Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy also known as Nasu–Hakola disease is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by autosomal recessive loss of function mutations in either the TREM2 or TYROBP gene that are found most frequently in the Finnish and Japanese populations.
Signs and symptoms
Symptoms appear in four stages over the course of the disease. The first is asymptomatic and lasts up to the early 20s. The second stage is characterized by persistent bone pain, usually accompanied by pathological fractures of these bones. Bones of the hands, feet, wrists, and ankles are typically affected first, then followed by the arms and legs. The third stage is marked by the onset of symptoms typical of a frontal lobe syndrome with memory loss. Epilepsy may occur during this period but are transient. This stage usually has its onset in the late 20s and early 30s. The final stage is characterized by severe dementia and paralysis. Death usually occurs in the late 40s or early 50s.Genetics
This condition has been associated with 2 different loss of function mutations in the TYRO protein tyrosine kinase binding protein gene and in the triggering receptor expressed on myeloid cells 2 gene. TYROBP is located on the long arm of chromosome 19 and TREM2 is located on short arm of chromosome 6. TYROBP codes for the DAP12 adaptor protein, and TREM2 codes for the cell-surface receptor. Mutations in either gene produce the same clinical symptoms and manifestation of the disease.Pathophysiology
The pathophysiology of the disease is not well understood, however, microglial dysfunction has been associated with the disease. TREM2 is an important receptor that plays a role in the regulation of proliferation, phagocytic activity, and lipid metabolism of microglia. Activation of TREM2 on microglia can promote phagocytosis of debris in the central nervous system. Therefore, lack of TREM2 expression in this disease results in dysfunctional microglia that cannot effectively clear out neuronal debris. Specifically, these microglia lacking TREM2 cannot remove myelin debris, eventually leading to the lack of remyelination. The disease ultimately causes robust loss of white matter and axons, specifically in anterior brain regions like the frontal, parietal, and some of the temporal lobes.Lack of TREM2 expression also has effects on the bones, such that osteoclasts, the cells that break down damaged bone, also normally express TREM2. TREM2/DAP12 signaling is involved in the differentiation of osteoclasts, and the lack of TREM2 alters the generation of osteoclasts, which results in the bone cysts seen in the disease.