Neuroradiological features of six kindreds with MELAStRNALeu A3243G point mutation: implications forpathogenesis

OBJECTIVE—To determinethe neuroradiological abnormalities associated with subjectscarrying the mitochondrial myopathy, encephalopathy, lacticacidosis, and strokelike episodes (MELAS) tRNA^Leu(UUR)A3243G point mutation
METHODS—Mitochondrialgenetic analysis was performed on 24 subjects from six kindreds withthe MELAS tRNA^Leu(UUR) A3243G point mutation. Cerebral CTand MRI were performed on 24 patients and 15 patients respectively.Previous neuroradiological investigations including cerebral CT fromfour deceased members of the families were also reviewed. Histologicalexamination of postmortem specimens of two patients within the kindredswas performed.
RESULTS—The commonestradiological finding was basal ganglia calcification. Otherabnormalities included focal lesions and cerebellar and cerebralatrophy. Basal ganglia calcification was progressive, symmetric, andasymptomatic. Histologically, basal ganglia calcification in onepatient was found to be in the pericapillary regions of the globuspallidus, with no neuronal involvement. Focal lesions most commonlyinvolved the grey matter of the parietal and occipital lobes andcerebellum. Histopathological examination suggested that these were dueto cellular rather than vascular dysfunction. Enlargement of the fourthventricle was the first sign of cerebellar atrophy. Cerebral andcerebellar atrophy were only present with severe disease.
CONCLUSIONS—Theseradiological findings, when considered in the context of the clinicaland pathological findings, seem to reflect two major disease processes:an intermittent abrupt loss of function associated with cell injuryfrom which there is at least partial recovery and a slowly progressivedegenerative process causing basal ganglia calcification, and cerebraland cerebellar atrophy. The clinical and radiological featuresresulting from these processes are distinctive and provide insight intothe consequences of mitochondrial dysfunction on the brain.