RESUMEN
About one-third of chronically constipated patients have an evacuation disorder, and dyssynergic defecation is a common cause of the evacuation disorder. In dyssynergic defecation, the coordination between abdominal and pelvic floor muscles during defecation is disrupted and patients cannot produce a normal bowel movement. The etiology of dyssynergic defecation is still unknown. Although a detailed history taking and a careful examination including digital rectal examination could be useful, other modalities such as anorectal manometry and balloon expulsion test are necessary for the diagnosis. Biofeedback therapy is one of the most effective and safe treatments. Here, we provide an overview of dyssynergic defecation as well as how to diagnose and manage this condition.
Asunto(s)
Canal Anal , Estreñimiento , Defecación , Humanos , Estreñimiento/diagnóstico , Estreñimiento/etiología , Estreñimiento/terapia , Manometría , Biorretroalimentación Psicológica , Tacto Rectal , Ataxia/patologíaRESUMEN
Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 µM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.
Asunto(s)
Ataxia/tratamiento farmacológico , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Nanocompuestos/química , Simvastatina/efectos adversos , Ubiquinona/deficiencia , Ubiquinona/farmacología , Animales , Ataxia/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/patología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Debilidad Muscular/patología , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/patología , Consumo de Oxígeno/efectos de los fármacos , Simvastatina/farmacología , Ubiquinona/química , Ubiquinona/genéticaRESUMEN
Coenzyme Q10 (CoQ10 ) deficiency is a rare disease characterized by a decreased accumulation of CoQ10 in cell membranes. Considering that CoQ10 synthesis and most of its functions are carried out in mitochondria, CoQ10 deficiency cases are usually considered a mitochondrial disease. A relevant feature of CoQ10 deficiency is that it is the only mitochondrial disease with a successful therapy available, the CoQ10 supplementation. Defects in components of the synthesis machinery caused by mutations in COQ genes generate the primary deficiency of CoQ10 . Mutations in genes that are not directly related to the synthesis machinery cause secondary deficiency. Cases of CoQ10 deficiency without genetic origin are also considered a secondary deficiency. Both types of deficiency can lead to similar clinical manifestations, but the knowledge about primary deficiency is deeper than secondary. However, secondary deficiency cases may be underestimated since many of their clinical manifestations are shared with other pathologies. This review shows the current state of secondary CoQ10 deficiency, which could be even more relevant than primary deficiency for clinical activity. The analysis covers the fundamental features of CoQ10 deficiency, which are necessary to understand the biological and clinical differences between primary and secondary CoQ10 deficiencies. Further, a more in-depth analysis of CoQ10 secondary deficiency was undertaken to consider its origins, introduce a new way of classification, and include aging as a form of secondary deficiency.
Asunto(s)
Envejecimiento/genética , Transferasas Alquil y Aril/genética , Ataxia/genética , GTP Fosfohidrolasas/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Debilidad Muscular/genética , Enfermedad de Niemann-Pick Tipo C/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Envejecimiento/metabolismo , Transferasas Alquil y Aril/metabolismo , Animales , Ataxia/metabolismo , Ataxia/patología , Metabolismo Energético/genética , GTP Fosfohidrolasas/metabolismo , Regulación de la Expresión Génica , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Mutación , Proteína Niemann-Pick C1/genética , Proteína Niemann-Pick C1/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/patología , Transducción de Señal , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H+) gradient across lysosome membranes to facilitate the breakdown of cellular waste products. Through the process of ageing, the body becomes deficient in CoQ10, resulting in several systemic manifestations. On a cellular level, one of the consequences of CoQ10 deficiency is apoptosis, which can be visualised in tissues of the central nervous system (CNS). Diseases affecting the retina and brain such as age-related macular degeneration (AMD), glaucoma, Alzheimer's disease (AD) and Parkinson's disease (PD) have shown defects in cellular biochemical reactions attributed to reduced levels of CoQ10. Through further research into the pathogenesis of such conditions, the effects of CoQ10 deficiency can be counteracted through supplementation, early detection and intervention.
Asunto(s)
Ataxia/metabolismo , Encéfalo/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Retina/metabolismo , Ubiquinona/deficiencia , Animales , Ataxia/complicaciones , Ataxia/patología , Encéfalo/patología , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Retina/patología , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMEN
Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine ß-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.
