RESUMEN
OBJECTIVE: Ophthalmologic and neurologic manifestations of the mitochondrial DNA mutation at position 8993 (MTATP*NARP8993) are reported and compared with previously published reports of patients with the 8993 mutation and other mitochondrial disorders. DESIGN: Pedigree analysis. SETTING: University referral center. PATIENTS: Eight subjects from two unrelated pedigrees that were positive for the mitochondrial DNA replacement mutation at nucleotide position 8993 were evaluated ophthalmologically and neurologically. RESULTS: Retinal abnormalities ranged from mild salt-and-pepper changes to severe retinitis pigmentosa-like changes with maculopathy. Neurologic manifestations were also highly variable and ranged from migraine headaches to severe dementia and Leigh's disease. CONCLUSIONS: The type and extent of retinal pigmentary changes and neurologic findings varied substantially, even among members of the same family. These changes, although not specific for the MTATP*NARP8993 mutation, are highly suggestive of mitochondrial disease.
Asunto(s)
ADN Mitocondrial/genética , Enfermedades del Sistema Nervioso/genética , Mutación Puntual , Retinitis Pigmentosa/genética , Adolescente , Adulto , Niño , Preescolar , Electrorretinografía , Femenino , Fondo de Ojo , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/patología , Linaje , Retinitis Pigmentosa/patología , Agudeza Visual , Campos VisualesRESUMEN
Subacute necrotizing encephalopathy (SNE) or Leigh's disease is associated with various defects in oxidative phosphorylation (OXPHOS). However, the relationships between these OXPHOS defects and nuclear DNA or mitochondrial DNA (mtDNA) mutations is still unclear. We evaluated three SNE pedigrees (two singleton cases and a pedigree) biochemically for OXPHOS abnormalities and genetically for four mtDNA point mutations. There was a complex I defect in all three pedigrees that was associated with a complex III defect in two individuals. An mtDNA mutation in the ATPase, subunit 6 gene (np 8993) was present in one SNE pedigree. This mutation was maternally inherited, heteroplasmic, produced marked clinical and biochemical heterogeneity between pedigree members, and varied along the maternal lineage at levels ranging from 0% to > 95% of the total mtDNAs. These mtDNA mutations were not present in the other two pedigrees. These observations emphasize the importance of screening for OXPHOS defects and mtDNA mutations in SNE cases.
Asunto(s)
Adenosina Trifosfatasas/genética , Enfermedad de Leigh/genética , Mutación , Fosforilación Oxidativa , Southern Blotting , ADN Mitocondrial/análisis , Femenino , Humanos , Lactante , Enfermedad de Leigh/enzimología , Músculos/enzimología , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
Diabetes mellitus (DM) is one of the most common chronic disorders of children and adults. Several reports have suggested an increased incidence of maternal transmission in some forms of DM. Therefore, we tested a pedigree with maternally transmitted DM and deafness for mitochondrial DNA mutations and discovered a 10.4 kilobase (kb) mtDNA deletion. This deletion is unique because it is maternally inherited, removes the light strand origin (OL) of mtDNA replication, inhibits mitochondrial protein synthesis, and is not associated with the hallmarks of mtDNA deletion syndromes. This discovery demonstrates that DM can be caused by mtDNA mutations and suggests that some of the heterogeneity of this disease results from the novel features of mtDNA genetics.
Asunto(s)
ADN Mitocondrial/genética , Sordera/genética , Diabetes Mellitus Tipo 2/genética , Adulto , Secuencia de Bases , Análisis Mutacional de ADN , Sordera/complicaciones , Sordera/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Fosforilación Oxidativa , Linaje , Biosíntesis de Proteínas , Eliminación de SecuenciaRESUMEN
A new quantitative procedure for the high-performance liquid chromatographic (HPLC) resolution of human brain gangliosides employing reversed-phase chromatography is described. To provide a derivative which can be determined by UV absorption techniques, p-nitrobenzyloxyamine was coupled to the gangliosides. Derivatization involves ozonation and cleavage of the ceramide double bond followed by oxime formation to the nascent aldehyde. Individual gangliosides, as they were resolved by HPLC, were collected. These fractions were then identified by thin-layer chromatography (TLC) and by gas chromatography of their monosaccharides. Quantitative results were obtained along with a marked increase in sensitivity over conventional resorcinol-hydrochloric acid quantitation of TLC-resolved gangliosides.
Asunto(s)
Química Encefálica , Gangliósidos/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Cromatografía por Intercambio Iónico , Cromatografía en Capa Delgada , Humanos , HidroxilaminasRESUMEN
The serum concentration and composition of gangliosides were examined in 80 humans including 10 normal subjects. A significant increase was found in the total gangliosides of serum in 7 patients with cerebral astrocytomas. There was also an increased percentage of serum gangliosides with simpler structure, particularly GM3. The serum of patients with other intracranial tumors, including pituitary adenomas, ependymoma, teratoma, and metastases, did not show an increase in total ganglioside; however the pattern of simplification was found in these and in a few patients with extracranial tumors as well. The findings suggest that astrocytoma tumors shed sialoglycolipids into the circulation, and their assay may be useful in monitoring oncological therapy.
