. When exogenous C0 was reduced, intracellular C0 and total AC in these deficiencies showed specific profiles clearly distinguishable from other FAO disorders and control cells. Also, the ratio of intracellular to extracellular C0 levels showed a significant difference in cells with these deficiencies compared with control. Hence, intracellular AC profiling using the IVP assay under reduced C0 conditions is a useful method for diagnosing PCD or CPT1 deficiency.


Asunto(s)
Cardiomiopatías/diagnóstico , Carnitina/análogos & derivados , Hiperamonemia/diagnóstico , Hipoglucemia/diagnóstico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Enfermedades Musculares/diagnóstico , Espectrometría de Masas en Tándem/métodos , Transporte Biológico , Cardiomiopatías/enzimología , Cardiomiopatías/metabolismo , Carnitina/análisis , Carnitina/deficiencia , Carnitina/metabolismo , Carnitina Aciltransferasas/deficiencia , Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/metabolismo , Células Cultivadas , Ácidos Grasos/metabolismo , Fibroblastos/química , Fibroblastos/enzimología , Fibroblastos/metabolismo , Humanos , Hiperamonemia/enzimología , Hiperamonemia/metabolismo , Hipoglucemia/enzimología , Hipoglucemia/metabolismo , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/metabolismo , Mitocondrias/metabolismo , Enfermedades Musculares/enzimología , Enfermedades Musculares/metabolismo , Oxidación-Reducción , Espectrometría de Masa por Ionización de Electrospray/métodos
11.
Mol Genet Metab ; 106(2): 160-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22503289

RESUMEN

All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-l-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. Founder NAGS knockout heterozygous mice were obtained from the trans-NIH Knock-Out Mouse Project. Genotyping of the mice was performed by PCR and confirmed by Western blotting of liver and intestine. NCG and L-citrulline (Cit) were used to rescue the NAGS knockout homozygous (Nags(-/-)) pups and the rescued animals were characterized. We observed an 85% survival rate of Nags(-/-) mice when they were given intraperitoneal injections with NCG and Cit during the newborn period until weaning and supplemented subsequently with both compounds in their drinking water. This regimen has allowed for normal development, apparent health, and reproduction. Interruption of this rescue intervention resulted in the development of severe hyperammonemia and death within 48 h. In addition to hyperammonemia, interruption of rescue supplementation was associated with elevated plasma glutamine, glutamate, and lysine, and reduced citrulline, arginine, ornithine and proline levels. We conclude that NAGS deprived mouse model has been developed which can be rescued by NCG and Cit and reared to reproduction and beyond. This biochemically salvageable mouse model recapitulates the clinical phenotype of proximal urea cycle disorders and can be used as a reliable model of induced hyperammonemia by manipulating the administration of the rescue compounds.


Asunto(s)
N-Acetiltransferasa de Aminoácidos/deficiencia , Modelos Animales de Enfermedad , Hiperamonemia/enzimología , Ratones , N-Acetiltransferasa de Aminoácidos/genética , N-Acetiltransferasa de Aminoácidos/metabolismo , Animales , Cruzamiento , Femenino , Orden Génico , Marcación de Gen , Genotipo , Glutamatos/uso terapéutico , Humanos , Hiperamonemia/tratamiento farmacológico , Hiperamonemia/genética , Hiperamonemia/mortalidad , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo
12.
Genet Med ; 14(5): 501-7, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22241104

RESUMEN

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.


