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1.
J Neurosci Res ; 100(4): 992-1007, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34713466

RESUMEN

Glutaric acidemia type I (GA-I) is an inborn error of metabolism of lysine, hydroxylysine, and tryptophan, caused by glutaryl-CoA-dehydrogenase (GCDH) deficiency, characterized by the buildup of toxic organic acids predominantly in the brain. After acute catabolic states, patients usually develop striatal degeneration, but the mechanisms behind this damage are still unknown. Quinolinic acid (QA), a metabolite of the kynurenine pathway, increases especially during infections/inflammatory processes, and could act synergically with organic acids, contributing to the neurological features of GA-I. The aim of this study was to investigate whether QA increases seizure susceptibility and modifies brain oscillation patterns in an animal model of GA-I, the Gcdh-/- mice taking high-lysine diet (Gcdh-/- -Lys). Therefore, the characteristics of QA-induced seizures and changes in brain oscillatory patterns were evaluated by video-electroencephalography (EEG) analysis recorded in Gcdh-/- -Lys, Gcdh+/+ -Lys, and Gcdh-/- -N (normal diet) animals. We found that the number of seizures per animal was similar for all groups receiving QA, Gcdh-/- -Lys-QA, Gcdh+/+ -Lys-QA, and Gcdh-/- -N-QA. However, severe seizures were observed in the majority of Gcdh-/- -Lys-QA mice (82%), and only in 25% of Gcdh+/+ -Lys-QA and 44% of Gcdh-/- -N-QA mice. All Gcdh-/- -Lys animals developed spontaneous recurrent seizures (SRS), but Gcdh-/- -Lys-QA animals had increased number of SRS, higher mortality rate, and significant predominance of lower frequency oscillations on EEG. Our results suggest that QA plays an important role in the neurological features of GA-I, as Gcdh-/- -Lys mice exhibit increased susceptibility to intrastriatal QA-induced seizures and long-term changes in brain oscillations.


Asunto(s)
Lisina , Ácido Quinolínico , Errores Innatos del Metabolismo de los Aminoácidos , Animales , Encéfalo/metabolismo , Encefalopatías Metabólicas , Modelos Animales de Enfermedad , Glutaril-CoA Deshidrogenasa/deficiencia , Humanos , Lisina/metabolismo , Lisina/farmacología , Ratones , Ratones Noqueados , Ácido Quinolínico/toxicidad , Convulsiones/inducido químicamente , Convulsiones/metabolismo
2.
Mol Genet Metab ; 133(3): 231-241, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33985889

RESUMEN

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.


Asunto(s)
Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/terapia , Metabolismo , Administración Intravenosa , Niño , Dieta Cetogénica , Glucosa/administración & dosificación , Humanos , Lípidos/administración & dosificación , Estado Nutricional , Vitaminas/administración & dosificación
3.
Hum Mol Genet ; 24(16): 4504-15, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25968119

RESUMEN

Glutaric acidemia type I (GA-I) is an inherited neurometabolic childhood disorder caused by defective activity of glutaryl CoA dehydrogenase (GCDH) which disturb lysine (Lys) and tryptophan catabolism leading to neurotoxic accumulation of glutaric acid (GA) and related metabolites. However, it remains unknown whether GA toxicity is due to direct effects on vulnerable neurons or mediated by GA-intoxicated astrocytes that fail to support neuron function and survival. As damaged astrocytes can also contribute to sustain high GA levels, we explored the ability of Gcdh-/- mouse astrocytes to produce GA and induce neuronal death when challenged with Lys. Upon Lys treatment, Gcdh-/- astrocytes synthetized and released GA and 3-hydroxyglutaric acid (3HGA). Lys and GA treatments also increased oxidative stress and proliferation in Gcdh-/- astrocytes, both prevented by antioxidants. Pretreatment with Lys also caused Gcdh-/- astrocytes to induce extensive death of striatal and cortical neurons when compared with milder effect in WT astrocytes. Antioxidants abrogated the neuronal death induced by astrocytes exposed to Lys or GA. In contrast, Lys or GA direct exposure on Gcdh-/- or WT striatal neurons cultured in the absence of astrocytes was not toxic, indicating that neuronal death is mediated by astrocytes. In summary, GCDH-defective astrocytes actively contribute to produce and accumulate GA and 3HGA when Lys catabolism is stressed. In turn, astrocytic GA production induces a neurotoxic phenotype that kills striatal and cortical neurons by an oxidative stress-dependent mechanism. Targeting astrocytes in GA-I may prompt the development of new antioxidant-based therapeutical approaches.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Astrocitos/metabolismo , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/metabolismo , Cuerpo Estriado/metabolismo , Glutaril-CoA Deshidrogenasa/deficiencia , Neuronas/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/patología , Animales , Astrocitos/patología , Encefalopatías Metabólicas/patología , Supervivencia Celular/genética , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Glutaril-CoA Deshidrogenasa/genética , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Ratones , Ratones Noqueados , Neuronas/patología
4.
Epilepsia ; 58(10): 1771-1781, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28762469

