RESUMEN
Mutations in the catalytic subunit of the mitochondrial DNA-polymerase gamma cause a wide spectrum of clinical disease ranging from infantile hepato-encephalopathy to juvenile/adult-onset spinocerebellar ataxia and late onset progressive external ophthalmoplegia. Several of these syndromes are associated with an encephalopathy that characteristically shows episodes of rapid neurological deterioration and the development of acute cerebral lesions. The purpose of this study was to investigate the nature, distribution and natural evolution of central nervous system lesions in polymerase gamma associated encephalopathy focusing particularly on lesions identified by magnetic resonance imaging. We compared radiological, electrophysiological and pathological findings where available to study potential mechanisms underlying the episodes of exacerbation and acute cerebral lesions. We studied a total of 112 magnetic resonance tomographies and 11 computed tomographies in 32 patients with polymerase gamma-encephalopathy, including multiple serial examinations performed during both the chronic and acute phases of the disease and, in several cases, magnetic resonance spectroscopy and serial diffusion weighted studies. Data from imaging, electroencephalography and post-mortem examination were compared in order to study the underlying disease process. Our findings show that magnetic resonance imaging in polymerase gamma-related encephalopathies has high sensitivity and can identify patterns that are specific for individual syndromes. One form of chronic polymerase gamma-encephalopathy, that is associated with the c.1399G > A and c.2243G > C mutations, is characterized by progressive cerebral and cerebellar atrophy and focal lesions of the thalamus, deep cerebellar structures and medulla oblongata. Acute encephalopathies, both infantile and later onset, show similar pictures with cortical stroke-like lesions occurring during episodes of exacerbation. These lesions can occur both with and without electroencephalographic evidence of concurrent epileptic activity, and have diffusion, spectroscopic and histological profiles strongly suggestive of neuronal energy failure. We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum.
Asunto(s)
Encefalopatías/genética , Encefalopatías/metabolismo , Encéfalo/metabolismo , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Metabolismo Energético , Mutación , Arginina , Encéfalo/patología , Encefalopatías/complicaciones , Encefalopatías/diagnóstico , Cerebelo/patología , Cisteína , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/genética , Esclerosis Cerebral Difusa de Schilder/metabolismo , Imagen de Difusión por Resonancia Magnética , Progresión de la Enfermedad , Electroencefalografía , Epilepsia/etiología , Epilepsia/genética , Epilepsia/metabolismo , Glicina , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Neocórtex/patología , Sensibilidad y Especificidad , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/metabolismo , Accidente Cerebrovascular/etiología , Síndrome , Tálamo/patología , Tomografía Computarizada por Rayos XAsunto(s)
Encéfalo/patología , Esclerosis Cerebral Difusa de Schilder/patología , Metabolismo de los Lípidos , Adulto , Ganglios Basales/patología , Encéfalo/enzimología , Tronco Encefálico/patología , Cerebelo/patología , Corteza Cerebral/patología , Colesterol/metabolismo , Esclerosis Cerebral Difusa de Schilder/enzimología , Esclerosis Cerebral Difusa de Schilder/genética , Esclerosis Cerebral Difusa de Schilder/metabolismo , Ácidos Grasos/metabolismo , Femenino , Fibroblastos/enzimología , Gangliósidos/metabolismo , Glucolípidos/metabolismo , Glicósido Hidrolasas/metabolismo , Humanos , Hígado/enzimología , Hígado/patología , Pulmón/patología , Masculino , Bulbo Raquídeo/patología , Nervio Óptico/patología , Linaje , Fosfolípidos/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Puente/patología , Médula Espinal/patología , Bazo/patología , Sulfatasas/metabolismo , Tálamo/patologíaAsunto(s)
Esclerosis Cerebral Difusa de Schilder/metabolismo , Lóbulo Frontal/metabolismo , Leucodistrofia Metacromática/metabolismo , Esfingolípidos/metabolismo , Adulto , Química Encefálica , Cerebrósidos/análisis , Cerebrósidos/metabolismo , Colesterol/análisis , Esclerosis Cerebral Difusa de Schilder/genética , Ácidos Grasos/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esfingomielinas/análisis , Esfingomielinas/metabolismo , Sulfoglicoesfingolípidos/análisis , Sulfoglicoesfingolípidos/metabolismoRESUMEN
Cultured fibroblasts derived from patients with late infantile metachromatic leukodystrophy incorporated arylsulfatase A from the growth medium. Upon exposure to cerebroside sulfate, they exhibited patterns of uptake and hydrolysis indistinguishable from cells derived from control subjects. Furthermore, inclusion granules formed in the metachromatic leukodystrophy fibroblasts upon exposure to sulfatides were cleared by subsequent supplementation of the growth medium with arylsulfatase A.