Nasu-Hakola disease

Nasu-Hakola disease, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is an extremely rare autosomal recessive disorder characterized by a combination of progressive presenile dementia and bone cysts. The disease affects two major body systems: the skeletal system and the central nervous system. It is caused by mutations in the TYROBP (DAP12) gene or the TREM2 gene, both of which encode proteins involved in signaling pathways critical for osteoclast and microglial cell function. The disease typically manifests in early adulthood with an osseous phase, usually beginning in the twenties, characterized by pain and swelling in the ankles and wrists due to bone cysts (polycystic osseous lesions), particularly in the long bones of the extremities. Pathological fractures may occur following minor trauma. The neurological phase typically begins in the thirties to forties, presenting with progressive frontal lobe syndrome including personality changes, loss of social inhibitions, euphoria, impaired concentration, and memory loss. This progresses to profound dementia. Brain imaging reveals progressive leukoencephalopathy with calcifications of the basal ganglia and cortical atrophy, particularly in the frontal and temporal lobes. There is currently no curative or disease-modifying treatment for Nasu-Hakola disease. Management is supportive and symptomatic, including orthopedic care for fractures, pain management, and neuropsychiatric support as dementia progresses. The disease is relentlessly progressive, and most patients become severely disabled by their forties, with death typically occurring by the fifth decade of life. The condition was first described independently by Nasu and Hakola in the early 1970s, and the majority of reported cases have been from Finland and Japan, though cases have been identified worldwide.

Common questions about Nasu-Hakola disease