Asunto(s)
Ataxia/patología , Carbono/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/patología , Debilidad Muscular/patología , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Sulfuros/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Ataxia/genética , Ataxia/metabolismo , Transporte de Electrón , Complejo I de Transporte de Electrón/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Glutatión/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/genética , Debilidad Muscular/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Transcriptoma , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/farmacología , Vitaminas/farmacologíaRESUMEN
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an important antioxidant present in all cellular membranes. CoQ deficiencies are frequent in aging and in age-related diseases, and current treatments are limited to CoQ supplementation. Strategies that rely on CoQ supplementation suffer from poor uptake and trafficking of this very hydrophobic molecule. In a previous study, the dietary flavonol kaempferol was reported to serve as a CoQ ring precursor and to increase the CoQ content in kidney cells, but neither the part of the molecule entering CoQ biosynthesis nor the mechanism were described. In this study, kaempferol labeled specifically in the B-ring was isolated from Arabidopsis plants. Kidney cells treated with this compound incorporated the B-ring of kaempferol into newly synthesized CoQ, suggesting that the B-ring is metabolized via a mechanism described in plant cells. Kaempferol is a natural flavonoid present in fruits and vegetables and possesses antioxidant, anticancer, and anti-inflammatory therapeutic properties. A better understanding of the role of kaempferol as a CoQ ring precursor makes this bioactive compound a potential candidate for the design of interventions aiming to increase endogenous CoQ biosynthesis and may improve CoQ deficient phenotypes in aging and disease.
Asunto(s)
Antioxidantes/metabolismo , Ataxia/genética , Quempferoles/metabolismo , Enfermedades Mitocondriales/genética , Debilidad Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Ataxia/metabolismo , Ataxia/patología , Células Epiteliales/metabolismo , Flavonoles/metabolismo , Humanos , Riñón/metabolismo , Riñón/patología , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Membranas Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Mutación/genética , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Background Coenzyme Q10 (CoQ10) serves as a shuttle for electrons from complexes I and II to complex III in the respiratory chain, and has important functions within the mitochondria. Primary CoQ10 deficiency is a mitochondrial disorder which has devastating effects, and which may be partially treated with exogenous CoQ10 supplementation. Case presentation A 9-month-old girl patient was referred to our clinic due to growth retardation, microcephaly and seizures. She was the third child of consanguineous parents (first-degree cousins) of Pakistani origin, born at 38 weeks gestation, weighing 2000 g after an uncomplicated pregnancy, and was hospitalized for 3 days due to respiratory distress. She had sustained clonic seizures when she was 4 months old. Physical examination showed microcephaly, truncal hypotonia and dysmorphic features. Metabolic tests were inconclusive. Abdominal ultrasonography revealed cystic appearance of the kidneys. Non-compaction of the left ventricle was detected in echocardiography. Cranial magnetic resonance imaging (MRI) showed hypoplasia of the cerebellar vermis and brain stem, corpus callosum agenesis, and cortical atrophy. A panel testing of 450 genes involved in inborn errors of metabolism (IEM) was performed that showed a novel frameshift c.384delG (Gly129Valfs*17) homozygous mutation in COQ9. A treatment of 5 mg/kg/day exogenous CoQ10 was started when she was 10 months old, and the dosage was increased to 50 mg/kg/day after the exact diagnosis. No objective neurological improvement could be observed after the adjustment of the drug dosage. Conclusions We report a case of CoQ10 deficiency due to a novel COQ9 gene mutation that adds clinical data from a newly diagnosed patient. Our case also outlines the importance of genetic panels used for specific diseases including IEM.
Asunto(s)
Ataxia/etiología , Mitocondrias/patología , Enfermedades Mitocondriales/etiología , Debilidad Muscular/etiología , Mutación , Enfermedades Raras/etiología , Ubiquinona/deficiencia , Ataxia/patología , Femenino , Humanos , Lactante , Mitocondrias/genética , Enfermedades Mitocondriales/patología , Debilidad Muscular/patología , Pronóstico , Enfermedades Raras/patología , Ubiquinona/genéticaRESUMEN
Objective: Cerebellar ataxia essentially includes deficient postural control. It remains unclear whether augmented sensory information might help cerebellar patients, as the cerebellum underlies processing of various sensory modalities for postural control. Here, we hypothesized that patients with cerebellar degeneration can still exploit audio-biofeedback (ABF) of trunk acceleration as a real-time assistive signal to compensate for deficient postural control. Methods: Effects on postural sway during stance were assessed in an ABF intervention group versus a no-ABF disease control group (23 vs. 17 cerebellar patients) in a clinico-experimental study. A single-session ABF paradigm of standing plus short exergaming under ABF was applied. Postural sway with eyes open and eyes closed was quantified prior to ABF, under ABF, and post ABF. Results: Postural sway in the eyes closed condition was significantly reduced under ABF. Both benefit of ABF and benefit of vision correlated with the extent of postural sway at baseline, and both types of sensory benefits correlated with each other. Patients with strongest postural sway exhibited reduced postural sway also with eyes open, thus benefitting from both vision and ABF. No changes were observed in the no-ABF control group. Interpretation: Our findings provide proof-of-principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia.
