A clinicopathological and genetic study of sporadic diffuse leukoencephalopathy with spheroids: a report of two cases

Abstract

Diffuse leukoencephalopathy with spheroids (DLS) is a white matter neurodegenerative disease characterized by progressive cognitive decline and motor symptoms 1–6, and histologically, by axonal swellings (‘spheroids’) and loss of axons and myelin 1–3,5,7–11. It was originally described as a rare, hereditary, autosomal dominant disorder (hereditary DLS: HDLS) 2, but there have been reports on DLS without family history as well (sporadic DLS: SDLS) 6,12–22. In 2012, Rademakers et al. 9 identified 14 different mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which are located in exons 12–22 and affect the tyrosine kinase domain of the protein, in 14 families with HDLS. Interestingly, this gene shares the same signalling pathway as TYROBP (DAP12) and TREM2, whose mutations are implicated in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, also known as Nasu-Hakola disease) 23–25. PLOSL shares similar clinicopathological profiles with DLS, such as a progressive neuropsychiatric decline and leukoencephalopathy with spheroids 26,27. In this paper we describe the clinicopathological features of two cases of SDLS. In one of them, genetic analyses of CSF1R, TYROBP and TREM2 were conducted, and no mutations in these genes were identified.