The dominant form of the pigmentary orthochromatic leukodystrophy

Constantinidis, J; Wisniewski, T. M.

doi:10.1007/bf00293382

Cited by 26 publications

(27 citation statements)

References 4 publications

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“…Some cases had macrophages with intracytoplasmic 'fingerprint' patterns. These patterns have been observed in previous case reports and are suggestive of ceroid [12,15,18] . Since oxidative stress or decreased lysosomal proteolytic activity can lead to ceroid or lipofuscin accumulation in human glial cells [40] , these patterns raise the possibility that oxidative damage plays a role in the pathogenesis of ALSP.…”

Section: Discussionsupporting

confidence: 62%

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Can Present as Frontotemporal Dementia Syndrome

Wong

Chow²,

Hazrati

2011

Dement Geriatr Cogn Disord

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Background/Aims: We review the characteristics of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia(ALSP) and determine prevalence of behavioral variant of frontotemporal dementia (bvFTD) features in ALSP. Methods: Clinical and pathological information was abstracted from histopathologically confirmed ALSP cases identified by a systematic literature search. A new case of ALSP presenting as bvFTD was also described. Results: We retrieved 51 ALSP cases. Mean age of onset was 42.2 years. Mean disease duration was 6.2 years, with 24 cases lasting 4 years or fewer. Fourteen cases had 3 or more of the 6 key bvFTD features. White matter hyperintensities on T2-weighted MRI, motor symptoms, seizures and amnesia were common. Conclusion: ALSP can underlie FTD syndrome, as well as rapidly progressive dementia.

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Section: Discussionsupporting

confidence: 62%

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Can Present as Frontotemporal Dementia Syndrome

Wong

Chow²,

Hazrati

2011

Dement Geriatr Cogn Disord

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“…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: 72%

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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“…As in this patient, extrapyramidal motor symptoms including cogwheel rigidity 3 or cerebellar ataxia 4,5 may be prominent early on, although pyramidal tract syndromes may be more frequent. 6,7 The age of onset is variable; the earliest symptomatic age is at birth 4 while other patients were not symptomatic until the fifth decade of life. 1 Most do not present before the third decade.…”

Section: Discussionmentioning

confidence: 99%

“…Autosomal dominant inheritance is likely in at least one kindred, 6 and autosomal recessive inheritance in others. 9 However, it is not entirely clear whether some of the cases labeled as autosomal recessive, particularly in the older literature, might conceivably be due to an autosomal dominant trait with variable penetrance.…”

Section: Discussionmentioning

confidence: 99%

A Rare Form of Adult Onset Leukodystrophy: Orthochromatic Leukodystrophy with Pigmented Glia

Shannon

Wherrett

Nag

1997

Can. j. neurol. sci.

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Background: Orthochromatic leukodystrophy with pigmented glia and scavenger cells is a rare leukodystrophy of unknown etiology. This report describes a 42-year-old man with a history of depression, dementia and parkinsonism having the pathological features of orthochromatic leukodystrophy with pigmented glia. Methods: We reviewed the clinical history and pathology of autopsy and brain biopsy material. Results: Imaging revealed bilateral cerebral white matter hypodensities. At autopsy, the brain demonstrated a leukodystrophy affecting predominantly the cerebral hemispheres and characterized by demyelination, and cytoplasmic pigment deposits in oligodendroglia and astrocytes. The pigment had the staining properties of ceroid-lipofuschin and on ultrastructural examination was composed of membrane-bound lipid and electron-dense inclusions which had a fingerprint-like pattern. Similar pigment inclusions were not observed on ultrastructural examination of renal, splenic or hepatic tissue obtained at autopsy. The brain biopsy contained cerebral cortex with sparse subcortical white matter in which a few oligodendroglia and fewer astrocytes at the grey/white junctions showed cytoplasmic pigmentary inclusions identical to those described above. However, due to the paucity of white matter in the specimen a definite diagnosis of orthochromatic leukodystrophy with pigmented glia was not made. Conclusions:The diagnosis of orthochromatic leukodystrophy with pigmented glia and scavenger cells can only be made antemortem if the brain biopsy contains adequate white matter and although a rare condition, it should be considered in the differential diagnosis of an adult onset leukodystrophy. RESUME: Une forme adulte rare de leucodystrophie: la leucodystrophie orthochromatique avec nevroglie pigmentee. Introduction: La leucodystrophie orthochromatique avec presence de nevroglie pigmentee et de phagocytes est une leucodystrophie rare d'etiologie inconnue. Methodes: Nous decrivons le cas d'un homme de 42 ans qui avait une histoire de depression, de demence et de parkinsonisme ayant les caracteristiques anatomopathologiques de la leucodystrophie orthochromatique avec cellules pigmentees. Nous revisons l'histoire clinique et l'anatomopathologie des tissus preleves a l'autopsie ainsi que du materiel obtenu par biopsie. Resultats: L'imagerie a revele des zones hypodenses de la substance blanche dans les deux hemispheres. A l'autopsie, le cerveau presentait une leucodystrophie atteignant surtout les hemispheres et caracterisee par une demyelinisation et des depots cytoplasmiques de pigment dans I'oligodendroglie et dans les astrocytes. Le pigment avait les proprietes tinctoriales de la ceroid-lipofuscine et Pexamen ultra structural a montre qu'il etait compose de lipides lies a la membrane et d'inclusions opaques aux electrons qui avaient un motif d'empreinte digitale. Des inclusions de pigment similaires n'ont pas ete observees a l'examen ultra structural de tissu renal, splenique ou hepatique obtenu a l'autopsie. La biopsie du c...

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The dominant form of the pigmentary orthochromatic leukodystrophy

Cited by 26 publications

References 4 publications

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Can Present as Frontotemporal Dementia Syndrome

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Can Present as Frontotemporal Dementia Syndrome

CSF1R mutations link POLD and HDLS as a single disease entity

A Rare Form of Adult Onset Leukodystrophy: Orthochromatic Leukodystrophy with Pigmented Glia

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