Objective: We describe the clinical, radiological and neuropathological phenotype of a patient carrying a novel variant in the CSF1R gene.

Background: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare disease with autosomal dominant inheritance caused by mutations in the colony stimulating factor 1 receptor (CSF-1R) gene. The clinical presentation is heterogeneous and includes atypical parkinsonism, psychiatric disorder, cognitive decline and seizures.

Method: A 56-year-old male presented with severe apathy and abulia syndrome associated with bilateral asymmetric akinetic-rigid parkinsonism and pyramidal signs for the last six months, as well as a rapidly progressive multidomain cognitive decline consisting of a severe frontal lobe syndrome, and language, memory and orientation deficits. He had a first-degree relative with a history of dementia with frontal lobe syndrome at the age of 65.

Results: The brain magnetic resonance imaging (MRI) showed moderate subcortical atrophy and an extensive fronto-parieto-temporal leukoencephalopathy affecting the corpus callosum, with the involvement of the pons. The cerebrospinal fluid and serum analysis, including the determination of antineuronal and onconeuronal antibodies was normal. Given the fast clinical decline, the atypical extrapyramidal and pyramidal signs with red flags and the extensive leukoencephalopathy, we aimed to rule out other treatable conditions with an atypical presentation, such as progressive multifocal leukoencephalopathy and intravascular lymphoma. Accordingly, a brain biopsy was performed demonstrating loss of myelin, glial reactivity, foamy macrophages and mild lymphocytic inflammation with T (CD3+) and B (CD20+) cells affecting mainly the white matter. The immunohistochemistry for neurofilaments revealed abundant neuronal spheroids. The ubiquitin, phosphorylated tau and amyloid-beta immunohistochemistry were negative. The genetic analysis identified the novel p.Leu672Pro variant in the CSFR1 gene.

Conclusion: In the presence of atypical parkinsonism, behavioral changes and rapidly progressive cognitive impairment with extensive leukoencephalopathy, especially in patients with positive family history, HDLS should be considered as part of the differential diagnosis. The p.Leu672Pro variant in the CSFR1 gene might be responsible for HDLS in this patient.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/atypical-parkinsonism-and-psychiatric-disorder-in-hereditary-diffuse-leukoencephalopathy-with-spheroids-a-novel-variant-in-the-csf1r-gene/