CNS manifestations of Nasu-Hakola disease - A frontal dementia with bone cysts

Background: Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a genetically heterogeneous disease characterized by a combination of systemic bone cysts and dementia . Objective: The authors present a neurologic, neuroradiologic, and neuropa thologic analysis of a series of PLOSL patients in which the diagnosis has been confirmed by molecular genetic methods. Methods: Clinical, neurophysio logic, and imaging follow-up data on eight patients as well as autopsy samp les of three patients were analyzed in this study. All eight patients were homozygous fora loss-of-function mutation in the DAP12 gene. Results. In mo st patients, the disease debuted with pain in ankles and wrists after strai n during the third decade, followed by fractures caused by cystic lesions i n the bones of the extremities. Frontal lobe syndrome and dementia began to develop by age 30, leading to death by age 40. Neuroimaging disclosed abno rmally high and progressively increasing bicaudate ratios and calcification s in the basal ganglia as well as increased signal intensities of the white matter on TP-weighted MR images even before the appearance of clinical neu rologic symptoms. Three patients who had undergone autopsies showed an adva nced sclerosing leukoencephalopathy with frontal accentuation, widespread a ctivation of microglia, and microvascular changes. Conclusions: Although PL OSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestatio ns. Consequently, patients with frontal-type dementia of unknown origin sho uld be investigated by x-ray of ankles and wrists. The current results sugg est early basal ganglia involvement in PLOSL.