RESUMEN

OBJECTIVES: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/- -Lys). METHODS: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. RESULTS: SRS were observed in 72% of Gcdh-/- -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/- -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/- -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/- -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. SIGNIFICANCE: Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh-/- mice under high lysine diet (Gcdh-/- -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh-/- -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Encefalopatías Metabólicas/genética , Encéfalo/efectos de los fármacos , Epilepsia/genética , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Ácido gamma-Aminobutírico/efectos de los fármacos , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Animales , Western Blotting , Encefalopatías Metabólicas/metabolismo , Cromatografía Líquida de Alta Presión , Epilepsia/metabolismo , Antagonistas del GABA/farmacología , Glutamato Descarboxilasa , Ácido Glutámico/efectos de los fármacos , Ácido Glutámico/metabolismo , Glutaril-CoA Deshidrogenasa/metabolismo , Ratones , Ratones Noqueados , Pentilenotetrazol/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Ácido gamma-Aminobutírico/metabolismo
5.
Mol Genet Metab ; 119(1-2): 50-6, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27397597

RESUMEN

Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Biomarcadores , Encefalopatías Metabólicas/genética , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Tamizaje Neonatal , Negro o Afroamericano/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/fisiopatología , Femenino , Frecuencia de los Genes , Glutaratos/metabolismo , Humanos , Recién Nacido , Masculino , Mutación , Fenotipo , Espectrometría de Masas en Tándem
7.
Mol Genet Metab ; 108(1): 30-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23218171

RESUMEN

Deficiency of glutaryl-CoA dehydrogenase (GCDH) activity or glutaric aciduria type I (GA I) is an inherited neurometabolic disorder biochemically characterized by predominant accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and other tissues. Affected patients usually present acute striatum necrosis during encephalopathic crises triggered by metabolic stress situations, as well as chronic leukodystrophy and delayed myelination. Considering that the mechanisms underlying the brain injury in this disease are not yet fully established, in the present study we investigated important parameters of oxidative stress in the brain (cerebral cortex, striatum and hippocampus), liver and heart of 30-day-old GCDH deficient knockout (Gcdh(-/-)) and wild type (WT) mice submitted to a normal lysine (Lys) (0.9% Lys), or high Lys diets (2.8% or 4.7% Lys) for 60 h. It was observed that the dietary supplementation of 2.8% and 4.7% Lys elicited noticeable oxidative stress, as verified by an increase of malondialdehyde concentrations (lipid oxidative damage) and 2-7-dihydrodichlorofluorescein (DCFH) oxidation (free radical production), as well as a decrease of reduced glutathione levels and alteration of various antioxidant enzyme activities (antioxidant defenses) in the cerebral cortex and the striatum, but not in the hippocampus, the liver and the heart of Gcdh(-/-) mice, as compared to WT mice receiving the same diets. Furthermore, alterations of oxidative stress parameters in the cerebral cortex and striatum were more accentuated in symptomatic, as compared to asymptomatic Gcdh(-/-) mice exposed to 4.7% Lys overload. Histopathological studies performed in the cerebral cortex and striatum of these animals exposed to high dietary Lys revealed increased expression of oxidative stress markers despite the absence of significant structural damage. The results indicate that a disruption of redox homeostasis in the cerebral cortex and striatum of young Gcdh(-/-) mice exposed to increased Lys diet may possibly represent an important pathomechanism of brain injury in GA I patients under metabolic stress.


