The genetic causes of basal ganglia calcification, dementia, and bone cysts

BACKGROUND: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. METHODS: The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. RESULTS: Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. CONCLUSIONS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.