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Alexander disease

Author
Amy T Waldman, MD
Section Editors
Francisco González-Scarano, MD
Douglas R Nordli, Jr, MD
Deputy Editor
John F Dashe, MD, PhD

INTRODUCTION

Alexander disease (MIM #203450) is one of a group of neurologic disorders, collectively referred to as leukodystrophies, which predominantly affect the central nervous system white matter. These disorders are caused by defects in the synthesis (ie, dysmyelination) or maintenance of the myelin sheath that insulates the nerves. While leukodystrophy is the predominant abnormality in the neonatal and infantile forms of Alexander disease, advances in genetics and imaging have revealed a broad phenotypic variability that includes juvenile and adult forms of the disorder without obvious leukodystrophy [1].

Prior to the identification of the genetic features, other names were used to describe the clinical features and pathology of Alexander disease, such as hyaline panneuropathy and dysmyelinogenic leukodystrophy [2]. These terms are no longer used.

This topic will review the pathology, pathogenesis, clinical features, and diagnosis of Alexander disease.

PATHOLOGY

Alexander disease was first described in 1949, when W. Stewart Alexander reported a 15-month-old child with megalencephaly, hydrocephalus, and psychomotor retardation [3]. The child died eight months later, and the brain pathology revealed "a progressive fibrinoid degeneration of fibrillary astrocytes." These astrocytic inclusions were later found to be identical to Rosenthal fibers [4]. The presence of glial fibrillary acidic protein (GFAP) in Rosenthal fibers led to the identification of mutations of the gene encoding GFAP as the cause of Alexander disease [5]. (See 'Pathogenesis' below.)

Rosenthal fibers, which are hyaline eosinophilic rods, are present in Alexander disease throughout the central nervous system. These intracytoplasmic astrocytic inclusions are the hallmark of Alexander disease [6]. They are commonly seen in subpial, subependymal, and perivascular regions. They are present in the perikarya, processes, and end-feet of astrocytes and appear round or oblong, with extensive glial intermediate filaments seen on electron microscopy. They also contain GFAP. In addition, alpha B-crystallin, heat shock protein 27, and ubiquitin are present in Rosenthal fibers [7-11].

                        

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Literature review current through: Nov 2016. | This topic last updated: Tue Mar 24 00:00:00 GMT+00:00 2015.
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