Adult-onset leukoencephalopathy caused by CSF1R mutations: Is all that glitters gold?

In a clinical and genetic characterization of 149 unrelated individuals with adult‐onset leukoencephalopathy, Tsai et al. identified 5 patients with CSF1R‐related hereditary leukodystrophy with spheroids (HLDS), including 1 with the p.Thr79Met variant located in the extracellular immunoglobulin‐like domain (IgLD). This finding may have a major clinical impact, as so far all the HLDS‐related variants were located in the intracellular tyrosine kinase domain (TyrKD). The p.Thr79Met variant has been considered as HLDS‐causing variant because of its absence in population databases, predictions of bioinformatics program, and in vitro functional analysis, showing the loss of CSF1‐induced autophosphorylation of CSF1 receptor (CSF1R) in HeLa cells transfected with the mutant CSF1R expression plasmid.

In our opinion, this conclusion needs further evidence. Indeed, the patient was very old at disease onset, being 86 years (which would be the latest age at HLDS onset ever reported), and had multiple risk factors for leukoaraiosis, including hypertension, diabetes, hyperlipidemia, smoking, and kidney failure. Moreover, no examination such as cerebral PET and CSF analysis for investigating common causes of dementia has been reported, and no consideration about genetic variant and disease co‐segregation has been given. Finally, in vitro functional analysis should be interpreted carefully, as the CSF1R function depends on the dimerization of two CSF1R, and in HLDS patients, a wild‐type CSF1R is co‐expressed with the mutant one, in contrast to in vitro experiments. Hence, the impact of loss‐of‐function (LOF) variants in vivo might be different based on their position in the TyrKD or IgLD (Fig. 1). , For instance, the p.Pro132Leu variant, located in the IgLD, has been associated with a recessive CSF1R‐related syndrome named BANDDOS (brain abnormalities, neurodegeneration, and dysosteosclerosis). Neither the proband's mother nor the maternal grandfather, both with the p.Pro132Leu variant in heterozygous state, developed HLDS, despite in vitro functional analysis suggested a LOF by showing a decrease of ~50% in the JNK phosphorylation level activated by CSF1 treatment.

Figure 1

Functional effects of different types of CSF1R variants. (A) Before CSF1 binding (yellow square), CSF1 receptor (CSF1R) presents as a monomer on the cellular surface. In the presence of CSF1, CSF1R monomers undergo non‐covalent dimerization (wild‐type [WT]/WT) followed by autophosphorylation and signaling through activation of multiple kinase pathways including JNK. (B) Loss‐of‐function (LOF) variants (red stars) altering residues in the intracellular tyrosine kinase domain (TyrKD) impair the autophosphorylation of intracellular tyrosine residues required for downstream signaling, whereas it is unlikely that they affect the CSF1‐dependent dimerization of CSF1R. Consequently, in the presence of WT monomers and monomers with a TyrKD mutation (WT/mutTyrKD), CSF1R should form in vivo WT homodimers (~25%), WT‐mutant heterodimers (~50%), and mutant homodimers (~25%). The mutant CSF1R subunit of the dimer cannot phosphorylate the WT subunit, and also, by a dominant negative effect, should impair the phosphorylation activity of the normal subunit. , Therefore, in HLDS patients, the LOF should be ~75%, given that the nonfunctional mutant receptors are threefold in excess in comparison with the WT receptors. (C) The hypothesis illustrated in the subfigure B may explain why patients with CSF1R variants such as the p.Gln481*, which cause non‐sense mediated RNA decay, do not develop HLDS. In these cases, where no WT mutant heterodimers exist, the LOF should be ~50%. (D) LOF mutations altering residues in the extracellular Ig‐like domain (IgLD), as is the case for p.T79M or p.P132L variants, , likely affect the CSF1‐dependent dimerization of CSF1R. Consequently, in the presence of WT monomers and monomers with an IgLD mutation (WT/mutIgLD), CSF1R should form in vivo only functional WT homodimers, the LOF will be ~50%, and the patients should not develop HLDS. HLDS, hereditary leukodystrophy with spheroids.

HLDS is an autosomal dominant disease characterized by relentlessly progressive dementia, incomplete penetrance, and highly variable age at onset and course even in the same family. , Hematopoietic stem cell transplantation may be a therapeutic strategy, but its appropriate timing is difficult to define, and it is associated with mortality and morbidity which increase with increasing age. This framework clearly shows why the erroneous interpretation of a CSF1R variant as HLDS‐causing variant is distressing for the patients and their families, and should be avoided as far as may be.

Conflicts of Interest

The authors declare no financial or other conflicts of interest.