Polycystic Lipomembranous Osteodysplasia With Sclerosing Leukoencephalopathy 2

A number sign (#) is used with this entry because of evidence that polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-2 (PLOSL2) is caused by homozygous mutation in the TREM2 gene (605086) on chromosome 6p21.

Description

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-2 (PLOSL2), or Nasu-Hakola disease, is a recessively inherited presenile frontal dementia with leukoencephalopathy and basal ganglia calcification. In most cases the disorder first manifests in early adulthood as pain and swelling in ankles and feet, followed by bone fractures. Neurologic symptoms manifest in the fourth decade of life as a frontal lobe syndrome with loss of judgment, euphoria, and disinhibition. Progressive decline in other cognitive domains begins to develop at about the same time. The disorder culminates in a profound dementia and death by age 50 years (summary by Klunemann et al., 2005).

For a discussion of genetic heterogeneity of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, see 221770.

Clinical Features

Bird et al. (1983) reported PLOSL in 4 of 10 sibs in an American family of Czechoslovakian ancestry. All patients had calcification of the basal ganglia. Electron microscopy of fat cells showed peculiar membrane convolutions. Limited neuropathologic material had shown gliosis and demyelination of white matter, senile plaques and neurofibrillary tangles. The authors noted other possible rare features, including leukemia and a disorder of intestinal motility. The prevalence of the disorder is unknown, partly because it may be confused with Alzheimer disease (see 104300) and fibrous dysplasia of bone. Bird et al. (1983) suggested that radiographs of hands and feet should be part of the evaluation of patients with unexplained presenile dementia.

Klunemann et al. (2005) reported 6 patients, including 2 sibs, with PLOSL2. Compared to patients with PLOSL1 (221770), caused by mutations in the DAP12 gene (604142) as described by Paloneva et al. (2001), patients with TREM2 mutations had onset of bone pain about 10 years later and bone fractures were diagnosed 4 years later. There was no difference between the 2 groups in age at onset of dementia or in neurologic symptoms or radiographic findings.

Molecular Genetics

In affected members of 5 families with PLOSL2, including the family reported by Bird et al. (1983), Paloneva et al. (2002) identified homozygous mutations in the TREM2 gene (605086.0001-605086.0005).

Klunemann et al. (2005) reported 6 patients, including 2 sibs, with PLOSL2 caused by homozygous mutations in the TREM2 gene (see, e.g., 605086.0006 and 605086.0007).