Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD) A single entity?

Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
Neurology (Impact Factor: 8.29). 07/2009; 72(22):1953-9. DOI: 10.1212/WNL.0b013e3181a826c0
Source: PubMed


Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

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    • "Another condition is metachromatic leukodystrophy – a lysosomal disease with sphingolipid storage caused by arylsulphatase A deficiency (Gieselmann & Krägeloh-Mann 2010). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (Marotti et al 2004), including hereditary diffuse leukoencephalopathy with neuroaxonal spheroids and pigmentary orthochromatic leukodystrophy (Wider et al 2009) are rarely occurring conditions; the inheritance is autosomal dominant, mutated colony stimulating factor 1 receptor gene (CSF1R) on chromosome 5q32 (Sundal et al 2012) , having insufficient data to this point how the mutation determines the leukoencephalopathic pattern (Van Gerpen et al 2008). "
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    • "Patients often present with sensorimotor and neuropsychiatric symptoms , including depression, behavioral changes, spastic paraplegia, dementia and seizures, leading to frequent and diverse clinical misdiagnoses . The initial symptoms progress to dementia and death (Axelsson et al., 1984; Guerreiro et al., 2013; Marotti et al., 2004; Sundal et al., 2012; Wider et al., 2009). By MRI, ALSP is characterized by patchy cerebral white matter lesions, often initially asymmetrical, but becoming confluent and symmetrical with disease progression (Freeman et al., 2009; Konno et al., 2014; Sundal et al., 2012; Van Gerpen et al., 2008). "
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    ABSTRACT: Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology. Copyright © 2014. Published by Elsevier Inc.
    Neurobiology of Disease 12/2014; 74. DOI:10.1016/j.nbd.2014.12.001 · 5.08 Impact Factor
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    • "An international consortium on HDLS was established in 2005 by one of the authors (ZKW) after the first Mayo Clinic kindred with HDLS was reported [10]. Since then, 14 additional families have been collected at the Mayo Clinic and 4 have been reported [2] [3]. In our research study brains and brain biopsy specimens have been collected both retrospectively and prospectively. "
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    ABSTRACT: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.
    Journal of the neurological sciences 11/2011; 314(1-2):130-7. DOI:10.1016/j.jns.2011.10.006 · 2.47 Impact Factor
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