CSF1R-related leukodystrophy is likely the second most common leukodystrophy in adults and is often mistaken for multiple sclerosis.
Summary
Cause
CSF1R-related leukodystrophy (OMIM #221820), also known as ALSP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia), is a primary microgliopathy caused by haploinsufficiency of the colony-stimulating factor 1 receptor (CSF1R).
The transmission is autosomal dominant, but with incomplete penetrance, meaning that not all individuals carrying a pathogenic variant of the CSF1R gene will necessarily develop neurological symptoms. Sporadic cases often arise from de novo mutations.
Symptoms
CSF1R-related leukodystrophy is possibly the second most common leukodystrophy in adults, resembling multiple sclerosis on brain imaging, and treatable by hematopoietic stem cell transplantation (HSCT).
It is a severe neurodegenerative disease that typically leads to death within a few years after symptom onset. Besides multiple sclerosis, this leukodystrophy is often misdiagnosed as frontotemporal dementia, vascular leukoencephalopathy, or, in some cases, Parkinson’s disease.
Patients frequently present with cognitive decline, behavioral symptoms, pyramidal and bulbar involvement, along with asymmetric white matter lesions. Extrapyramidal involvement is also possible. Motor-onset forms are typically distinguished from cognitive-onset forms.
Treatment
Under normal conditions, CSF1R is primarily expressed in macrophages and microglia. CSF1R is essential for the development, maintenance, and activation of microglia. HSCT appears to be a highly relevant therapy for this leukodystrophy by correcting CSF1R haploinsufficiency in macrophages and, over time, in microglia.
HSCT has shown major benefit in halting disease progression in patients with CSF1R-related leukodystrophy.