Asunto(s)
Encéfalo/metabolismo , Glutaril-CoA Deshidrogenasa/metabolismo , Homeostasis , Lisina/administración & dosificación , Animales , Suplementos Dietéticos , Glutaril-CoA Deshidrogenasa/genética , Ratones , Ratones Noqueados , Oxidación-Reducción , Estrés Oxidativo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
8.
Mol Genet Metab ; 106(1): 31-8, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22445450

RESUMEN

In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA-RS), 2-7-dihydrodichlorofluorescein (DCFH) oxidation, sulfhydryl content, and reduced glutathione (GSH) concentrations. We also measured the activities of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD). Under basal conditions glutaric (GA) and 3-OH-glutaric (3OHGA) acids were elevated in all tissues of the Gcdh(-/-) mice, but were essentially absent in WT animals. In contrast there were no differences between WT and Gcdh(-/-) mice in any of the indicators or oxidative stress under basal conditions. Following a single intra-peritoneal (IP) injection of lysine (Lys) there was a moderate increase of brain GA concentration in Gcdh(-/-) mice, but no change in WT. Lys injection had no effect on brain 3OHGA in either WT or Gcdh(-/-) mice. The levels of GA and 3OHGA were approximately 40% higher in striatum compared to cerebral cortex in Lys-treated mice. In the striatum, Lys administration provoked a marked increase of lipid peroxidation, DCFH oxidation, SOD and GR activities, as well as significant reductions of GSH levels and GPx activity, with no alteration of sulfhydryl content, CAT and G6PD activities. There was also evidence of increased lipid peroxidation and SOD activity in the cerebral cortex, along with a decrease of GSH levels, but to a lesser extent than in the striatum. In the hippocampus only mild increases of SOD activity and DCFH oxidation were observed. In contrast, Lys injection had no effect on any of the parameters of oxidative stress in the liver or heart of Gcdh(-/-) or WT animals. These results indicate that in Gcdh(-/-) mice cerebral tissue, particularly the striatum, is at greater risk for oxidative stress than peripheral tissues following Lys administration.


Asunto(s)
Antioxidantes/metabolismo , Encéfalo/metabolismo , Glutaril-CoA Deshidrogenasa , Lisina/administración & dosificación , Estrés Oxidativo , Animales , Encéfalo/enzimología , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Peroxidación de Lípido , Hígado/enzimología , Hígado/metabolismo , Lisina/efectos adversos , Ratones , Ratones Transgénicos , Miocardio/enzimología , Miocardio/metabolismo , Distribución Tisular
9.
Mol Genet Metab ; 107(3): 375-82, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22999741

RESUMEN

Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+-ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.7%) diet. When a baseline (0.9% Lys) diet was given, we verified mild alterations of the activities of some respiratory chain complexes in cerebral cortex and hippocampus, but not in striatum from Gcdh-/- mice as compared to WT animals. Furthermore, the mitochondrial respiratory parameters and the activities of α-KGDH and CK were not modified in all brain structures from Gcdh-/- mice. In contrast, we found a significant reduction of Na(+), K(+)-ATPase activity associated with a lower degree of its expression in cerebral cortex from Gcdh-/- mice. Furthermore, a high Lys (4.7%) diet did not accentuate the biochemical alterations observed in Gcdh-/- mice fed with a normal diet. Since Na(+), K(+)-ATPase activity is required for cell volume regulation and to maintain the membrane potential necessary for a normal neurotransmission, it is presumed that reduction of this enzyme activity may represent a potential underlying mechanism involved in the brain swelling and cortical abnormalities (cortical atrophy with leukodystrophy) observed in patients affected by GA I.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/patología , Corteza Cerebral/patología , Cuerpo Estriado/patología , Glutaril-CoA Deshidrogenasa/deficiencia , Hipocampo/patología , ATPasa Intercambiadora de Sodio-Potasio/genética , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Animales , Encefalopatías Metabólicas/enzimología , Corteza Cerebral/enzimología , Cuerpo Estriado/enzimología , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Regulación hacia Abajo , Transporte de Electrón/genética , Alimentos Formulados , Expresión Génica , Glutaril-CoA Deshidrogenasa/genética , Hipocampo/enzimología , Humanos , Complejo Cetoglutarato Deshidrogenasa/genética , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Ratones , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/metabolismo , Fosforilación Oxidativa , ATPasa Intercambiadora de Sodio-Potasio/metabolismo
10.
Mol Genet Metab ; 107(1-2): 81-6, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22578804

