Sporadic adult-onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

Aims: Adult-onset orthochromatic leucodystrophy, associated with pigmented macrophages and hereditary diffuse leucoencephalopathy with spheroids, are two disorders with similar clinical manifestations, radiological characteristics and neuropathological findings. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene are the hallmark of this spectrum of disease. Furthermore, polycystic membranous lipomembranous osteodysplasia with sclerosing leucoencephalopathy is caused by mutations in two genes, DAP12 and TREM2, which encode proteins involved in the same pathways as CSF1R. We describe a case of sporadic adult-onset orthochromatic leucodystrophy associated with pigmented macrophages diagnosed by biopsy without harbouring mutations in the known targeted genes. Methods and results: A 51-year-old woman, with no familial history of neurological diseases, developed a progressive neurological deterioration showing inappropriate behaviour, ataxia, spasticity, axial dystonia and agitation. Radiological images and a stereotaxic biopsy were conclusive with adult-onset orthochromatic leucodystrophy associated with pigmented macrophages. Genetic analysis did not show mutations in either CSF1R, DAP12 or TREM2. Conclusions: We add support to the idea that all these entities are closely related diseases linked to a convergent metabolic pathway, but caused by different genes or perhaps by the combination of individually non-pathogenic variations of selected genes. Genetic defects are still barely known in a substantial number of adult leucodystrophies.