Hereditary diffuse leucoencephalopathy with spheroids

The clinical, genetic, and morphological features of a previously unknown progressive neuropsychiatric disease are presented. By genealogical investigation of the background of an uncharacteristic case of presumed organic psychosis, we traced 71 relatives from four generations. The anamnestic data showed various combinations of psychiatric symptoms (depression, anxiety, aggressiveness, and severe dementia), neurological symptoms (impaired balance with retropulsion, hyperkinesia, and epilepsy), and somatic symptoms (gastrointestinal disorders, arthritis, and gynaecological problems) in 17 (11 dead and 6 living) members of the family. Age at onset varied between 8 and 60 years. Some patients rapidly developed severe dementia and died a few months after the onset of symptoms, while in others the course was prolonged with dementia over several decades. The genetic interpretation indicated an autosomal dominant inheritance with possible full penetrance but widely variable expressivity. Morphological studies were performed on the central nervous system of four decreased family members (three siblings and their maternal uncle). The same type of widespread leucoencephalopathy was seen in the four autopsy cases. It was characterised by degeneration and loss of myelin sheaths and axons, occurrence of numerous neuroaxonal spheroids in the affected white matter, accumulation of lipid-laden macrophages, and gliosis. The bilateral, frontal, fronto-parietal, and temporal locations of the most pronounced, diffusely demarcated lesions corresponded fairly well to the symptoms of an organic psychosyndrome with its main substrate in the forebrain. For this new clinico-pathological entity, the name "hereditary diffuse leucoencephalopathy with spheroids" (HDLS) is proposed. As a working hypothesis, it is suggested that not only genetic, but also immunological and possible endocrine factors may contribute to the development of the disease.