Asunto(s)
Aciduria Argininosuccínica/diagnóstico , Aciduria Argininosuccínica/genética , Arginina/metabolismo , Arginina/uso terapéutico , Argininosuccinatoliasa/genética , Ácido Argininosuccínico/sangre , Ácido Argininosuccínico/metabolismo , Ácido Argininosuccínico/orina , Aciduria Argininosuccínica/terapia , Preescolar , Citrulina/sangre , Trastornos del Conocimiento/enzimología , Trastornos del Conocimiento/genética , Dieta con Restricción de Proteínas , Fumaratos/metabolismo , Pruebas Genéticas , Glucosa/uso terapéutico , Humanos , Hiperamonemia/enzimología , Hiperamonemia/genética , Hipertensión/enzimología , Hipertensión/genética , Lactante , Recién Nacido , Lípidos/uso terapéutico , Hepatopatías/enzimología , Hepatopatías/genética , Trasplante de Hígado , Tamizaje Neonatal , Fenilbutiratos/uso terapéutico , Benzoato de Sodio/uso terapéutico
13.
Neurochem Res ; 37(1): 171-81, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21922254

RESUMEN

Acute hyperammonemia (HA) induced oxidative stress in the brain is considered to play critical roles in the neuropathology of end stage hepatic encephalopathy (HE). Moderate grade HA led minimal/moderate type HE is more common in the patients with chronic liver failure. However, implication of oxygen free radical ([Formula: see text]) based oxidative mechanisms remain to be defined during moderate grade HA. This article describes profiles of all the antioxidant enzymes Vis a Vis status of oxidative stress/damage in the brain slices exposed to 0.1-1 mM ammonia, reported to exist in the brain of animals with chronic liver failure and in liver cirrhotic patients. Superoxide dismutase catalyzes the first step of antioxidant mechanism and, with concerted activity of catalase, neutralizes [Formula: see text] produced in the cells. Both these enzymes remained unchanged up to 0.2-0.3 mM ammonia, however, with significant increments (P < 0.01-0.001) in the brain slices exposed to 0.5-1 mM ammonia. This was consistent with the similar pattern of production of reactive oxygen species in the brain slices. However, level of lipid peroxidation remained unchanged throughout the ammonia treatment. Synchronized activities of glutathione peroxidase and glutathione reductase regulate the level of glutathione to maintain reducing equivalents in the cells. The activities of both these enzymes also increased significantly in the brain slices exposed to 0.5-1 mM ammonia with concomitant increments in GSH/GSSG ratio and in the levels of total and protein bound thiol. The findings suggest resistance of brain cells from ammonia induced oxidative damage during moderate grade HA due to concordant activations of antioxidant enzymes.


Asunto(s)
Encéfalo/metabolismo , Hiperamonemia/enzimología , Estrés Oxidativo , Animales , Encéfalo/enzimología , Electroforesis en Gel de Poliacrilamida , Activación Enzimática , Femenino , Técnicas In Vitro , Peroxidación de Lípido , Ratas , Especies Reactivas de Oxígeno/metabolismo
14.
Anesth Analg ; 113(4): 858-61, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21821508

RESUMEN

We present a case of significant deterioration of chronic hyperammonemia after general anesthesia for neurosurgery despite aggressive treatment. Preoperative evaluation demonstrated that hyperammonemia was most likely related to valproic acid treatment. Genomic analysis revealed that the patient was heterozygotic for a missense polymorphism in the carbamoyl phosphate synthase 1 gene (4217C>A, rs1047891). This mutation was previously suggested to be associated with chronic hyperammonemia. Replacement of threonine with asparagine decreases the activity of carbamoyl phosphate synthase in the urea cycle. Genetic screening can potentially identify a population at risk before initiation of antiepileptic therapy.


Asunto(s)
Carbamoil-Fosfato Sintasa (Amoniaco)/genética , Hiperamonemia/etiología , Procedimientos Neuroquirúrgicos/efectos adversos , Trastornos Innatos del Ciclo de la Urea/genética , Ácido Valproico/efectos adversos , Adulto , Carbamoil-Fosfato Sintasa (Amoniaco)/deficiencia , Enfermedad por Deficiencia de Carbamoil-Fosfato Sintasa I , Enfermedad Crónica , Análisis Mutacional de ADN , Remoción de Dispositivos , Suministros de Energía Eléctrica , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Hiperamonemia/inducido químicamente , Hiperamonemia/enzimología , Hiperamonemia/genética , Masculino , Mutación Missense , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Trastornos Innatos del Ciclo de la Urea/complicaciones , Estimulación del Nervio Vago/instrumentación
15.
Mol Genet Metab ; 103(1): 89-91, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21353613

RESUMEN

Glutamine deficiency with hyperammonemia due to an inherited defect of glutamine synthetase (GS) was found in a 2 year old patient. He presented neonatal seizures and developed chronic encephalopathy. Thus, GS deficiency leads to severe neurological disease but is not always early lethal.