Asunto(s)
Ataxia/fisiopatología , Percepción Auditiva/fisiología , Biorretroalimentación Psicológica/fisiología , Ataxia Cerebelosa/fisiopatología , Adulto , Anciano , Ataxia/patología , Ataxia Cerebelosa/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Equilibrio Postural/fisiología , Postura/fisiología , Propiocepción/fisiología , Visión Ocular/fisiologíaRESUMEN
Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q10 (CoQ10) deficiency, suggesting dysregulation of the mevalonate pathway. Secondary CoQ10 deficiency was associated with mitochondrial depolarization and mitophagy activation in FH fibroblasts. Persistent mitophagy altered autophagy flux and induced inflammasome activation accompanied by increased production of cytokines by mutant cells. All the pathological alterations in FH fibroblasts were also reproduced in a human endothelial cell line by LDL-receptor gene silencing. Both increased intracellular cholesterol and mitochondrial dysfunction in FH fibroblasts were partially restored by CoQ10 supplementation. Dysregulated mevalonate pathway in FH, including increased expression of cholesterogenic enzymes and decreased expression of CoQ10 biosynthetic enzymes, was also corrected by CoQ10 treatment. Reduced CoQ10 content and mitochondrial dysfunction may play an important role in the pathophysiology of early atherosclerosis in FH. The diagnosis of CoQ10 deficiency and mitochondrial impairment in FH patients may also be important to establish early treatment with CoQ10.
Asunto(s)
Ataxia/complicaciones , Colesterol/metabolismo , Fibroblastos/patología , Hiperlipoproteinemia Tipo II/complicaciones , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Ubiquinona/deficiencia , Ataxia/metabolismo , Ataxia/patología , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/patología , Lipoproteínas LDL/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Mitofagia , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Especies Reactivas de Oxígeno/metabolismo , Receptores de LDL/metabolismo , Ubiquinona/metabolismoRESUMEN
Primary disorders of the human coenzyme Q10 (CoQ10) biosynthesis pathway are a known cause of severe pediatric diseases. So far, oral administration of CoQ10 is the only treatment strategy for affected individuals. However, the real benefit of CoQ10 supplementation remains questionable and clinical studies regarding efficiency are lacking. Here we provide an outlook on novel treatment approaches using CoQ precursor compounds. These metabolic bypass strategies might be a promising alternative for oral CoQ10 supplementation regimens.
Asunto(s)
Ataxia/tratamiento farmacológico , Hidroxibenzoatos/uso terapéutico , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Apoptosis/efectos de los fármacos , Ataxia/genética , Ataxia/patología , Vías Biosintéticas/efectos de los fármacos , Vías Biosintéticas/genética , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Modelos Animales de Enfermedad , Humanos , Hidroxibenzoatos/farmacología , Ratones , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Debilidad Muscular/genética , Debilidad Muscular/patología , Pirimidinas/metabolismo , Solubilidad , Resultado del Tratamiento , Ubiquinona/biosíntesis , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.