RESUMEN

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric (GA) and 3-hydroxyglutaric (3HGA) acids in the brain and other tissues. Affected patients usually present with hypotonia and brain damage and acute encephalopathic episodes whose pathophysiology is not yet fully established. In this study we investigated important parameters of cellular bioenergetics in brain, heart and skeletal muscle from 15-day-old glutaryl-CoA dehydrogenase deficient mice (Gcdh(-/-)) submitted to a single intra-peritoneal injection of saline (Sal) or lysine (Lys - 8 µmol/g) as compared to wild type (WT) mice. We evaluated the activities of the respiratory chain complexes II, II-III and IV, α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and synaptic Na(+), K(+)-ATPase. No differences of all evaluated parameters were detected in the Gcdh(-/-) relatively to the WT mice injected at baseline (Sal). Furthermore, mild increases of the activities of some respiratory chain complexes (II-III and IV) were observed in heart and skeletal muscle of Gcdh(-/-) and WT mice after Lys administration. However, the most marked effects provoked by Lys administration were marked decreases of the activities of Na(+), K(+)-ATPase in brain and CK in brain and skeletal muscle of Gcdh(-/-) mice. In contrast, brain α-KGDH activity was not altered in WT and Gcdh(-/-) injected with Sal or Lys. Our results demonstrate that reduction of Na(+), K(+)-ATPase and CK activities may play an important role in the pathogenesis of the neurodegenerative changes in GA I.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Creatina Quinasa/metabolismo , Lisina/farmacología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encefalopatías Metabólicas/tratamiento farmacológico , Modelos Animales de Enfermedad , Transporte de Electrón/efectos de los fármacos , Transporte de Electrón/fisiología , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/metabolismo , Corazón/efectos de los fármacos , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Lisina/administración & dosificación , Ratones , Ratones Noqueados , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miocardio/metabolismo
11.
J Clin Invest ; 117(11): 3258-70, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17932566

RESUMEN

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.


Asunto(s)
Envejecimiento/fisiología , Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas Innatas , Glutaratos/metabolismo , Glutaril-CoA Deshidrogenasa/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Encefalopatías Metabólicas Innatas/dietoterapia , Encefalopatías Metabólicas Innatas/patología , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Dieta , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Glucosa/metabolismo , Glucosa/uso terapéutico , Ácido Glutámico/metabolismo , Glutaril-CoA Deshidrogenasa/genética , Homoarginina/metabolismo , Homoarginina/uso terapéutico , Humanos , Lisina/metabolismo , Lisina/uso terapéutico , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Neuronas/metabolismo , Neuronas/patología , Neuronas/ultraestructura , Resonancia Magnética Nuclear Biomolecular , Triptófano/metabolismo , Ácido gamma-Aminobutírico/metabolismo
12.
Mol Neurobiol ; 56(1): 648-657, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29779173

RESUMEN

Glutaric acidemia type I (GA-I) is a neurometabolic disease caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH) that results in accumulation of metabolites derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA-I patients typically develop encephalopatic crises with striatal degeneration and progressive white matter defects. However, late onset patients as well as Gcdh-/- mice only suffer diffuse myelinopathy, suggesting that neuronal death and white matter defects are different pathophysiological events. To test this hypothesis, striatal myelin was studied in Gcdh-/- mice fed from 30 days of age during up to 60 days with a diet containing normal or moderately increased amounts of Lys (2.8%), which ensure sustained elevated levels of GA-I metabolites. Gcdh-/- mice fed with 2.8% Lys diet showed a significant decrease in striatal-myelinated areas and progressive vacuolation of white matter tracts, as compared with animals fed with normal diet. Myelin pathology increased with the time of exposure to high Lys diet and was also detected in 90-day old Gcdh-/- mice fed with normal diet, suggesting that dietary Lys accelerated the undergoing white matter damage. Gcdh-/- mice fed with 2.8% Lys diet also showed increased GRP78/BiP immunoreactivity in oligodendrocytes and neurons, denoting ER stress. However, the striatal and cortical neuronal density was unchanged with respect to normal diet. Thus, myelin damage seen in Gcdh-/- mice fed with 2.8% Lys seems to be mediated by a long-term increased levels of GA-I metabolites having deleterious effects in myelinating oligodendrocytes over neurons.


