Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: Case report

Kinoshita, M; Yoshida, Katsumi; Oyanagi, Kiyomitsu; Hashimoto, Takao; Ikeda, Shu‐ichi

doi:10.1016/j.jns.2012.03.012

Cited by 52 publications

(40 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In family 5901, we identified the known p.M766T mutation, previously found in HDLS family CA1, whereas the mutation identified in family FTD368, p.R782H, had not been identified in our previous study. While this work was underway, the p.R782H mutation was reported by an independent group as a causative mutation in a biopsyproven HDLS family, 17 further strengthening the evidence of homogeneity between these diseases.…”

mentioning

confidence: 52%

“…7,8,[13][14][15][16][17][21][22][23][24][25] The clinical presentation in POLD family FTD368 included symptoms of depression, abnormal behavior, and an inability to function, progressing to dementia in the 3 siblings from the second generation. The proband Figure 3 Functional effects of CSFR1 mutations in cell culture CSF-1 treatment leads to autophosphorylation of wild-type but not mutant CSF1R.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CSF1R mutations link POLD and HDLS as a single disease entity

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 52%

mentioning

confidence: 99%

CSF1R mutations link POLD and HDLS as a single disease entity

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Immediately before this patient was referred to us, we experienced another patient with leukoencephalopathy who exhibited presenile dementia and a thin corpus callosum on MRI, similar to our patient, and was diagnosed as having HDLS based on a brain biopsy and a CSF1R analysis (9). Therefore, we first searched for the CSF1R mutation after obtaining informed consent from the patient's wife and parents.…”

Section: Case Reportmentioning

confidence: 85%

Early Involvement of the Corpus Callosum in a Patient with Hereditary Diffuse Leukoencephalopathy with Spheroids Carrying the <i>de novo</i> K793T Mutation of <i>CSF1R</i>

et al. 2013

Self Cite

View full text Add to dashboard Cite

We herein report the case of a 41-year-old Japanese man with hereditary diffuse leukoencephalopathy with spheroids (HDLS) who carried the de novo K793T mutation in the colony-stimulating factor 1 receptor gene (CSF1R). He showed a gradual decline of his cognitive and mental functions over the following six months. On brain MRI, a thin corpus callosum with T2-and FLAIR-high signal intensity in the splenium was conspicuous, whereas cerebral deep and periventricular white matter lesions were mild. We propose that a diagnosis of HDLS should be considered in patients with presenile dementia presenting with corpus callosum lesions on MRI, even in cases with a lack of any apparent family history.

show abstract

“…Mutations in CSF1R were identified in all patients. Three patients (patients 1, 3 and 4) had a family history consistent with autosomal inheritance (15), and two patients (patients 2 and 6) were confirmed to carry a de novo CSF1R mutation. One patient (patient 5) with a CSF1R mutation also had an affected brother; however, detailed information on their parents was not available.…”

Section: Subjectsmentioning

confidence: 98%

Corpus Callosum Atrophy in Patients with Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids: An MRI-based Study

et al. 2014

Self Cite

View full text Add to dashboard Cite

Objective Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is an adult-onset white matter disease that presents clinically with cognitive, mental and motor dysfunction. Several autopsy reports have indicated that the corpus callosum (CC), the largest bundle of white matter, is severely affected in patients with HDLS. The aim of this study was to evaluate corpus callosum atrophy (CCA) quantitatively in HDLS patients. Methods We assessed CCA in six genetically-proven HDLS patients (HDLS group), in comparison with that observed in 20 patients with vascular dementia (VaD group) and 24 age-matched patients without organic central nervous system (CNS) disease (non-CNS group). Using midsagittal MR images, five measurements of the CC were obtained: the width of the rostrum (aa'), body (bb') and splenium (cc'), the anterior to posterior length (ab) and the maximum height (cd). Next, the corpus callosum index (CCI) was calculated as (aa' + bb' + cc')/ab. Results All HDLS patients had white matter lesions in the CC and frontoparietal lobes on the initial MRI scans. Compared with that observed in the VaD and age-matched non-CNS groups, the CCI was significantly decreased in the HDLS group (with VaD group, p<0.01; with non-CNS group, p<0.01). Conclusion This study showed significant atrophy of the CC in all HDLS patients on the initial MRI scans obtained 6-36 months after onset. We propose that the early appearance of CCA, frequently accompanied by high-intensity in the genu and/or splenium, on T2 images is an important diagnostic clue to HDLS.Key words: hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS), colony stimulating factor 1 receptor (CSF1R), white matter lesions (WMLs), corpus callosum atrophy (CCA), corpus callosum index (CCI)

show abstract

Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: Case report

Cited by 52 publications

References 14 publications

CSF1R mutations link POLD and HDLS as a single disease entity

CSF1R mutations link POLD and HDLS as a single disease entity

Early Involvement of the Corpus Callosum in a Patient with Hereditary Diffuse Leukoencephalopathy with Spheroids Carrying the <i>de novo</i> K793T Mutation of <i>CSF1R</i>

Corpus Callosum Atrophy in Patients with Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids: An MRI-based Study

Contact Info

Product

Resources

About