Asunto(s)
Ataxia/inmunología , Dependovirus/inmunología , Vectores Genéticos/administración & dosificación , Meningitis Aséptica/inmunología , Convulsiones/inmunología , Animales , Ataxia/inducido químicamente , Ataxia/mortalidad , Ataxia/patología , Dependovirus/genética , Evaluación Preclínica de Medicamentos , Drogas en Investigación , Femenino , Terapia Genética/métodos , Vectores Genéticos/química , Vectores Genéticos/inmunología , Inyecciones Espinales , Interleucina-10/genética , Interleucina-10/inmunología , Masculino , Meningitis Aséptica/inducido químicamente , Meningitis Aséptica/mortalidad , Meningitis Aséptica/patología , Convulsiones/inducido químicamente , Convulsiones/mortalidad , Convulsiones/patología , Análisis de Supervivencia , PorcinosRESUMEN
This review aims at summarizing and discussing previous and recent findings concerning the cerebral manifestations of mitochondrial disorders (MIDs). MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) either already at onset or later in the course. After the muscle, the brain is the organ second most frequently affected in MIMODS. Cerebral manifestations of MIDs are variable and may present with or without a lesion on imaging or functional studies, but there can be imaging/functional lesions without clinical manifestations. The most well-known cerebral manifestations of MIDs include stroke-like episodes, epilepsy, headache, ataxia, movement disorders, hypopituitarism, muscle weakness, psychiatric abnormalities, nystagmus, white and gray matter lesions, atrophy, basal ganglia calcification, and hypometabolism on 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron-emission tomography. For most MIDs, only symptomatic therapy is currently available. Symptomatic treatment should be supplemented by vitamins, cofactors, and antioxidants. In conclusion, cerebral manifestations of MIDs need to be recognized and appropriately managed because they strongly determine the outcome of MID patients.
Asunto(s)
Ataxia/patología , Encéfalo/patología , Enfermedades Mitocondriales/patología , Accidente Cerebrovascular/patología , Ataxia/diagnóstico , Atrofia/patología , Humanos , Enfermedades Mitocondriales/diagnóstico , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/patología , Accidente Cerebrovascular/diagnósticoRESUMEN
In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.
Asunto(s)
Ataxia/metabolismo , Cerebelo/metabolismo , Enfermedades Mitocondriales/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Anciano , Anciano de 80 o más Años , Ataxia/complicaciones , Ataxia/patología , Estudios de Casos y Controles , Cerebelo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Estrés Oxidativo/fisiología , Ubiquinona/metabolismoRESUMEN
Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1). Several mouse mutants exist that harbor mutations in the orthologous Cacna1a gene. The spontaneous Cacna1a mutants Rolling Nagoya (tg(rol)), Tottering (tg) and Leaner (tg(ln)) mice exhibit behavioral motor phenotypes, including ataxia. Transgenic knock-in (KI) mouse strains with the human FHM1 R192Q and S218L missense mutations have been generated. R192Q KI mice are non-ataxic, whereas S218L KI mice display a complex behavioral phenotype that includes cerebellar ataxia. Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype. Herein we quantified functional GABAA receptors and pharmacologically dissociated cerebellar GABAA receptors in several Cacna1a mutants. We did not identify differences in the expression of GABAA receptor subunits or in the number of functional GABAA receptors in the non-ataxic R192Q KI strain. In contrast, tg(rol) mice had a â¼15% decrease in the number of functional GABAA receptors, whereas S218L KI mice showed a â¼29% increase. Our data suggest that differential changes in cerebellar GABAA receptor expression profile may contribute to the neurological phenotype of cerebellar ataxia and that targeting GABAA receptors might represent a feasible complementary strategy to treat cerebellar ataxia.
Asunto(s)
Canales de Calcio Tipo N/metabolismo , Cerebelo/metabolismo , Cerebelo/patología , Neuronas/metabolismo , Neuronas/patología , Animales , Ataxia/metabolismo , Ataxia/patología , Canales de Calcio Tipo N/genética , Técnicas de Sustitución del Gen , Humanos , Ratones Transgénicos , Mutación , Fenotipo , Receptores de GABA-A/metabolismoRESUMEN
Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.