Asunto(s)
Encefalopatías Metabólicas/enzimología , Glutamato-Amoníaco Ligasa/deficiencia , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/patología , Preescolar , Exantema/patología , Glutamato-Amoníaco Ligasa/genética , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/enzimología , Hiperamonemia/patología , Masculino , Mutación/genética
16.
Am J Med Genet C Semin Med Genet ; 157C(1): 45-53, 2011 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21312326

RESUMEN

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.


Asunto(s)
Argininosuccinatoliasa/genética , Aciduria Argininosuccínica/diagnóstico , Aciduria Argininosuccínica/genética , Aciduria Argininosuccínica/metabolismo , Arginasa/genética , Arginasa/metabolismo , Arginina/genética , Arginina/metabolismo , Ácido Argininosuccínico/metabolismo , Aciduria Argininosuccínica/terapia , Carboxiliasas/genética , Carboxiliasas/metabolismo , Humanos , Hiperamonemia/enzimología , Hiperamonemia/genética , Hiperamonemia/metabolismo , Recién Nacido , Hepatopatías/enzimología , Hepatopatías/genética , Hepatopatías/metabolismo , Tamizaje Neonatal , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Ornitina/genética , Ornitina/metabolismo , Trastornos Innatos del Ciclo de la Urea/enzimología , Trastornos Innatos del Ciclo de la Urea/genética , Trastornos Innatos del Ciclo de la Urea/metabolismo
17.
Mol Genet Metab ; 102(3): 349-55, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21190881

RESUMEN

Pyruvate dehydrogenase kinase 4 (PDK4) mRNA has been reported as an up-regulated gene in the heart and skeletal muscle of carnitine-deficient juvenile visceral steatosis (JVS) mice under fed conditions. PDK4 plays an important role in the inhibition of glucose oxidation via the phosphorylation of pyruvate dehydrogenase complex (PDC). This study evaluated the meaning of increased PDK4 mRNA in glucose metabolism by investigating PDK4 protein levels, PDC activity and glucose uptake by the heart and skeletal muscle of JVS mice. PDK4 protein levels in the heart and skeletal muscle of fed JVS mice were increased in accordance with mRNA levels, and protein was enriched in the mitochondria. PDK4 protein was co-fractionated with PDC in sucrose density gradient centrifugation, like PDK2 protein; however, the activities of the pyruvate dehydrogenase complex (PDC) active form in the heart and skeletal muscle of fed JVS mice were similar to those in fed control mice. Fed JVS mice showed significantly higher glucose uptake in the heart and similar uptake in the skeletal muscle compared with fed control mice. Thus, in carnitine deficiency under fed conditions, glucose was preferentially utilized in the heart as an energy source despite increased PDK4 protein levels in the mitochondria. The preferred glucose utilization may be involved in developing cardiac hypertrophy from carnitine deficiency in fatty acid oxidation abnormality.


