RESUMEN
BACKGROUND: Valproate-induced Fanconi syndrome is a rare adverse effect of valproate. Severely disabled patients who require tube feeding are reported to be susceptible to valproate-induced Fanconi syndrome. Although most patients with valproate-induced Fanconi syndrome are asymptomatic and detected incidentally with findings such as hypophosphatemia, hypouricemia, increased urinary ß2-microglobulin, and generalized hyperaminoaciduria, clinical symptoms such as bone fracture, fever, tachypnea, and edema have been reported. PATIENT DESCRIPTION: This 15-year-old, severely disabled, tube-fed, male patient with cytochrome oxidase deficiency had taken valproate for 3 years when he developed fever for 3 weeks. Hypophosphatemia, hypouricemia, hypokalemia, increased urinary ß2-microglobulin, and generalized hyperaminoaciduria, as well as hypocarnitinemia, were found, indicating that he had Fanconi syndrome. Valproate was the most likely cause of Fanconi syndrome in this patient. After discontinuation of valproate, the fever resolved immediately, and the laboratory findings normalized. CONCLUSION: Valproate-induced Fanconi syndrome should be considered when individuals taking valproate develop fever of unknown origin.
Asunto(s)
Inhibidores Enzimáticos/efectos adversos , Síndrome de Fanconi/inducido químicamente , Síndrome de Fanconi/fisiopatología , Fiebre de Origen Desconocido/fisiopatología , Ácido Valproico/efectos adversos , Adolescente , Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Síndrome de Fanconi/complicaciones , Humanos , MasculinoRESUMEN
Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients' fibroblasts. We show that RSV stimulates the expression of a panel of proteins representing structural subunits or assembly factors of the five RC complexes, in control fibroblasts. In moderate RC-deficient patients' cells, RSV treatment increases the amount of mutated proteins and stimulates residual enzyme activities. In these patients' cells, we establish that up-regulation of RC enzyme activities induced by RSV translates into increased cellular O2 consumption rates and results in the correction of RC deficiencies. Importantly, RSV also prevents the accumulation of lactate that occurred in RC-deficient fibroblasts. Different complementary approaches demonstrate that RSV induces a mitochondrial biogenesis that might underlie the increase in mitochondrial capacities. Finally, we showed that, in human fibroblasts, RSV stimulated mitochondrial functions mainly in a SIRT1- and AMPK-independent manner and that its effects rather involved the estrogen receptor (ER) and estrogen-related receptor alpha (ERRα) signaling pathways. These results represent the first demonstration that RSV could have a beneficial effect on inborn CI and CIV deficiencies from nuclear origin, in human fibroblasts and might be clinically relevant for the treatment of some RC deficiencies.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Complejo IV de Transporte de Electrones/metabolismo , Receptor alfa de Estrógeno/metabolismo , Fibroblastos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Piel/efectos de los fármacos , Estilbenos/farmacología , Anticarcinógenos/farmacología , Western Blotting , Células Cultivadas , Deficiencia de Citocromo-c Oxidasa/metabolismo , Deficiencia de Citocromo-c Oxidasa/patología , Transporte de Electrón/efectos de los fármacos , Complejo I de Transporte de Electrón/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Lactatos , Membranas Mitocondriales/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Piruvatos , ARN Interferente Pequeño/genética , Resveratrol , Transducción de Señal/efectos de los fármacos , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Sirtuina 1/metabolismo , Piel/metabolismo , Piel/patología , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients' cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. METHODS: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. RESULTS: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 µM BZF, and peaked at 400 µM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 µM CuCl2 and 200 µM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. CONCLUSIONS: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined.
