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The clinical spectrum of late-onset Alexander disease: a systematic literature review

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Abstract

Following the discovery of glial fibrillary acidic protein (GFAP) mutations as the causative factor of Alexander disease (AxD), new case reports have recently increased, prompting a more detailed comprehension of the clinical features of the three disease subtypes (infantile, juvenile and adult). While the clinical pattern of the infantile form has been substantially confirmed, the late-onset subtypes (i.e., juvenile and adult), once considered rare manifestations of AxD, have displayed a wider clinical spectrum. Our aim was to evaluate the clinical phenotype of the adult and juvenile forms by reviewing the previously reported cases. Data were collected from previously published reports on 112 subjects affected by neuropathologically or genetically proven adult and juvenile Alexander disease. Although the late-onset forms of AxD show a wide clinical variability, a common pattern emerges from comparing previously reported cases, characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Late-onset AxD cases can no longer be considered as rare manifestations of the disease. The clinical pattern usually reflects the topographic localization of the lesions, with adult cases displaying a predominant infratentorial localization of the lesions. Juvenile cases show clinical and radiological features which are intermediate between adult and infantile forms.

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Authors and Affiliations

  1. Clinical Neurophysiology, Scientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’, via per Montescano, 27040, Montescano, PV, Italy

    Pietro Balbi, Silvana Salvini, Cira Fundarò & Dibo Mosah

  2. Department of Neurorehabilitation, Scientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’, via per Montescano, 27040, Montescano, PV, Italy

    Giuseppe Frazzitta

  3. Department of Biomedical Engineering, Scientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’, via per Montescano, 27040, Montescano, PV, Italy

    Roberto Maestri

  4. Neuroradiological Department, Neurological Institute IRCCS ‘Fondazione C. Mondino’, via Mondino 2, 27100, Pavia, Italy

    Carla Uggetti

  5. Institute of Clinical Neurology, University of Sassari, viale San Pietro 10, Edificio D, Sassari, Italy

    GianPietro Sechi

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  1. Pietro Balbi
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Correspondence to Pietro Balbi.

Electronic database information

Accession number and the URL for data in this article are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.gov/Omim (for Alexander disease [MIM 203450] and GFAP [MIM 137780]). Alexander disease on Waisman Centre, University of Wisconsin-Madison, USA, http://www.waisman.wisc.edu/alexander/index.html. ‘Human Intermediate Filament Database’ of the Centre for Molecular Medicine and the Bioinformatics Institute in Singapore, http://www.interfil.org/details.php?id=NM_002055. ‘GeneTests Web site’ hosted by National Center for Biotechnology Information at http://www.ncbi.nlm.nih.gov/sites/GeneTests.

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Balbi, P., Salvini, S., Fundarò, C. et al. The clinical spectrum of late-onset Alexander disease: a systematic literature review. J Neurol 257, 1955–1962 (2010). https://doi.org/10.1007/s00415-010-5706-1

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