Cortical dysplasia with prominent Rosenthal fiber formation in a case of intractable pediatric epilepsy

Khanlou, Négar; Mathern, Gary W.; Mitchell, Wendy G.; Salamon, Noriko; Pope, Whitney B.; Yong, William H.; Vinters, Harry V.

doi:10.1016/j.humpath.2009.02.012

Cited by 6 publications

(9 citation statements)

References 22 publications

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“…It is also interesting to note that pronounced astrocytic abnormalities have been described in severe FCD with intractable pediatric epilepsy, including astrocytes with high densities of Rosenthal fibers (Fig. 6 b, c), comparable to those seen in Alexander’s disease [ 111 ], a genetic disorder with mutation of the GFAP gene that is also associated with seizures and other symptoms (see below).…”

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 57%

“…It is interesting to note that high densities of Rosenthal fibers, comparable to those seen in Alexander’s disease, have been described in the context of pronounced astrocytic abnormalities in severe FCD with intractable pediatric epilepsy (Fig. 6 b) [ 111 ] (see above).…”

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 91%

“…The density of the Rosenthal fibers suggested the diagnosis of ‘focal’ Alexander’s disease. However, testing of the GFAP gene revealed no mutations (for details, see [ 111 ]). c Comparable section to b showing abundant GFAP immunoreactive astrocytes and associated Rosenthal fibers ( arrows ).…”

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 99%

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Astrocytes: biology and pathology

2009

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Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to longlasting scar formation with rearrangement of tissue structure.Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 57%

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 91%

Section: Astrocyte Appearance and Roles In Cns Disorders And Pathologmentioning

confidence: 99%

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Astrocytes: biology and pathology

2009

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“…For example, RFs are regularly found in pilocytic astrocytomas and chronic astrocyte scars [4, 11, 26]. Occasionally astrocytes in other disorders, such as cortical dysplasias and tuberous sclerosis, contain RFs [13, 14]. Presumably the common denominator is the accumulation of very large amounts of GFAP inside the astrocyte [16].…”

Section: Introductionmentioning

confidence: 99%

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

Sosunov

McKhann

Goldman

2017

acta neuropathol commun

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Rosenthal fibers (RFs) are cytoplasmic, proteinaceous aggregates. They are the pathognomonic feature of the astrocyte pathology in Alexander Disease (AxD), a neurodegenerative disorder caused by heterozygous mutations in the GFAP gene, encoding glial fibrillary acidic protein (GFAP). Although RFs have been known for many years their origin and significance remain elusive issues. We have used mouse models of AxD based on the overexpression of human GFAP (transgenic, TG) and a point mutation in mouse GFAP (knock-in, KI) to examine the formation of RFs and to find astrocyte changes that correlate with the appearance of RFs. We found RFs of various sizes and shapes. The smallest ones appear as granular depositions on intermediate filaments. These contain GFAP and the small heat shock protein, alphaB-crystallin. Their aggregation appears to give rise to large RFs. The appearance of new RFs and the growth of previously formed RFs occur over time. We determined that DAPI is a reliable marker of RFs and in parallel with Fluoro-Jade B (FJB) staining defined a high variability in the appearance of RFs, even in neighboring astrocytes. Although many astrocytes in AxD with increased levels of GFAP and with or without RFs change their phenotype, only some cells with large numbers of RFs show a profound reconstruction of cellular processes, with a loss of fine distal processes and the appearance of large, lobulated nuclei, likely due to arrested mitosis. We conclude that 1) RFs appear to originate as small, osmiophilic masses containing both GFAP and alphaB-crystallin deposited on bundles of intermediate filaments. 2) RFs continue to form within AxD astrocytes over time. 3) DAPI is a reliable marker for RFs and can be used with immunolabeling. 4) RFs appear to interfere with the successful completion of astrocyte mitosis and cell division.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0425-9) contains supplementary material, which is available to authorized users.

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“…Pronounced astrocytic abnormalities occur in focal cortical dysplasia with intractable pediatric epilepsy (Khanlou et al, 2009) and in early-onset AxD patients (Springer et al, 2000). In mice, overexpression of GFAP R236H also causes increased sensitivity to kainic acid-induced seizures (Hagemann et al, 2006), and several rodent models of pilocarpine-induced status epilepticus also show dose-dependent GFAP changes (Estrada et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease

et al. 2014

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Alexander disease (AxD) is the only known human pathology caused by mutations in an astrocyte-specific gene, glial fibrillary acidic protein (GFAP). These mutations result in abnormal GFAP accumulations that promote seizures, motor delays and, ultimately, death. The exact contribution of increased, abnormal levels of astrocytic mutant GFAP in the development and progression of the epileptic phenotype is not clear, and we addressed this question using two mouse models of AxD. Comparison of brain seizure activity spontaneously and after traumatic brain injury (TBI), an effective way to trigger seizures, revealed that abnormal GFAP accumulation contributes to abnormal brain activity (increased interictal discharges) but is not a risk factor for the development of epilepsy after TBI. These data highlight the need to further explore the complex and heterogeneous response of astrocytes towards injury and the involvement of GFAP in the progression of AxD.

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Cortical dysplasia with prominent Rosenthal fiber formation in a case of intractable pediatric epilepsy

Cited by 6 publications

References 22 publications

Astrocytes: biology and pathology

Astrocytes: biology and pathology

The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease

Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease

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