Asunto(s)
Bezafibrato/farmacología , Proteínas Portadoras/genética , Cobre/farmacología , Deficiencia de Citocromo-c Oxidasa/genética , Fibroblastos/efectos de los fármacos , Proteínas Mitocondriales/genética , Mutación , Adenosina Trifosfato/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular , Células Cultivadas , Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Fibroblastos/metabolismo , Células HEK293 , Células HeLa , Humanos , Proteínas Mitocondriales/metabolismo , Chaperonas MolecularesRESUMEN
Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for mitochondrial disease. We tested this hypothesis on three recombinant mouse models characterized by defective cytochrome c-oxidase (COX) activity: a knockout (KO) mouse for Surf1, a knockout/knockin mouse for Sco2, and a muscle-restricted KO mouse for Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle on a Surf1 KO background showed robust induction of mitochondrial biogenesis and increase of mitochondrial respiratory chain activities, including COX. No such effect was obtained by treating both Surf1(-/-) and Cox15(-/-) mice with the pan-PPAR agonist bezafibrate, which instead showed adverse effects in either model. Contrariwise, treatment with the AMPK agonist AICAR led to partial correction of COX deficiency in all three models, and, importantly, significant motor improvement up to normal in the Sco2(KO/KI) mouse. These results open new perspectives for therapy of mitochondrial disease.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Complejo IV de Transporte de Electrones/metabolismo , Transactivadores/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/uso terapéutico , Animales , Bezafibrato/farmacología , Deficiencia de Citocromo-c Oxidasa/metabolismo , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/genética , Técnicas de Sustitución del Gen , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/farmacología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Chaperonas Moleculares , Músculo Esquelético/metabolismo , Fosforilación Oxidativa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ribonucleótidos/uso terapéutico , Transducción de Señal , Factores de TranscripciónRESUMEN
Neuromuscular disorders with defects in the mitochondrial ATP-generating system affect a large number of children and adults worldwide, but remain without treatment. We used a mouse model of mitochondrial myopathy, caused by a cytochrome c oxidase deficiency, to evaluate the effect of induced mitochondrial biogenesis on the course of the disease. Mitochondrial biogenesis was induced either by transgenic expression of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) in skeletal muscle or by administration of bezafibrate, a PPAR panagonist. Both strategies successfully stimulated residual respiratory capacity in muscle tissue. Mitochondrial proliferation resulted in an enhanced OXPHOS capacity per muscle mass. As a consequence, ATP levels were conserved resulting in a delayed onset of the myopathy and a markedly prolonged life span. Thus, induction of mitochondrial biogenesis through pharmacological or metabolic modulation of the PPAR/PGC-1alpha pathway promises to be an effective therapeutic approach for mitochondrial disorders.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Mitocondrias Musculares/metabolismo , Miopatías Mitocondriales/tratamiento farmacológico , Miopatías Mitocondriales/genética , PPAR gamma/metabolismo , Transactivadores/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Bezafibrato/administración & dosificación , Deficiencia de Citocromo-c Oxidasa/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Femenino , Ratones , Ratones Endogámicos , Ratones Transgénicos , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/genética , Miopatías Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , PPAR gamma/agonistas , PPAR gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tasa de Supervivencia , Transactivadores/genética , Factores de Transcripción , TransgenesRESUMEN
Cytochrome c oxidase (COX) deficiency is the most commonly recognized respiratory chain defect in childhood. The disease is clinically heterogeneous with phenotypes including Leigh syndrome, hepatic failure and myopathies. COX deficiency has been associated with mitochondrial DNA mutations in COX I, II, and III with large-scale deletions of the mitochondrial genome and with point mutations in mitochondrial tRNA genes. Here we report on a 3.5-year-old girl with a rare type of isolated myopathy due to COX deficiency.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/patología , Preescolar , Deficiencia de Citocromo-c Oxidasa/complicaciones , Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Femenino , Humanos , Hipotonía Muscular/tratamiento farmacológico , Hipotonía Muscular/etiología , Hipotonía Muscular/patología , Ubiquinona/uso terapéuticoRESUMEN
Leigh syndrome (LS) is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Typically, signs and symptoms commence in infancy or childhood, although rare cases of adult onset have been described. Progressive deterioration is the norm. The authors describe a 22-year-old woman with partial cytochrome c oxidase deficiency who developed fulminant LS following an acute febrile illness and who subsequently showed dramatic clinical and neuroradiologic improvement.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Enfermedad de Leigh/tratamiento farmacológico , Enfermedad de Leigh/enzimología , Adulto , Ácido Ascórbico/administración & dosificación , Encéfalo/patología , Quimioterapia Combinada , Femenino , Humanos , Enfermedad de Leigh/diagnóstico , Imagen por Resonancia Magnética , Inducción de Remisión , Riboflavina/administración & dosificación , Tiamina/administración & dosificación , Ubiquinona/administración & dosificaciónRESUMEN
