First Polish case of CSF1R-related leukoencephalopathy

Abstract

10]. Fortunately, these nomenclature difficulties stemming from similarities in clinical and pathologic presentations have been solved by advances in genetic technology. The nomenclature introduced by Konno et al. [3] simplifies it, and now we identify these two separate conditions as CSF1R-related leukoencephalopathy, formerly POLD families, and AARS2-related leukoencephalopathy, formerly HDLS families (Tab. 1). Unfortunately, there are also published and unpublished cases/ families suspected for CSF1R-related leukoencephalopathy or AARS2-related leukoencephalopathy with negative genetic testing for both CSF1R and AARS2 gene mutations [11, and personal observation]. Thus, the concept of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), initially introduced by Marotti et al. [6] and further popularized by Wider et al. [11], is still quite useful. Konno et al.[3] make this distinction even more specific by introducing the term, CSF1R/AARS2-negative ALSP. It is very likely that there are other so far unidentified genes in which mutations are responsible for clinical and pathologic phenotypes currently indistinguishable from those seen in CSF1R-related leukoencephalopathy and AARS2-related leukoencephalopathy.The third and most important reason is that clinical features of CSF1R-related leukoencephalopathy are very broad, encompassing headaches, seizures, spasticity, rigidity, tremors, psychiatric features, dementia, among others, thus leading to misdiagnosis or delayed diagnosis. Fortunately, a much wider availability of clinical genetic testing at this juncture makes

Neuroimaging phenotypes of CSF1R‐related leukoencephalopathy: Systematic review, meta‐analysis, and imaging recommendations

“…In addition, there are known cases that are phenotypically and pathologically indistinguishable but lack mutations in these genes. They are collectively classified as CSF1R/AARS-negative adultonset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) [7,8], (Z. K. Wszolek, personal communication, August 24, 2021).…”

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

“…However, the original Swedish family (HDLS-S) was recently found to carry a different genetic makeup with the affected family members displaying the alanyl-transfer (t) RNA synthetase (AARS) gene mutation as the likely cause of Swedish type HDLS with spheroids (4). Thus, this family belongs to yet another class of genetic disorders identified as AARS-related leukoencephalopathy (5)(6)(7).…”

Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

“…On the other hand, the patients diagnosed with HDLS including the original Swedish family reported in 1984 are belonged to "alanyl-transfer tRNA synthetase 2 gene (AARS2)-related leukoencephalopathy." 7,8 CSF1R-related leukoencephalopathy has become increasingly recognized, and it is estimated to account for 10% of adult-onset leukodystrophy in the Caucasian populations. 9,10 CSF1R encodes for a tyrosine kinase transmembrane receptor that regulates the survival, proliferation, and differentiation of mononuclear phagocytic cells, including microglia in the brain.…”

“…Patients with ALSP usually develop early‐onset dementia, behavior changes, depression, gait ataxia and parkinsonism in the fourth or fifth decade of life, and rapidly deteriorate to bed‐ridden status within 3–5 years 3,4 . With the discovery of causative genes, 5,6 these two clinic‐pathologically similar conditions (i.e., POLD and HDLS) now can be clearly distinguished 7 . For patients diagnosed with POLD and some literature cases pathologically mislabeled as HDLS, the new nomenclature is “colony‐stimulating factor 1 receptor gene ( CSF1R )‐related leukoencephalopathy.” On the other hand, the patients diagnosed with HDLS including the original Swedish family reported in 1984 are belonged to “alanyl‐transfer tRNA synthetase 2 gene ( AARS2 )‐related leukoencephalopathy.” 7,8 CSF1R ‐related leukoencephalopathy has become increasingly recognized, and it is estimated to account for 10% of adult‐onset leukodystrophy in the Caucasian populations 9,10 …”