Asunto(s)
Dieta , Glutaril-CoA Deshidrogenasa/deficiencia , Lisina/efectos adversos , Sustancia Blanca/enzimología , Sustancia Blanca/lesiones , Animales , Recuento de Células , Muerte Celular/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Chaperón BiP del Retículo Endoplásmico , Glutaril-CoA Deshidrogenasa/metabolismo , Ratones , Vaina de Mielina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Sustancia Blanca/patología
13.
Mol Genet Metab ; 95(4): 201-5, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18974016

RESUMEN

We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the pharmacokinetic factors of successful biotin treatment. A girl exhibited abnormal skin at birth, and developed in the first days of life neonatal respiratory distress syndrome and metabolic abnormalities diagnostic of multiple carboxylase deficiency. Enzyme assays showed low carboxylase activities. Fibroblast analysis showed poor incorporation of biotin into the carboxylases, and low transfer of biotin by the holocarboxylase synthetase enzyme. Kinetic studies identified an increased Km but a preserved Vmax. Mutation analysis showed the child to be a compound heterozygote for a new nonsense mutation Q379X and for a novel missense mutation Y663H. This mutation affects a conserved amino acid, which is located the most 3' of all recorded missense mutations thus far described, and extends the region of functional biotin interaction. Treatment with biotin 100mg/day gradually improved the biochemical abnormalities in blood and in cerebrospinal fluid (CSF), corrected the carboxylase enzyme activities, and provided clinical stability and a normal neurodevelopmental outcome. Plasma concentrations of biotin were increased to more than 500 nM, thus exceeding the increased Km of the mutant enzyme. At these pharmacological concentrations, the CSF biotin concentration was half the concentration in blood. Measuring these pharmacokinetic variables can aid in optimizing treatment, as individual tailoring of dosing to the needs of the mutation may be required.


Asunto(s)
Biotina/administración & dosificación , Ligasas de Carbono-Nitrógeno/deficiencia , Deficiencia de Holocarboxilasa Sintetasa/tratamiento farmacológico , Secuencia de Aminoácidos , Biotina/metabolismo , Ligasas de Carbono-Nitrógeno/química , Ligasas de Carbono-Nitrógeno/genética , Células Cultivadas , Femenino , Deficiencia de Holocarboxilasa Sintetasa/genética , Deficiencia de Holocarboxilasa Sintetasa/metabolismo , Humanos , Recién Nacido , Cinética , Datos de Secuencia Molecular , Mutación , Alineación de Secuencia
14.
Brain ; 129(Pt 4): 899-910, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16446282

RESUMEN

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/etiología , Dieta/efectos adversos , Proteínas en la Dieta/toxicidad , Modelos Animales de Enfermedad , Glutaratos/orina , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Barrera Hematoencefálica , Permeabilidad Capilar/efectos de los fármacos , Cuerpo Estriado/irrigación sanguínea , Proteínas en la Dieta/administración & dosificación , Femenino , Glutaratos/farmacología , Lisina/toxicidad , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/patología , Análisis de Supervivencia , Técnicas de Cultivo de Tejidos
15.
JCI Insight ; 2(21)2017 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-29093265

RESUMEN

Maternal obesity is a global health problem that increases offspring obesity risk. The metabolic pathways underlying early developmental programming in human infants at risk for obesity remain poorly understood, largely due to barriers in fetal/infant tissue sampling. Utilizing umbilical cord-derived mesenchymal stem cells (uMSC) from offspring of normal weight and obese mothers, we tested whether energy metabolism and gene expression differ in differentiating uMSC myocytes and adipocytes, in relation to maternal obesity exposures and/or neonatal adiposity. Biomarkers of incomplete ß-oxidation were uniquely positively correlated with infant adiposity and maternal lipid levels in uMSC myocytes from offspring of obese mothers only. Metabolic and biosynthetic processes were enriched in differential gene expression analysis related to maternal obesity. In uMSC adipocytes, maternal obesity and lipids were associated with downregulation in multiple insulin-dependent energy-sensing pathways including PI3K and AMPK. Maternal lipids correlated with uMSC adipocyte upregulation of the mitochondrial respiratory chain but downregulation of mitochondrial biogenesis. Overall, our data revealed cell-specific alterations in metabolism and gene expression that correlated with maternal obesity and adiposity of their offspring, suggesting tissue-specific metabolic and regulatory changes in these newborn cells. We provide important insight into potential developmental programming mechanisms of increased obesity risk in offspring of obese mothers.


