A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442+2T>C mutation in the CSF1R gene.

Clinical phenotypes of hereditary diffuse leukoencephalopathy with spheroids (HDLS), a familial progressive neurodegenerative disorder affecting the white matter of the brain, are heterogenous and may include behavioral and personality changes, memory impairment, parkinsonism, seizure, and spasticity. Thus, HDLS is frequently unrecognized and misdiagnosed. Heterozygous mutations located within the kinase domain of the gene encoding the colony-stimulating factor 1 receptor (CSF1R), a cell surface receptor with key roles in development and innate immunity, have been shown in HDLS. These different gene mutations may be related to the various clinical phenotypes. We report here a newly identified family with HDLS harboring a mutation in the CSF1R gene. We examined clinical and neuropathological features in three members of this family. These patients presented with affective incontinence, memory impairment, and executive dysfunction at onset, and revealed nonfluent aphasia, parkinsonism, and seizure as the disease progressed. We identified a novel CSF1R splice site mutation (c.2442+2T>C) in intron 18 for two of the patients. MRI of these patients revealed progressive, frontotemporal-predominant, confluent leukoencephalopathy. We also observed severe myelin loss, axonal degeneration, and abundant axonal spheroids, astrocytes, and microglia in the cerebral white matter, consistent with HDLS neuropathological features. Additionally, we identified atypical neuropathological findings for HDLS, including neuronal loss and gliosis with ballooned neurons and central chromatolysis in the frontal cortex and hippocampus. This report provides further evidence for the clinical and neuropathological heterogeneity of HDLS.

Alzheimer's disease or Alzheimer's syndrome?: a longitudinal computed tomography neuroradiological follow-up study of 56 cases diagnosed clinically as Alzheimer's disease.

BACKGROUND: Some 200 patients, including those with Alzheimer's disease and other types of dementia, stay year-round in Yokohama - Houyuu Hospital. They undergo computed tomography (CT) neuroradiological examination at least once or twice a year. For this study, the accumulative data, including clinical and neuroradiological, were analyzed. METHODS: Differential diagnoses of Alzheimer's disease were performed in accordance with the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The 56 patients (15 men, 41 women) included in this study underwent in-hospital observation on average for 4.4 years (range: 1-10 years). The patients were classified into four groups according to the age of disease onset. The CT findings were summarized for each group and then compared among the groups to determine if there were any differences related to age of onset and, if so, to identify and analyze them. RESULTS: (1) The duration of deceased cases' total clinical course (in years) compared among the four groups. In general, the degree of dementia was more severe among those with earlier disease onset. (2) In cases admitted within 2 years from onset (n =14), the suspected initiating focus of cortical atrophy occurred in the frontal lobe (n = 6), the temporal lobe (n = 6), or the fronto-temporal lobes (n = 2). (3) Although CT findings generally showed that the more severe cases had earlier onset, serial CT examinations in each case showed widely different pathologies in degree, nature and manner of progression, regardless of group classification. (4) The earliest sites of brain atrophy, sites of its severest involvement within the brain, and neuroradiological development of the cerebral cortex pathology in combination with hemispheric white matter, lateral ventricles, and third ventricles varied among the four groups and between case within each group. Alzheimer's disease could not be subclassified simply by the age of clinical onset. CONCLUSION: Cases of so-called Alzheimer's disease, as observed through continued clinical follow-up and serial CT examinations, appear so diverse in symptomatology and radiological pathomorphology that it is difficult to consider them a single nosological entity. The pathology of Alzheimer's disease has to be reconsidered in accordance with the variety observed in the sequential development of neuroradiological findings. The pathology must be reconstructed in terms of topographical dimensions and chronological developments. The diagnosis of Alzheimer's disease appears to be not so simple based on any conventional diagnostic operational standards.