Asunto(s)
Transferasas Alquil y Aril/genética , Ataxia/diagnóstico , Ataxia/genética , Mitocondrias Musculares/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Debilidad Muscular/diagnóstico , Debilidad Muscular/genética , Mutación Puntual , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Acidosis Láctica/sangre , Acidosis Láctica/genética , Acidosis Láctica/patología , Transferasas Alquil y Aril/deficiencia , Ataxia/sangre , Ataxia/patología , Consanguinidad , Resultado Fatal , Femenino , Expresión Génica , Insuficiencia Hepática/sangre , Insuficiencia Hepática/genética , Insuficiencia Hepática/patología , Humanos , Recién Nacido , Discapacidad Intelectual/sangre , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/patología , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/patología , Debilidad Muscular/sangre , Debilidad Muscular/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Proteinuria/sangre , Proteinuria/genética , Proteinuria/patología , Aminoacidurias Renales/sangre , Aminoacidurias Renales/genética , Aminoacidurias Renales/patología , Análisis de Secuencia de ADN , Ubiquinona/sangre , Ubiquinona/genéticaRESUMEN
Focal lesions of brainstem, thalamus, and subcortical white matter may cause movement disorders that are clinically indistinguishable from cerebellar symptoms. It is suspected that ataxia in these cases is due to damage of efferent or afferent pathways of the cerebellum. However, the precise anatomical correlate often remains undefined. We used deterministic diffusion tensor magnetic resonance imaging (DTI) tractography to study the anatomical relationship between lesions causing ataxia and efferent cerebellar pathways. Study subjects were six male patients with focal lesions of different etiology (demyelination, hemorrhage, ischemia, neoplasm) outside the cerebellum. Five patients had cerebellar-like ataxia with prominent contralateral upper limb involvement. One patient with an almost midline mesencephalic lesion had a symmetrical ataxic syndrome. We used 3T MRI (Intera, Philips Medical Systems, Best, Netherlands) and DTI tractography (32 directions, StealthViz DTI, Medtronic Navigation, Louisville, USA) to delineate the dentato-rubro-thalamo-cortical tract (DRT). In all patients, tractography demonstrated focal lesions affecting the DRT in different locations. We conclude that in vivo mapping of cerebral pathways using DTI tractography in patients with focal extracerebellar brain lesions may provide direct evidence of circumscribed damage to the DRT, causing unilateral cerebellar-like ataxia. Also, a unilateral mesencephalic lesion at the level of the crossing of the DRT may cause bilateral ataxia.
Asunto(s)
Ataxia/patología , Núcleos Cerebelosos/patología , Corteza Cerebral/patología , Imagen de Difusión Tensora/métodos , Tálamo/patología , Temblor/patología , Adolescente , Anciano , Anciano de 80 o más Años , Ataxia Cerebelosa/patología , Vías Eferentes/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of the present study was to analyze a role of the ERK1/2 signaling pathway in the regulation of excitation and inhibitory neurons in the hippocampus and the temporal cortex of Krushinsky-Molodkina rats during seizure development finalizing with ataxia. Analysis was done by Western bloting as well as by immunohistochemistry. The results demonstrated significant up-regulation of ERK1/2 activity in the hippocampus in several seconds after sound stimulation. At the same time increased ERK1/2 activity was correlated with enhanced level of SNARE protein SNAP-25 and activation of synapsin I, the proteins which regulate exocytosis machinery. Decreased level of VGLUT2 associated with activation of ERK1/2 and exocytosis proteins supposed activation of glutamate release in the hippocampus, while in the temporal cortex diminished activity of ERK1/2 and synapsin I associated with VGLUT2 up-regulation assumed inhibition of glutamatergic transmission. Our data let us supposed that decreasing of glutamate release in th& temporal cortex could be a trigger for the inhibition of hippocampal glutamatergic system and the beginning of further ataxia stage. Our data demonstrated correlation between expression and activity of exocytosis proteins and ERK1/2 mainly in the glutamategic neurons of the hippocampus and the temporal cortex that let us proposed significant role of ERK1/2 kinases as a positive regulator of glutamate release and as a result initiation of seizure expression.
Asunto(s)
Ataxia/genética , Epilepsia Refleja/genética , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Convulsiones/genética , Estimulación Acústica , Animales , Animales Endogámicos , Ataxia/metabolismo , Ataxia/patología , Epilepsia Refleja/metabolismo , Epilepsia Refleja/patología , Exocitosis/genética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Ratas , Convulsiones/metabolismo , Convulsiones/patología , Transducción de Señal , Sinapsinas/genética , Sinapsinas/metabolismo , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patología , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life. METHODS: An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage. RESULTS: At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2. CONCLUSIONS: In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.
