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

DAP12 and TREM2

From the Departments of Psychiatry and Psychotherapy (Drs. Klünemann and Klein) and Nuclear Medicine (Dr. Marienhagen), University of Regensburg School of Medicine, Germany; Dementia Research Centre (Drs. Ridha and Rossor), National Hospital for Neurology and Neurosurgery, London, UK; Neurology Service (Dr. Magy), Dupuytren University Hospital, Limoges, France; Division of Neurology (Dr. Wherrett), Toronto Western Hospital and University of Toronto, Ontario, Canada; Department of Neurology (Drs. Hemelsoet and De Bleecker), Ghent University Hospital, Belgium; The Royal National Orthopaedic Hospital (Dr. Keen), Stanmore, UK; and Department of Molecular Medicine (Drs. Peltonen and Paloneva), National Public Health Institute, Helsinki, Finland.

Address correspondence and reprint requests to Dr. Hans H. Klünemann, Certified Neurologist (American Board of Psychiatry & Neurology), Department of Psychiatry, Universitätsstr. 84, University of Regensburg School of Medicine, 93053 Regensburg, Germany; e-mail: hans.kluenemann{at}medbo.de

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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article.

Supported by the Academy of Finland (The Center of Excellence in Disease Genetics), the Ulla Hjelt Fond of the Foundation for Pediatric Research, the Helsinki Biomedical Graduate School, the Finnish Cultural Foundation, the Paulo Foundation, and the ReForM program of the University of Regensburg. Dr. Peltonen is the Gordon and Virginia McDonald Distinguished Chair in Human Genetics, UCLA.

Received May 13, 2004. Accepted in final form January 3, 2005.

This article has been cited by other articles:

				M. M. Bianchin, J. E. Lima, J. Natel, A. C. Sakamoto, H. Klunemann, B.H. Ridha, L. Magy, J.R. Wherrett, D.M. Hemelsoet, R.W. Keen, et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2 Neurology, February 28, 2006; 66(4): 615 - 616. [Full Text] [PDF]

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