Journal Article

Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature

Davide Pareyson, Roberto Fancellu, Caterina Mariotti, Silvia Romano, Andrea Salmaggi, Francesco Carella, Floriano Girotti, Grazietta Gattellaro, Maria Rita Carriero, Laura Farina, Isabella Ceccherini and Mario Savoiardo

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 9, pages 2321-2331
Published in print September 2008 | ISSN: 0006-8950
Published online August 2008 | e-ISSN: 1460-2156 | DOI:
Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature

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Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem–spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction—with dysarthria, dysphagia, dysphonia (seven patients)—, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.

Keywords: Alexander disease; GFAP; brainstem diseases; medulla oblongata atrophy; palatal myoclonus

Journal Article.  6913 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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