Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), Nasu-Hakola disease, is a globally distributed recessively inherited disease. PLOSL is characterized by cystic bone lesions, osteoporotic features, and loss of white matter in the brain leading to spontaneous bone fractures and profound presenile dementia. We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2. DAP12 is a transmembrane adaptor protein that associates with the cell surface receptor TREM2. The DAP12–TREM2 complex is involved in the maturation of dendritic cells. To test a hypothesis that osteoclasts would be the cell type responsible for the bone pathogenesis in PLOSL, we analyzed the differentiation of peripheral blood mononuclear cells isolated from DAP12- and TREM2-deficient PLOSL patients into osteoclasts. Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro. These results indicate an important role for DAP12–TREM2 signaling complex in the differentiation and function of osteoclasts.

Homicidal behavior in a country with a relatively low crime rate appears to have a statistical association with some specific mental disorders classified according to DSM-III-R classifications.

Although PLOSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestations. Consequently, patients with frontal-type dementia of unknown origin should be investigated by x-ray of ankles and wrists. The current results suggest early basal ganglia involvement in PLOSL.

Objectives: To study the prevalence of hypovitaminosis D, the effect of vitamin D supplementation on serum 25-hydroxyvitamin D [S-25(OH)D], and the intakes of vitamin D and calcium in Finnish 9-to 15-year-old athletic and nonathletic girls. Design: 1-year follow-up study (February 1997-March 1998 with three months of vitamin D supplementation (10 mgad) from October to January. Setting: Turku University Central Hospital, Finland. Subjects: 191 female volunteers aged 9 ± 15 y (131 athletes and 60 controls). Methods: Vitamin D and calcium intakes were estimated by a four-day food recording and a semi-quantitative food frequency questionnaire (FFQ). S-25(OH)D was followed by radioimmunoassay (RIA). Results: At baseline the mean S-25(OH)D concentration was 33.9 nmolal among all girls. In winter severe hypovitaminosis D (S-25(OH)D`20 nmolal) occurred in 13.4% of the participants and in 67.7% S-25(OH)D was below 37.5 nmolal. By the next summer the mean S-25(OH)D concentration was 62.9 nmolal and in 1.6% of the subjects it was below 37.5 nmolal. The prevalence of severe hypovitaminosis D was not signi®cantly reduced by three months of vitamin D (10 mgad) supplementation. At baseline, the mean intake of vitamin D was 2.9 mgad by food recording and 4.3 mgad by FFQ. The mean calcium intake was 1256 mgad and 1580 mgad, respectively. The intakes of vitamin D and calcium remained unchanged during the follow-up period. The athletes consumed more calcium than nonathletic controls, whereas the intake of vitamin D was quite similar among both groups. The vitamin D intake by FFQ correlated with the S-25(OH)D concentration in wintertime (r 0.28, P`0.01). Conclusion: Hypovitaminosis D is fairly common in growing Finnish girls in the wintertime, and three months of vitamin D supplementation with 10 mgad was insuf®cient in preventing hypovitaminosis D. The daily dietary vitamin D intake was insuf®cient (`5 mgad) in the majority of participants, while the calcium intake was usually suf®cient.