MS-like presentation of Alexander disease with multifocal lesions and oligoclonal bands

Abstract

Alexander disease is a leukodystrophy characterized by Rosenthal fiber accumulation, which is caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP) [1]. Depending on the age at onset, three subtypes (infantile-, juvenile-, and adult-onset) can be distinguished [1], characterized by different phenotypes. Once considered a rare condition, recent studies reveal an increasing number of cases of the adult-onset condition with pseudobulbar signs, ataxia, and spasticity and abnormalities in the medulla and upper cervical cord on neuroimaging [2, 3]. We present MR imaging of a patient with a novel mutation in the GFAP gene and CSF inflammatory signs that broadens the clinical spectrum of adult-onset Alexander disease. A 43 year old woman was admitted to the Department of Neurology at the University Hospital Bonn complaining about recurrent singultus for 1 year and left-sided tonic seizures for 1 month. Cerebrospinal fluid analysis revealed CSF-specific oligoclonal bands without pleocytosis. MRI showed hyperintense T2 and FLAIR signal in the brainstem (Fig. 1a–e) and cervical cord (Fig. 1g) and a contrast-enhancing lesion in the medulla oblongata (Fig. 1f). Taking into account the CSF results, the diagnosis of a chronic inflammatory CNS disease was discussed. However, the patient did not respond to an i.v. course of methylprednisolone. The patient’s condition deteriorated slowly over the next year. She subsequently developed dysphagia, and recurrent vomiting. Repeated brain MRIs over 11 months did not show relevant change. Based on the MRI imaging, adult-onset Alexander disease was suspected. Subsequent genetic analysis of the GFAP gene revealed a novel missense mutation in exon 6 (c.1051G [ C; p.D351H positions according to RefSeq NM_002055) in heterozygous state. This mutation results in an amino acid exchange in codon 351 from aspartate to histidine and it was not detected in 1,038 control chromosomes in a cohort of ethnically matched healthy blood donors from Germany. Analysis of this new amino acid exchange is predicted as ‘‘disease causing’’ using the web-based mutation taster analysis tool [4]. In addition, one sequence variant in intron 3 in heterozygous state (c.619-35_-21del; 1/965 control chromosomes) as well as one polymorphism in exon 2 in heterozygous state (rs59291670) were detected, for which pathogenic impact is unlikely. H. J. Tschampa (&) S. Greschus H. Urbach Departments of Radiology and Neuroradiology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail: Henriette.Tschampa@ukb.uni-bonn.de