Asunto(s)
Adiposidad/fisiología , Regulación del Desarrollo de la Expresión Génica , Células Madre Mesenquimatosas/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Adiposidad/genética , Aminoácidos/análisis , Biomarcadores , Carnitina/análogos & derivados , Carnitina/análisis , Colorado , Transporte de Electrón/genética , Metabolismo Energético/genética , Ácidos Grasos/metabolismo , Femenino , Humanos , Lactante , Recién Nacido , Insulina/metabolismo , Metabolismo de los Lípidos , Lípidos/análisis , Estudios Longitudinales , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Células Madre Mesenquimatosas/patología , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales , Células Musculares/metabolismo , Células Musculares/patología , Embarazo
16.
Mol Neurobiol ; 54(6): 4795-4805, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-27510504

RESUMEN

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-ß and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-ß and NF-ƙB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/patología , Astrocitos/patología , Encefalopatías Metabólicas/patología , Corteza Cerebral/patología , Glutaril-CoA Deshidrogenasa/deficiencia , Mitocondrias/metabolismo , Degeneración Nerviosa/patología , Estrés Oxidativo/efectos de los fármacos , Vitamina K 3/toxicidad , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Animales , Antioxidantes/metabolismo , Astrocitos/efectos de los fármacos , Encefalopatías Metabólicas/enzimología , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fluoresceínas/metabolismo , Glutatión Peroxidasa/metabolismo , Mediadores de Inflamación/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Degeneración Nerviosa/enzimología , Óxido Nítrico/metabolismo , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo
17.
JIMD Rep ; 25: 15-19, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26141459

RESUMEN

2-Ketoadipic aciduria (OMIM 204750), a defect in the catabolic pathway of tryptophan, lysine, and hydroxylysine, is characterized by elevations in 2-ketoadipic, 2-aminoadipic, and 2-hydroxyadipic acids. Patients with the aforementioned biochemical profile have been described with a wide range of clinical presentations, from early-onset developmental delay, epilepsy, ataxia, and microcephaly to completely normal. This broad range of phenotypes has led some to question whether 2-ketoadipic aciduria represents a true disease state or if the biochemical abnormalities found in these patients merely reflect an ascertainment bias. We present four additional individuals from two families, with 2-ketoadipic aciduria with compound heterozygous or homozygous mutations in DHTKD1, three of which remain asymptomatic.

18.
J Neurol Sci ; 359(1-2): 133-40, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26671102

RESUMEN

Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh(+/+)) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh(-/-)) mice fed a baseline chow. Oxidative stress parameters were also measured after acute lysine overload. Finally, mRNA expression of NMDA subunits and GLT1 transporter was determined in cerebral cortex and striatum of these animals fed a baseline or high lysine (4.7%) chow. No significant alterations of bioenergetics or redox status were observed in these mice. In contrast, mRNA expression of the NR2B glutamate receptor subunit and of the GLT1 glutamate transporter was higher in cerebral cortex of Gcdh(-/-) mice. Furthermore, NR2B expression was markedly elevated in striatum of Gcdh(-/-) animals receiving chronic Lys overload. These data indicate higher susceptibility of Gcdh(-/-) mice to excitotoxic damage, implying that this pathomechanism may contribute to the cortical and striatum alterations observed in GA I patients.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Encefalopatías Metabólicas/complicaciones , Lesiones Encefálicas/etiología , Regulación de la Expresión Génica/genética , Glutaril-CoA Deshidrogenasa/deficiencia , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Catalasa/metabolismo , Modelos Animales de Enfermedad , Transportador 2 de Aminoácidos Excitadores/metabolismo , Fluoresceínas/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Glutaril-CoA Deshidrogenasa/genética , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Malondialdehído/metabolismo , Ratones , Ratones Transgénicos , NAD/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/metabolismo
19.
Brain Res ; 1620: 116-29, 2015 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-25998543