Asunto(s)
Transferasas Alquil y Aril/genética , Ataxia/genética , Cardiomiopatía Hipertrófica/genética , Epilepsias Mioclónicas/genética , Enfermedades Mitocondriales/genética , Debilidad Muscular/genética , Mutación/genética , Síndrome Nefrótico/genética , Ubiquinona/deficiencia , Ataxia/complicaciones , Ataxia/patología , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/patología , Imagen de Difusión por Resonancia Magnética , Electroencefalografía , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/patología , Pruebas Genéticas , Humanos , Lactante , Riñón/patología , Riñón/ultraestructura , Espectroscopía de Resonancia Magnética , Masculino , Microscopía Electrónica de Transmisión , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Músculo Esquelético/patología , Síndrome Nefrótico/etiología , Síndrome Nefrótico/patología , Ubiquinona/genéticaRESUMEN
Fibromyalgia (FM) is characterized by generalized pain and chronic fatigue of unknown etiology. To evaluate the role of oxidative stress in this disorder, we measured plasma levels of ubiquinone-10, ubiquinol-10, free cholesterol (FC), cholesterol esters (CE), and free fatty acids (FFA) in patients with juvenile FM (n=10) and in healthy control subjects (n=67). Levels of FC and CE were significantly increased in juvenile FM as compared with controls, suggesting the presence of hypercholesterolemia in this disease. However, plasma level of ubiquinol-10 was significantly decreased and the ratio of ubiquinone-10 to total coenzyme Q10 (%CoQ10) was significantly increased in juvenile FM relative to healthy controls, suggesting that FM is associated with coenzyme Q10 deficiency and increased oxidative stress. Moreover, plasma level of FFA was significantly higher and the content of polyunsaturated fatty acids (PUFA) in total FFA was significantly lower in FM than in controls, suggesting increased tissue oxidative damage in juvenile FM. Interestingly, the content of monoenoic acids, such as oleic and palmitoleic acids, was significantly increased in FM relative to controls, probably to compensate for the loss of PUFA. Next, we examined the effect of ubiquinol-10 supplementation (100 mg/day for 12 weeks) in FM patients. This resulted in an increase in coenzyme Q10 levels and a decrease in %CoQ10. No changes were observed in FFA levels or their composition. However, plasma levels of FC and CE significantly decreased and the ratio of FC to CE also significantly decreased, suggesting that ubiquinol-10 supplementation improved cholesterol metabolism. Ubiquinol-10 supplementation also improved chronic fatigue scores as measured by the Chalder Fatigue Scale.
Asunto(s)
Ataxia/patología , Fibromialgia/patología , Hipercolesterolemia/tratamiento farmacológico , Enfermedades Mitocondriales/patología , Debilidad Muscular/patología , Estrés Oxidativo , Ubiquinona/análogos & derivados , Adolescente , Antioxidantes/metabolismo , Ataxia/tratamiento farmacológico , Ataxia/metabolismo , Estudios de Casos y Controles , Niño , Colesterol/sangre , Suplementos Dietéticos , Método Doble Ciego , Fatiga/tratamiento farmacológico , Fatiga/metabolismo , Fatiga/patología , Ácidos Grasos Monoinsaturados/metabolismo , Ácidos Grasos no Esterificados/sangre , Femenino , Fibromialgia/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Masculino , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/metabolismo , Ácido Oléico/sangre , Dimensión del Dolor/métodos , Ubiquinona/administración & dosificación , Ubiquinona/sangre , Ubiquinona/deficiencia , Ubiquinona/metabolismo , Ubiquinona/uso terapéuticoRESUMEN
Tropical ataxic neuropathy (TAN) and epidemic spastic paraparesis (konzo) are two neurological disorders associated with the consumption of cassava (Manihot esculenta) in several African countries. TAN is characterized by sensory polyneuropathy, sensory ataxia, bilateral optic atrophy and bilateral sensori-neural deafness. It occurs in elderly individuals subsisting on a monotonous cassava diet with minimal protein supplementation. Konzo is a syndrome of symmetrical spastic paraparesis with a predilection for children and young women and invariably associated with consumption of inadequately processed bitter cassava roots with minimal protein supplementation. Despite numerous epidemiological, clinical and biochemical studies aimed at elucidating the etiological mechanisms of these disorders, their etiologies remain unknown, and there is no known treatment. The diseases continue to be prevalent in endemic areas, causing significant disability and increased mortality. A fresh appraisal of the putative etiologic mechanisms proposed for these intriguing and enigmatic syndromes is presented in this paper. Evidences against a causal role for cyanide intoxication are discussed, and evidences implicating thiamine deficiency as a unifying etiological mechanism for these neurological syndromes are presented. It is concluded that urgent research is needed to evaluate thiamine status and implement a therapeutic trial of thiamine in these debilitating neurological disorders.