Abstract
We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled “hereditary diffuse leukencephalopathy with axonal spheroids” (HDLS) and “pigmentary orthochromatic leukodystrophy” (POLD), disorders which now appear to form a disease continuum. The term “adult-onset leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.
Highlights
We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the ColonyStimulating Factor 1 Receptor gene (CSF1R)
The majority of families reported to date have shown a clear dominant family history together with a mutation that segregates appropriately, a recent publication has found a significant proportion of de-novo CSF1R mutations in their cohort[10]
The mutation in the family we report is present in exon 18, CSF1R:p.R782G
Summary
We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the ColonyStimulating Factor 1 Receptor gene (CSF1R). The few recently reported families with CSF1R mutations had been previously labelled “hereditary diffuse leukencephalopathy with axonal spheroids” (HDLS) and “pigmentary orthochromatic leukodystrophy” (POLD), disorders which appear to form a disease continuum. Mutations in the Colony-Stimulating Factor 1 Receptor gene (CSF1R), have been associated with causing hereditary diffuse leukencephalopathy with axonal spheroids (HDLS)[6,7] and pigmentary orthochromatic leukodystrophy (POLD)[8]. Families reported so far with changes in this gene have presented with a mean age of onset in the fourth decade and an average disease course of six to nine years[6,9]. The mutation in the family we report is present in exon 18, CSF1R:p.R782G
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