A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids

Abstract

We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C>T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.

Keywords: Behavioural change; CSF1R; Dementia; Frontal dementia; HDLS; Leucoencephalopathy.

Fig. 1

Family pedigree. Black colour indicates affected by dementia.

Fig. 2

MR imaging of 1.5 showing widespread white matter change with a frontal predominance. There is associated atrophy and thinning of the corpus callosum.

Fig. 3

Molecular analysis of CSF1R. A novel heterozygous mutation (c.2342C > T, p.A781V) was found in exon 18 of CSF1R. cDNA and protein references used were NM_005211.3 starting at the translation initiation codon and NP_005202.2, respectively. Protein sequence alignment around the mutation site (A781) is shown for different CSF1R orthologues: this residue of the CSF1R protein is highly conserved between species.

Fig. 4

Distribution of all the mutations described so far in the three-dimensional structure of the tyrosine kinase domain of the CSF1R protein, including the mutation here identified (p.A781V). Protein representation made using the Protein Workshop .