We evaluated the clinicopathological features of familial amyotrophic lateral sclerosis (ALS) with the fused in sarcoma (FUS) P525L mutation. Two sisters and their mother had a similar clinical course, which was characterized by the development of limb weakness at a young age with rapid disease progression. An elder sister, patient 1, progressed into a totally locked-in state requiring mechanical ventilation and died 26 years after the onset of the disease. In contrast, the younger sister, patient 2, died in the early stages of the disease. The patients had neuropathological findings that indicated a very active degeneration of motor neurons and multiple system degeneration, which led to marked brain and spinal cord atrophy in the long term clinical outcome. The multiple system degeneration included the frontal lobe, the basal ganglia and substantia nigra, cerebellum and related area. Compared with previously reported ALS cases, the severe degeneration of the frontal lobe and the striatum were the characteristic features in the patient 1 in this case study. The degeneration spread over multiple systems might be caused not only by the appearance of the FUS immunoreactive neuronal cytoplasmic inclusions but also by the degeneration of neuronal connections from the primary motor cortex and related areas.
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