Hereditary Diffuse Leukoencephalopathy with Spheroids via the CSF1R Gene

CSF1R-related disorders comprise two conditions and phenotypes. One is hereditary diffuse leukoencephalopathy with spheroids, which is a rapidly progressive neurodegenerative disorder with adult-onset. The mean age of onset is 43 years (18–78 years), and women have a significantly younger age of onset than men. The major symptoms include cognitive impairment, memory loss, dementia, Parkinsonism, apraxia, rigidity, bradykinesia, shuffling gait, spasticity, and seizures. The minor features include depression and behavioral changes. Brain MRI shows diffusion-restricted lesions and calcifications in the white matter, thin corpus callosum and abnormal signal in pyramidal tracts, dilation of the lateral ventricles and cortical atrophy. The phenotype of this disease is also affected by sex. For example, in addition to a significantly younger age of onset than men, motor dysfunctions were the most frequent initial symptom in women (Karle et al. 2013. PubMed ID: 24198292; Konno et al. 2014. PubMed ID: 24336230; Konno et al. 2017. PubMed ID: 27680516; Abe et al. 2017. PubMed ID: 28025469).

The other condition is brain abnormalities with neurodegeneration and dysosteosclerosis. Onset can be as early as prenatal (Oosterhof et al. 2019. PubMed ID: 30982608). The major symptoms include structural brain anomalies, skeletal dysplasia, dysosteosclerosis, and osteopetrosis. Some patients may have dysmorphic facial features (Oosterhof et al. 2019. PubMed ID: 30982608; Guo et al. 2019. PubMed ID: 30982609).

As leukoencephalopathy can be caused by defects in hundreds of genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

Hereditary diffuse leukoencephalopathy with spheroids is inherited in an autosomal dominant manner whereas CSF1R-related brain abnormalities with neurodegeneration and dysosteosclerosis is inherited in an autosomal recessive manner. Pathogenic variants in CSF1R include missense, nonsense, splicing, and small deletions and duplications. Large deletions and complex rearrangements have also been reported in the CSF1R locus (Human Gene Mutation Database). De novo pathogenic variants were found in one-third of patients (Karle et al. 2013. PubMed ID: 24198292). Seventy-nine percent of the pathogenic variants were located in the distal part of the tyrosine kinase domain of CSF1R (Konno et al. 2017. PubMed ID: 27680516).

CSF1R encodes a tyrosine kinase growth factor receptor for colony-stimulating factor 1, the macrophage- and monocyte-specific growth factor. CSF1R is expressed in microglia, which is important for neuronal and brain development, and in osteoclasts, which plays an essential role in bone mineralization. A zebrafish model (csf1rDM) with Csf1r malfunction showed brains that lacked microglia (Oosterhof et al. 2019. PubMed ID: 30982608). This is also supported by a knock-out mouse model of Csf1r-null presenting various anatomical abnormalities in developing brains, and sclerosing skeletal dysplasia, which eventually resulted in death (Guo et al. 2019. PubMed ID: 30982609; Erblich et al. 2011. PubMed ID: 22046273; Dai et al. 2002. PubMed ID: 11756160).

Clinical sensitivity of CSF1R testing is high. Pathogenic variants in CSF1R were detected in 6 of 7 patients with hereditary diffuse leukoencephalopathy with spheroids (Konno et al. 2014. PubMed ID: 24336230).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CSF1R gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).