OBJECTIVE: To study the effectiveness of dimethylglycine (DMG) on oxygen consumption (VO(2)) in children with Saguenay-Lac-Saint-Jean cytochrome-c oxidase (SLSJ-COX) deficiency (OMIM 220111). STUDY DESIGN: In a crossover randomized double-blind clinical trial, 5 children with SLSJ-COX deficiency, who were stable and old enough to comply with VO(2) measurement, were treated with placebo or DMG for 3 days, and with the alternate treatment after a 2-week washout period. VO(2) was measured by indirect calorimetry before and after treatment. Dietary caloric intake was calculated for 3 days before each measurement. Mean caloric intakes per day were 1562 and 1342 kcal x m(-2) before and during placebo, 1,336 and 1,380 before and during DMG, respectively. RESULTS: DMG was well tolerated and, in all cases, resulted in markedly increased blood DMG levels (617 + 203 mmol x L(-1)), versus 0 to 2 mmol x L(-1) without treatment. Mean VO(2) was lower after administration of either DMG (-1 +/- 3 mL x min(-1) x m(-2)) or placebo (-6 +/- 4), but neither difference was statistically significant. There was no detectable effect of DMG treatment on blood levels of lactate, pyruvate, bicarbonate, or pH. VO(2) values of patients (range, 101-135 mL x min(-1) x m(-2)) were lower than published norms (150-160 mL x min(-1) x m(-2)). CONCLUSION: This study suggests that treatment with DMG does not substantially change VO(2) in children with SLSJ-COX deficiency.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Deficiencia de Citocromo-c Oxidasa/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Sarcosina/análogos & derivados , Sarcosina/administración & dosificación , Niño , Preescolar , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
The neuroprotective effect of Ginkgo biloba extract (EGb 761) against ischemic injury has been demonstrated in animal models. In this study, we compared the protective effect of bilobalide, a purified terpene lactone from EGb 761, and EGb 761 against ischemic injury. We measured neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in vulnerable hippocampal regions of gerbils. At 7 days of reperfusion after 5 min of transient global forebrain ischemia, a significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected CA1 neurons from death and from ischemia-induced reductions in COX III mRNA. In addition, both bilobalide and EGb 761 protected against ischemia-induced reductions in COX III mRNA in CA1 neurons prior to their death, at 1 day of reperfusion. These results suggest that oral administration of bilobalide and EGb 761 protect against ischemia-induced neuron death and reductions in mitochondrial gene expression.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Ciclopentanos/farmacología , Diterpenos , Furanos/farmacología , Degeneración Nerviosa/tratamiento farmacológico , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatología , Recuento de Células , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Deficiencia de Citocromo-c Oxidasa/tratamiento farmacológico , Deficiencia de Citocromo-c Oxidasa/genética , Deficiencia de Citocromo-c Oxidasa/fisiopatología , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Complejo IV de Transporte de Electrones/efectos de los fármacos , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Gerbillinae , Ginkgo biloba/química , Ginkgólidos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Degeneración Nerviosa/fisiopatología , Degeneración Nerviosa/prevención & control , Neuronas/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatologíaRESUMEN
OBJECTIVE: The clinicopathological analysis of eight patients with lipid storage myopathy are presented. The pathogeny and therapeutic effect are probed into. METHODS: Eight cases of lipid storage myopathy diagnosed by muscle biopsies with microscopic and electron-microscopic examination are analyzed. Quadriceps or biceps were biopsied. Muscle samples were stained with routine histology and histochemical enzyme and inspected by microscopy. Thin sections were stained with uranyl acetate followed by lead citrate prior to examination in a electron microscopy. Also, the therapeutic drugs of eight patients were evaluated. RESULTS: Vacuole or crack of muscular fibers involved all eight patients. Sudan Black B and Oil Red O stains demonstrated increase of lipid droplets within muscle fibers. Ultrastructural examination revealed numerous lipid droplets dispersed throughout the residual myofilaments. Three cases with pathologic changed muscular fibers occupying less than 1/5 were belong to low-grade, two cases (between 1/5 to 1/3) were moderate, three cases (more than 1/2) were severe. There was one case accompanying glycogen storage disease. One case was concomitant with deficiency of cytochrome C oxidase. After prednisone treatment, seven cases had greatly improved and one case failed to respond to. Treatment using vitamin B(2) together with other vitamins brought about a striking effect. Carnitine was very effective on the patients with system deficiency of carnitine. CONCLUSIONS: The pathogeny of lipid storage myopathy is varied. The confirmed diagnosis is depend on pathological features of muscle biopsy. Treatment with prednisone, carnitine, vitamins and food containing carnitine rich is very effective. It should be select the special treatment method if the pathogeny is clear.