Asunto(s)
Modelos Animales de Enfermedad , Glucosa/metabolismo , Miocardio/enzimología , Proteínas Quinasas/metabolismo , Animales , Cardiomiopatías/enzimología , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Carnitina/deficiencia , Carnitina/genética , Carnitina/metabolismo , Femenino , Hiperamonemia/enzimología , Hiperamonemia/genética , Hiperamonemia/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Debilidad Muscular/enzimología , Debilidad Muscular/genética , Debilidad Muscular/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Musculares , Proteínas Quinasas/genética , Transporte de Proteínas , Complejo Piruvato Deshidrogenasa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Fracciones Subcelulares/metabolismo
18.
Bull Exp Biol Med ; 150(1): 36-8, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21161045

RESUMEN

We studied the effect of acute ammonia poisoning and CCl4-induced subacute hepatitis on activities of AMP deaminase and adenosine deaminase in rat liver. Both models of liver failure were accompanied by an increase in activities of AMP deaminase and adenosine deaminase in the cytoplasmic fraction of the liver (by 2.4-4.2 times compared to the control). A direct correlation was found between activities of AMP deaminase and adenosine deaminase. We believe that two parallel pathways of AMP degradation are activated simultaneously, which leads to rapid depletion of adenylate reserves under pathological conditions.


Asunto(s)
AMP Desaminasa/metabolismo , Adenosina Desaminasa/metabolismo , Amoníaco/toxicidad , Hepatitis/enzimología , Hiperamonemia/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Análisis de Varianza , Animales , Tetracloruro de Carbono/toxicidad , Hepatitis/etiología , Hiperamonemia/inducido químicamente , Masculino , Ratas , Ratas Wistar
19.
Am J Obstet Gynecol ; 203(1): e10-1, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20471629

RESUMEN

Carbamyl phosphate synthetase (CPS) is an enzyme that converts ammonia to carbamyl phosphate in the urea cycle. CPS deficiency is a genetic disorder that causes hyperammonemia because of enzyme activity deficiency. It is primarily diagnosed in neonates and infants and has a poor prognosis. We report an adult woman with CPS deficiency who developed hyperammonemia postpartum.


Asunto(s)
Carbamoil-Fosfato Sintasa (Amoniaco)/deficiencia , Hiperamonemia/enzimología , Periodo Posparto/sangre , Adulto , Amoníaco/sangre , Femenino , Humanos , Hiperamonemia/sangre , Hiperamonemia/diagnóstico , Hiperamonemia/terapia , Embarazo , Diálisis Renal
20.
Arch Dis Child ; 95(4): 296-301, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20335238

RESUMEN

OBJECTIVE: Mitochondrial disturbances of energygenerating systems in childhood are a heterogeneous group of disorders. The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene. METHODS: Retrospective clinical data and metabolic profiles were collected and evaluated in 25 patients (14 boys, 11 girls) from seven European countries with a c.317-2A-->G mutation in the TMEM70 gene. RESULTS: Severe muscular hypotonia (in 92% of newborns), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%) and profound lactic acidosis (lactate 5-36 mmol/l; 92%) with hyperammonaemia (100-520 micromol/l; 86%) were present from birth. Ten patients died within the first 6 weeks of life. Most patients surviving the neonatal period had persisting muscular hypotonia and developed psychomotor delay. HCMP was non-progressive and even disappeared in some children. Hypospadia was present in 54% of the boys and cryptorchidism in 67%. Increased excretion of lactate and 3-methylglutaconic acid (3-MGC) was observed in all patients. In four surviving patients, life-threatening hyperammonaemia occurred during childhood, triggered by acute gastroenteritis and prolonged fasting. CONCLUSIONS: ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of critically ill neonates with early neonatal onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. However, phenotype severity may vary significantly. The disease occurs frequently in the Roma population and molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis without need of muscle biopsy in affected children.


Asunto(s)
Proteínas de la Membrana/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación , Edad de Inicio , Criptorquidismo/enzimología , Criptorquidismo/genética , Femenino , Humanos , Hiperamonemia/enzimología , Hiperamonemia/genética , Hipospadias/enzimología , Hipospadias/genética , Lactante , Recién Nacido , Masculino , Encefalomiopatías Mitocondriales/enzimología , ATPasas de Translocación de Protón Mitocondriales/deficiencia , Fenotipo , Estudios Retrospectivos
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