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Front. Neurol. | doi: 10.3389/fneur.2019.01124

A novel mutation of GFAP causing adult-onset Alexander disease

 Andrea Ciammola1*, Davide Sangalli1,  Jenny Sassone2,  Barbara Poletti1,  Laura Carelli1,  Paolo I. Banfi3,  Gabriele Pappacoda3,  Isabella Ceccherini4, Alice Grossi4, Luca Maderna1, Monica Pingue5, Floriano Girotti1 and Vincenzo Silani1
  • 1Department of Neurology, IRCCS Italian Auxological Institute, Italy
  • 2Vita-Salute San Raffaele University, Italy
  • 3Fondazione Don Carlo Gnocchi Onlus (IRCCS), Italy
  • 4Giannina Gaslini Institute (IRCCS), Italy
  • 5San Raffaele Hospital (IRCCS), Italy

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms.
Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD.
We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.

Keywords: Alexander Disease, GFAP - Glial fibrillary acidic protein, Leukodystrophy, gene mutation, adult onset

Received: 18 Jun 2019; Accepted: 08 Oct 2019.

Copyright: © 2019 Ciammola, Sangalli, Sassone, Poletti, Carelli, Banfi, Pappacoda, Ceccherini, Grossi, Maderna, Pingue, Girotti and Silani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD. Andrea Ciammola, Department of Neurology, IRCCS Italian Auxological Institute, Milano, Italy,