Abstract
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder that typically presents with early-onset cognitive decline or personality change. The disease is associated with heterozygous mutations in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R activation regulates microglial survival, proliferation, and differentiation. The different gene mutations may be related to the various clinical phenotypes. Here, we described comprehensive clinical, neuroimaging, neuropathological, and genetic analyses of a family with HDLS. A novel splicing mutation in intron 13 (c.1858+1G>T) of CSF1R was found in this family. It is located at the splice site of intron 13, resulting in a splice donor site leading to exon 13 skipping from the CSF1R mRNA. The mother and two elderly siblings of the proband had the same CSF1R mutation as the proband but showed very mild neuroimaging abnormalities and mild memory loss, which did not affect daily life, indicating very uneven penetrance and distinctly different disease progression among family members. This report provides diverse neuroimaging and clinical characteristics of a novel CSF1R mutation with different disease penetrance. The large clinical heterogeneity in the same family who all had the same mutation indicates that modifying genes and environmental factors may play a role in the pathogenesis of HDLS.
Highlights
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration and corpus callosum atrophy (Axelsson et al, 1984)
Clinical symptoms often start with neuropsychiatric problems, including behavioral changes and cognitive declines, followed by or concurrent with motor and gait disturbances caused by pyramidal, extrapyramidal or cerebellar damage
Age of onset, dysarthria, motor and gait disorder, cognitive decline, sweating and constipation, and tremors are all typical symptoms of HDLS except the 20-kg weight loss in 2 months without any evidence of loss of appetite, tumor, infection or even vasculitis
Summary
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration and corpus callosum atrophy (Axelsson et al, 1984). No known variants in the CSF1R gene were found, while the WES test in the proband showed a c.1858+1G>T mutation in exon 13 of CSF1R (Figure 2A), which is a novel mutation of CSF1R. This mutation was not found in the Exome Aggregation Consortium, The Human Gene Mutation Database (HGMD), and the 1,000 Genomes Project (1000G). Hyperintense lesions within the white matter were found in his mother (Figure 3A), elder brother (Figure 3B), and elder sister (Figure 3C), but much less than this patient, indicating that this mutation had different penetrance among family members. The products were purified and confirmed by Sanger sequencing, and sequencing analysis showed that the splice-site mutation caused the deletion of exon 13 of the CSF1R gene during mRNA splicing (Figures 4B,C)
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