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We highlight the therapeutic importance of the paper by Mochel et al on stem cell transplant in CSF1R-related leukoencephalopathy
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive neurodegenerative disorder caused by mutations in Colony Stimulating Factor 1 Receptor (CSF1R). Patients typically present with a combination of cognitive decline, spasticity and ataxia with prominent leukoencephalopathy on imaging. Death occurs on average 6 years from first symptom onset, with affected individuals reported from age 18 to 78 years.1 2 Bi-allelic mutations in CSF1R, in which most are consistent with loss of function, cause a paediatric-onset leukoencephalopathy3 that can be associated with a skeletal dysplasia4 and on neuropathology, almost complete absence of microglia within the brain, suggesting a developmental absence of microglia. There is currently no effective therapy to halt disease progression, but in their JNNP letter, Mochel et al 5 describe the first prospective use of haematopoietic stem cell transplantation (HSCT) in a patient affected by ALSP, and show how this led to disease stabilisation.
HSCT has already shown to be effective in stabilising patients affected with cerebral adrenoleukodystrophy.6 A clue that HSCT might be effective in CSF1R disease came from a retrospective report published in 2016, in which a patient, who received a transplant for what was thought to be metachromatic leukodystrophy and stabilised afterwards, was ultimately found to have ALSP.7 This patient, reported by Eichler et al 7 had onset of symptoms at 35 years, and maintained stable language and cognitive function for 15 years after successful engraftment.
Mochel et al 5 now report the first patient to prospectively undergo HSCT for CSF1R-related leukoencephalopathy. The patient developed neurological symptoms in her early 30s, with typical MRI changes of ALSP, including progressive T2/Fluid-attenuated inversion recovery (FLAIR) signal abnormality of the white matter and changes on diffusion-weighted imaging. There was continued neurological deterioration, and 18 months from symptom onset, there was spastic quadriparesis with an EDSS score of 7. She underwent myeloablative conditioning followed by a transplant from her unaffected half-sister. Neurological stabilisation occurred from 6 months after the transplant, with remarkable fall off in Expanded Disability Status Scale (EDSS) progression tracked to 30 months, as well as improvement in several markers on imaging.
The work presented by Mochel et al 5 highlights the potential for HSCT in CSF1R-related leukoencephalopathies and the implementation; particularly disease caused by genetic defects in the microglial pathway as well as the possibility for other leukoencephalopathies. There is also potential to use this therapy in the bi-allelic CSF1R defects that cause the severe paediatric-onset leukoencephalopathy.3 4 In all scenarios, genetic analysis of all leukoencephalopathies is mandatory and the emergence of this treatment will encourage genetic analysis and wider family members to be tested early. We must still employ clinical caution, as although bi-allelic CSF1R children have extreme life limitation and few other options, there is significant variation in the onset and progression of ALSP, and while the mean duration of symptoms is 6 years, survival up to 29 years has been reported.1 We must take this into account when assessing this single report, which also highlights the great need for biomarkers of disease onset and progression (ie, early biomarkers of demyelination). A larger study of affected patients will be important and required in the future to confirm the efficacy of HSCT for this form of genetic leukoencephalopathy.
Contributors DSL and HH wrote the editorial together.
Funding This study was funded by the Medical Research Council, Wellcome Trust.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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