ORIGINAL COMMUNICATION Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation Kirk Kleinfeld • Bret Mobley • Peter Hedera • Adam Wegner • Subramaniam Sriram • Siddharama Pawate Received: 15 March 2012 / Revised: 30 August 2012 / Accepted: 13 September 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spher- oids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly pro- gressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadri- paresis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cere- brospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony- stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are nor- mal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are normal. Diagnosis may be made without histopathological evidence when a disease- causing mutation is demonstrated in the CSF1R gene. Keywords Leukodystrophy Á White matter disease Á CSF1R Á Mutation Introduction Leukodystrophies comprise a diverse group of disorders of the white matter with a genetic basis that run an invariably progressive clinical course with a fatal outcome. A leu- koencephalopathy is a broader term that encompasses diseases that predominantly affect the white matter, and include infectious and inflammatory and vascular disorders (for recent reviews see [1–4]). The neuropathological features of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), an adult-onset leukodystrophy, were described in 1984 [5]. HDLS is characterized by the presence of widespread loss of myelin and the presence of neuroaxonal dilations (spheroids). Since then, additional case series of HDLS have been reported, including some cases in which a family Kirk Kleinfeld and Bret Mobley contributed equally to this manuscript. K. Kleinfeld Á P. Hedera Á A. Wegner Á S. Sriram Á S. Pawate (&) Department of Neurology, Vanderbilt Multiple Sclerosis Center, Vanderbilt University Medical Center, 719 Thompson Lane # 24100, Nashville, TN 37204, USA e-mail: siddharama.pawate@vanderbilt.edu B. Mobley Division of Neuropathology, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA 123 J Neurol DOI 10.1007/s00415-012-6680-6