CSF1R mutations link POLD and HDLS as a single disease entity

Abstract

Objective: Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD.Methods: We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed.Results: We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T.C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G.A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wildtype CSF1R. Conclusions:We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity. Familial pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are white matter disorders. Thus far considered distinct diseases, clinical and pathologic features suggest that POLD and HDLS are of the same disease spectrum. The pigmented macrophages identified in HDLS families are similar to those in POLD, 1-5 whereas axonal dilations found in POLD families coincide with axonal spheroids described in HDLS. 3,[5][6][7] Clinically, most patients with familial POLD and HDLS present with psychiatric symptoms, which progress into dementia, often of a frontotemporal phenotype. 3,5,[8][9][10][11] MRIs are consistent with this clinical presentation, because both POLD and HDLS patients portray frontal-predominant atrophy. 12Although clinical and pathologic data are strikingly similar between POLD and HDLS, a common genetic cause would further solidify these diseases as a single entity.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases

“…Case 1 showed severe myelin and axon loss with abundant axonal spheroids, which was compatible with a diagnosis of HDLS, and case 2 showed pigmented macrophages and glia in a background of extensive myelin and axon loss, which is consistent with a diagnosis of POLD. However, both diseases were caused by a mutation in a single disease gene, CSF1R, supporting the recent proposal that HDLS and POLD are a single clinicopathological entity, ALSP [6,12].…”

“…The p.A781V mutation detected in cases 1 and 3 has been previously seen in UK and German families, but pathological examinations were not performed in those cases [10,16]. The p.R782H mutation in case 2 was also found in American POLD and Japanese HDLS families [6,11]. However, the Japanese HDLS family with the R782H mutation was Gross findings of the brain in case 1 (left) and case 2 (right).…”

“…Since mutations in the colony-stimulating factor 1 receptor (CSF1R) gene on chromosome 5q32 have been identified as an underlying genetic defect of ALSP, the diagnosis can be made relatively easily through genetic screening for possible cases, compared to the previous process which was entirely dependent on neuropathological examination [5,6]. In other words, prompting genetic testing for CSF1R mutations is useful for distinguishing ALSP from adult-onset leukodystrophies and other young-onset leukoencephalopathies whose clinical and radiological features are indistinguishable [7][8][9].…”

Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

“…HDLS and pigmented orthochromatic leukodystrophy cases, carriers of CSF1R mutations, are characterized as having 'adult-onset leukoencephalopathy with axonal spheroids and pigmented glia' (ALSP) [4]. Interestingly, CSF1R mutations are not always found in pathologically-confirmed HDLS cases [6].…”

CSF-1 Receptor Signaling in Myeloid Cells

“…Dominant inactivating mutations in the CSF-1R lead to adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (Rademakers et al 2011;Nicholson et al 2013). Inappropriate expression of the CSF-1R contributes to the development of leukemias and lymphomas, and autocrine and paracrine regulation of the CSF-1R enhances the progression and metastasis of solid tumors (reviewed in Pollard 2009;Chitu and Stanley 2014).…”