Osteodysplasia lipomembranous Polycystic with sclerosing leukoencephalopathy -PLOSP- (Polycystic lipomembranous osteodysplasia With sclerosing leukoencephalopathy -PLOSP-) - Genes TREM2 and TYROBP (DAP12).  

Polycystic osteodysplasia with sclerosing leukoencephalopathy lipomembranous, commonly known as PLOSL, is a progressive disorder that affects the bones and the brain.

Bone abnormalities associated with PLOSL usually do not appear in the early 20s. In the most affected people, the first symptoms of the disease are pain and tenderness in the ankles and feet. Several years later, the bones begin to fracture frequently, especially the bones of the ankles, feet, wrists and hands. Bone pain and fractures are caused by osteoporosis and the appearance of cysts. These abnormalities cause weakening of the bones and makes them more likely to fracture. Abnormalities characteristic of the disease in the brain usually appear in the early 30s. The first noticeable signs and symptoms include personality changes, followed by a loss of judgment, euphoria, loss of inhibition and lack of concentration. These neurological changes cause significant problems in social and family life of an affected person. As the disease progresses, dementia develops. Ultimately, affected people become unable to walk, talk or care for themselves. People with this disease usually live only thirty or forty years.

This process is due to mutations in the gene TREM2, located on the short arm of chromosome 6 (6p21.1) or TYROBP gene, located on the long arm of chromosome 19 (19q13.1). Proteins produced from these two genes (trigger receptor expressed on myeloid cells 2 and TYRO -binding protein tyrosine kinase- to) act together to activate certain cell types. These proteins appear to be particularly important in osteoclasts, which are involved in bone remodeling, replacing old bone tissue with new bone. The TREM2 and TYROBP proteins are also critical for the normal function of microglia in the central nervous system. Although these proteins play essential roles in osteoclasts and microglia is unclear the exact role in these cells.

They have identified at least 10 mutations in the gene TREM2 and at least 6 mutations in the gene causing polycystic TYROBP lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Some mutations prevent protein production, while others lead to production of an abnormally short, nonfunctional version of the protein. Other mutations change the structure of the protein TREM2, preventing it from reaching the cell surface. These changes cause a faulty signaling between TREM2 derived proteins and TYROBP disrupting normal bone growth and causing progressive brain abnormalities in people with the disease. It is thought that the bone changes seen with this disorder are related to the malfunction of osteoclasts, which are less able to reabsorb bone tissue during bone remodeling. In the central nervous system, the faulty signaling through TYROBP-TREM2 complex causes generalized alterations of microglia. Work is underway to determine how these abnormalities lead to progressive neurological problems associated with PLOSL.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, by complete PCR amplification of exons and TYROBP TREM2 gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).