RESUMEN

Bioenergetics dysfunction has been postulated as an important pathomechanism of brain damage in glutaric aciduria type I, but this is still under debate. We investigated activities of citric acid cycle (CAC) enzymes, lactate release, respiration and membrane potential (ΔΨm) in mitochondrial preparations from cerebral cortex and striatum of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh-/-) and wild type mice fed a baseline or a high lysine (Lys, 4.7%) chow for 60 or 96h. Brain histological analyses were performed in these animals, as well as in 90-day-old animals fed a baseline or a high Lys chow during 30 days starting at 60-day-old. A moderate reduction of citrate synthase and isocitrate dehydrogenase activities was observed only in the striatum from 30-day-old Gcdh-/- animals submitted to a high Lys chow. In contrast, the other CAC enzyme activities, lactate release, the respiratory parameters state 3, state 4, the respiratory control ratio and CCCP-stimulated (uncoupled) state, as well as ΔΨm were not altered in the striatum. Similarly, none of the evaluated parameters were changed in the cerebral cortex from these animals under baseline or Lys overload. On the other hand, histological analyses revealed the presence of intense vacuolation in the cerebral cortex of 60 and 90-day-old Gcdh-/- mice fed a baseline chow and in the striatum of 90-day-old Gcdh-/- mice submitted to Lys overload for 30 days. Taken together, the present data demonstrate mild impairment of bioenergetics homeostasis and marked histological alterations in striatum from Gcdh-/- mice under a high Lys chow, suggesting that disruption of energy metabolism is not mainly involved in the brain injury of these animals.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Encefalopatías/metabolismo , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Metabolismo Energético , Glutaril-CoA Deshidrogenasa/deficiencia , Lisina/administración & dosificación , Animales , Encefalopatías/patología , Corteza Cerebral/patología , Cuerpo Estriado/patología , Dieta , Modelos Animales de Enfermedad , Glutaril-CoA Deshidrogenasa/genética , Glutaril-CoA Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Potencial de la Membrana Mitocondrial/fisiología , Ratones de la Cepa 129 , Ratones Noqueados , Consumo de Oxígeno/fisiología
20.
J Neurol Sci ; 346(1-2): 260-7, 2014 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-25241940

RESUMEN

The role of excitotoxicity on the neuropathology of glutaric acidemia type I (GA I) is still under debate. Therefore, in the present work, we evaluated glutamate uptake by brain slices and glutamate binding to synaptic membranes, as well as glutamine synthetase activity in cerebral cortex and striatum from glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice along development (7, 15, 30 and 60 days of life) in the hopes of clarifying this matter. We also tested the influence of glutaric acid (GA) added exogenously on these parameters. [(3)H]Glutamate uptake was not significantly altered in cerebral cortex and striatum from Gcdh(-/-) mice, as compared to WT mice. However, GA provoked a significant decrease of [(3)H]glutamate uptake in striatum from both WT and Gcdh(-/-) mice older than 7 days. This inhibitory effect was more pronounced in Gcdh(-/-), as compared to WT mice. The use of a competitive inhibitor of glutamate astrocytic transporters indicated that the decrease of [(3)H]glutamate uptake caused by GA was due to the competition between this organic acid and glutamate for the same astrocytic transporter site. We also found that Na(+)-dependent [(3)H]glutamate binding (binding to transporters) was increased in the striatum from Gcdh(-/-) mice and that GA significantly diminished this binding both in striatum and cerebral cortex from Gcdh(-/-), but not from WT mice. Finally, we observed that glutamine synthetase activity was not changed in brain cortex and striatum from Gcdh(-/-) and WT mice and that GA was not able to alter this activity. It is therefore presumed that a disturbance of the glutamatergic neurotransmission system caused by GA may potentially be involved in the neuropathology of GA I, particularly in the striatum.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Glutaratos/farmacología , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Animales , Encefalopatías Metabólicas/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Glutamato-Amoníaco Ligasa/metabolismo , Glutaril-CoA Deshidrogenasa/metabolismo , Ratones , Ratones Noqueados
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