RESUMEN
Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate. Taken together we report a diagnostic metabolic fingerprint for mitochondrial aconitase 2 deficiency.
Asunto(s)
Aconitato Hidratasa/deficiencia , Aconitato Hidratasa/genética , Ácido Aconítico/sangre , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Trastornos Heredodegenerativos del Sistema Nervioso/sangre , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Humanos , Hidroxibutiratos/sangre , Isocitratos/sangre , Ácidos Cetoglutáricos/sangre , Masculino , Metabolómica/métodos , Fosfoenolpiruvato/sangreRESUMEN
Polyglutamine (poly-Q) diseases are late-onset neurodegenerative disorders arising from the expansion of an unstable CAG repeat in the affected gene, which is translated to a tract of glutamine residues. This kind of mutant proteins may be aggregated and accumulated, and thereby enhance cellular oxidative stress. In one of our previous studies (Free Radic. Res. 2003;37:1307-17), we found that alteration in the leukocyte mtDNA content is very sensitive to the level of oxidative stress in blood. Thus, we proposed that leukocyte mtDNA content may be used as a biomarker to predict the severity of clinical manifestation of poly-Q diseases. We recruited 50 healthy subjects and 114 patients with poly-Q diseases, including spinal cerebellar atrophy 2/3, spinal bulbar muscular atrophy, and Huntington chorea. We found that mtDNA in leukocytes was depleted in patients with poly-Q diseases (P<0.05). Moreover, the results showed that patients with lower mtDNA content more frequently manifested multiple-symptom disorders and had high CAG repeat numbers in the mutant genes. In conclusion, we suggest that leukocyte mtDNA content correlates with the length of GAG repeat and may serve as an index of the severity of poly-Q diseases.
Asunto(s)
ADN Mitocondrial/metabolismo , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Leucocitos/metabolismo , Péptidos/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Secuencia de Bases/genética , Análisis Mutacional de ADN , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Regulación hacia Abajo/genética , Femenino , Dosificación de Gen/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Trastornos Heredodegenerativos del Sistema Nervioso/sangre , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/sangre , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Mutación/genética , Estrés Oxidativo/genética , Valor Predictivo de las Pruebas , Ataxias Espinocerebelosas/sangre , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genéticaRESUMEN
Described are the outcomes of 11 Italian patients with Aicardi-Goutières syndrome. Neurologic symptoms progressed in the first year of life and stabilized by the end of the second year in 10 patients. White matter abnormalities remained stable; cerebral atrophy was stable in four patients and progressive in two. Calcifications increased (in number and size) in two of six patients. Serial CSF and serum interferon-alpha measurements (three patients) showed reduced CSF interferon-alpha levels.