A novel CSF-1R mutation in a family with hereditary diffuse leukoencephalopathy with axonal spheroids misdiagnosed as hydrocephalus

Xinqing Zhang,Miaomiao Wang

doi:10.1007/s10048-019-00579-0

Abstract

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene that often results in cognitive impairment, psychiatric disorders, motor dysfunction and seizure. We report familial cases of a novel CSF1R mutation causing HDLS similar to hydrocephalus. The patients initially presented with a gait disturbance and then developed progressive cognitive decline, urinary incontinence, epileptic seizures and became bedridden as the disease progressed. A brain magnetic resonance imaging (MRI) scan revealed striking ventricular enlargement and diffuse brain atrophy with frontotemporal predominance, which was later accompanied by white matter changes. Genetic testing in this family showed a novel c.2552T>C (p.L851P) mutation in exon 19 of the CSF1R gene. However, three gene carriers in the family remained clinically asymptomatic. Because of its heterogeneous clinical phenotypes, HDLS patients are often misdiagnosed with other diseases. This is the first genetically proven HDLS case resembling hydrocephalus, and the clinical symptoms of HDLS may be related to the specific genetic mutation.

Highlights

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a progressive neurodegenerative disease first described and pathologically defined in a large Swedish family in 1984 by Axelsson R et al [1]
Spotty calcification detected on computer tomography (CT) in the frontal pericallosal regions has been reported as a specific finding in patients with HDLS [3] and brain magnetic resonance imaging (MRI) shows asymmetric deep white matter lesions with frontoparietal predominance, followed by brain atrophy [4, 5]
We report a new HDLS family with a novel colony stimulating factor 1 receptor (CSF1R) mutation, in which the prominent clinical characteristics are associated with hydrocephalus

Summary

Introduction

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a progressive neurodegenerative disease first described and pathologically defined in a large Swedish family in 1984 by Axelsson R et al [1]. At age 32, the patient gradually became bedridden and unable to manage herself due to dysphagia, urinary and bowel incontinence, rigidity, apathy and dementia She was diagnosed with HDLS, as confirmed by genetic analyses, which revealed a heterozygous mutation (c.2552T>C) in exon 19 of the CSF-1R gene on chromosome 5, resulting in an amino acid substitution of leucine (L) to proline (P) at codon position 851 (p.L851P). This patient was a 27-year-old female and the youngest sister of patient III-1.

Discussion

Conclusion