Reply to: “The First Allogeneic Hematopoietic Stem Cell Transplantation in a Polish Patient with Adult‐Onset Leukoencephalopathy with Spheroids and Pigmented Glia”

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rapidly progressive microgliopathy that manifests with a broad range of neurologic symptoms in early adulthood. The most common cause of ALSP is variation within the CSF1R gene in which case the term “CSF1R-related leukoencephalopathy” (“CSF1RL”) is appropriate. In 2021, _ Zur-Wyrozumska and colleagues reported the first Polish patient with genetically proven CSF1RL. This case highlighted the utility of genetic testing that will undoubtedly reveal more cases of CSF1RL in Poland. We now congratulate _ ZurWyrozumska on successfully administering hematopoietic stem cell transplantation (HSCT) to that same patient. The patient described by _ Zur-Wyrozumska began experiencing neurological symptoms (bradykinesia with gait and speech difficulties followed by cognitive decline and autonomic dysfunction) in his mid-30s. Genetic testing identified a c.2375 C > A mutation in exon 18 of the CSF1R gene. The patient’s parents both tested negative for CSF1R mutations, leading _ Zur-Wyrozumska and colleagues to report this as a de novo mutation, which has been previously reported in CSF1RL cases. Although de novo mutations are possible, there are some circumstances, both biological and nonbiological, that lead to the appearance of sporadic disease (Table 1). In addition to true de novo mutations, there are several genetic phenomena that may lead to the appearance of sporadic CSF1RL. Konno et al reported a 10% penetrance of CSF1R variants at age 27 years, and this increased to 95% by age 60. This age-dependent penetrance could explain a small percentage of seemingly sporadic CSF1R variants. Alternatively, mosaicism is a plausible reason why CSF1R variants may appear sporadic. In one of the first reports of HSCT administration for CSF1RL, Eichler et al identified a “sporadic” CSF1R variant carrier whose mother’s blood and saliva both showed mosaicism for the CSF1R variant. CSF1RL may appear sporadic if parents of CSF1R variant carriers are not tested for the mutation. This scenario is more likely if parents are asymptomatic. Because CSF1RL is a microgliopathy, medications or other factors affecting the immune system could alter an individual’s resilience to symptomatic disease. We previously described an asymptomatic CSF1R variant carrier who was chronically exposed to immunosuppressive agents, including glucocorticoids. Although the woman’s daughter developed symptomatic CSF1RL at age 39, she lived to age 72 at which time postmortem evaluation identified neuropathological features of CSF1RL. We hypothesized that chronic glucocorticoid exposure reapproximated microglial homeostasis and suspect that it may be possible for other environmental factors to favorably influence this mechanism. In the meantime, two other similar cases came to our attention (unpublished). Accurately characterizing genetic inheritance patterns will facilitate a deeper understanding of CSF1RL. In addition to the biological influences, nonbiological circumstances of undisclosed adoption or false maternity/paternity may lead to incorrect conclusions about the nature of a CSF1RL.