RESUMEN

BACKGROUND: Mitochondrial DNA point mutations are especially deleterious to tissues with high energy demand, including the peripheral nervous system. Neuropathy has been associated with several mitochondrial diseases, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). OBJECTIVE: To evaluate nerve conduction in a genotypically and phenotypically homogeneous group of patients with MELAS and the A3243G mutation. DESIGN: We studied 30 patients with MELAS and the A3243G mutation using neurophysiological techniques, medical history questionnaires, laboratory tests, and a standardized neurological examination. RESULTS: Twenty-three subjects (77%) had abnormal nerve conduction measures. Symptoms suggestive of neuropathy were present in only half of the patients, but almost all had decreased reflexes or distal sensory findings on examination. Nerve conduction abnormalities were predominantly axonal and sensory and mainly present in the legs. Patients with nerve conduction abnormalities tended to be older and were more likely male. CONCLUSIONS: Peripheral nerve impairment is common in those with MELAS and the A3243G mutation, and may be subclinical. Male sex and older age may add to the genetic disposition to develop neuropathy.

Asunto(s)

ADN Mitocondrial/genética , Síndrome MELAS/genética , Síndrome MELAS/fisiopatología , Conducción Nerviosa/fisiología , Mutación Puntual , Adulto , Análisis Mutacional de ADN/métodos , Estimulación Eléctrica/métodos , Femenino , Humanos , Masculino , Examen Neurológico/métodos , Sistema Nervioso Periférico/fisiopatología , Sistema Nervioso Periférico/efectos de la radiación , Encuestas y Cuestionarios

RESUMEN

Impaired glucose transport across the blood-brain barrier results in Glut-1 deficiency syndrome (Glut-1 DS, OMIM 606777), characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. We studied 16 new Glut-1 deficiency syndrome patients focusing on clinical and laboratory features, molecular genetics, genotype-phenotype correlation, and treatment. These patients were classified phenotypically into three groups. The mean cerebrospinal fluid glucose concentration was 33.1 +/- 4.9mg/dl equal to 37% of the simultaneous blood glucose concentration. The mean cerebrospinal fluid lactate concentration was 1.0 +/- 0.3mM, which was less than the normal mean value of 1.63mM. The mean V(max) for the 3-O-methyl-D-glucose uptake into erythrocytes was 996 fmol/10(6) red blood cells per second, significantly less (54 +/- 11%; t test, p < 0.05) than the mean control value of 1,847. The mean Km value for the patient group (1.4 +/- 0.5mM) was similar to the control group (1.7 +/- 0.5mM; t test, p > 0.05). We identified 16 rearrangements, including seven missense, one nonsense, one insertion, and seven deletion mutations. Fourteen were novel mutations. There were no obvious correlations between phenotype, genotype, or biochemical measures. The ketogenic diet produced good seizure control.

Asunto(s)

Errores Innatos del Metabolismo de los Carbohidratos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Cetosas/uso terapéutico , Proteínas de Transporte de Monosacáridos/deficiencia , Mutación/genética , 3-O-Metilglucosa/sangre , Adolescente , Glucemia/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Dietoterapia/métodos , Electroencefalografía/métodos , Exones , Femenino , Glucosa/líquido cefalorraquídeo , Transportador de Glucosa de Tipo 1 , Humanos , Lactante , Ácido Láctico/líquido cefalorraquídeo , Masculino , Proteínas de Transporte de Monosacáridos/genética , Fenotipo , Polimorfismo Genético

RESUMEN

Testing for common mutations in mitochondrial DNA (mtDNA), including the A3243G MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) mutation, is routinely done in DNA isolated from blood. Since the blood level of the A3243G mutation may be low in probands and even lower in asymptomatic or oligosymptomatic maternal relatives, we assessed the proportion of A3243G mutant genomes in other accessible tissues. We studied five tissues (leukocytes, skin fibroblasts, hair roots, urinary sediment, and cheek mucosa) in 61 individuals from 22 families harboring the A3243G mutation. Although mutational loads varied widely among these tissues, as a rule DNA from urinary sediment had the highest and blood the lowest proportion of mutant genomes; individual hair roots differed markedly from one another; fibroblasts and cheek mucosa tended to have higher mutation loads than blood but lower than urinary sediment. In all individuals in whom the mutation was detectable in blood, it was also detected in other tissues. Conversely, in some individuals the mutation was undetectable in blood but clearly present in other tissues. We conclude that urinary sediment and cheek mucosa are tissues of choice for the diagnosis of mtDNA mutations, as they are easy to obtain and the mutation load is almost always greater than in blood.

Asunto(s)

ADN Mitocondrial/genética , Mutación Puntual , Análisis Mutacional de ADN , ADN Mitocondrial/sangre , ADN Mitocondrial/orina , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Cabello/metabolismo , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Masculino , Membrana Mucosa/metabolismo , Linaje

RESUMEN

PURPOSE: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent. EXPERIMENTAL DESIGN: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients. RESULTS: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient. CONCLUSIONS: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Receptores ErbB/genética , Amplificación de Genes , Eliminación de Gen , Glioblastoma/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 19/genética , Estudios de Cohortes , ADN de Neoplasias/genética , Femenino , Frecuencia de los Genes , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Pronóstico , Tasa de Supervivencia