Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD)

Wider, Christian; Gerpen, Jay A. van; DeArmond, Stephen J.; Shuster, Elizabeth A.; Dickson, Dennis W.; Wszołek, Zbigniew K.

doi:10.1212/wnl.0b013e3181a826c0

Cited by 104 publications

(130 citation statements)

References 31 publications

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“…HDLS is neuropathologically characterized by the extensive loss of myelin sheaths, axonal destruction and the presence of numerous axonal spheroids, pigmented macrophages and astrogliosis (2,(9)(10)(11)(12)(13)(14). These changes were clearly observed in the centrum semiovale of the cerebral white matter in one of our patients (patient 2) (8).…”

Section: Discussionmentioning

confidence: 67%

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

et al. 2014

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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)

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Section: Discussionmentioning

confidence: 67%

“…HDLS is characterized clinically by cognitive, psychiatric and motor dysfunction that is frequently accom- panied by epilepsy (2). The age of onset is quite variable, ranging from 8 to 78 years, and the mean duration of the illness has been reported to be 10 years (2) or 5.8 years (3).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Archival tissue from FTD368 II-1 and II-2, reported previously, 14 was re-evaluated with histologic and immunohistochemical methods as in previous reports. 2,5,8,15 The findings in II-1 and II-2 were essentially the same. For comparison, FTD368 II-2 (figure 2, C and E) was compared with an HDLS case with a documented CSF1R Figure 1 Families with POLD and CSF1R mutations Shown are abbreviated pedigrees of 2 families, family FTD368 (A) and family 5901 (B) affected by pigmented orthochromatic leukodystrophy (POLD) included in this study.…”

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confidence: 52%

“…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.…”

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confidence: 99%

CSF1R mutations link POLD and HDLS as a single disease entity

et al. 2013

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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.

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“…DISCUSSION Our report describes the MRI pattern of HDLS in patients with CSF1R gene mutations. MRI findings in patients with HDLS have been described previously in 20 reports, 5,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] however, without knowledge of the CSF1R gene mutation carrier status. 4 We developed an HDLS MRI severity scoring system, modified from those devised for X-ALD, Krabbe disease, and MLD.…”

Section: Resultsmentioning

confidence: 81%

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

Sundal¹,

Gerpen²,

Nicholson³

et al. 2012

Neurology

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Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods:We reviewed 20 brain MRI scans of 15 patients with autopsy-or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0Ϫ57) for each MRI scan. Results:Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10Ϫ33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion:Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion. Neurology ® 2012;79:566-574 GLOSSARY CI ϭ confidence interval; CSF1R ϭ colony-stimulating factor 1 receptor; FLAIR ϭ fluid-attenuated inversion recovery; HDLS ϭ hereditary diffuse leukoencephalopathy with spheroids; MLD ϭ metachromatic leukodystrophy; MS ϭ multiple sclerosis; SI ϭ signal intensity; WM ϭ white matter; WNL ϭ white matter lesion; X-ALD ϭ X-linked adrenoleukodystrophy.

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Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD)

Cited by 104 publications

References 31 publications

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

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

CSF1R mutations link POLD and HDLS as a single disease entity

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

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