- Amy T Waldman, MD
Amy T Waldman, MD
- Assistant Professor of Child Neurology
- Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine
- Section Editors
- Francisco Gonzalez-Scarano, MD
Francisco Gonzalez-Scarano, MD
- Section Editor — Multiple Sclerosis; Neurovirology & NeuroAIDS
- John P. Howe, III, MD, Distinguished Chair in Health Policy
- The University of Texas Health Science Center at San Antonio
- Douglas R Nordli, Jr, MD
Douglas R Nordli, Jr, MD
- Section Editor — Pediatric Neurology
- Chief of Neurology
- Children’s Hospital Los Angeles
- Vice Chair of Neurology
- USC Keck School of Medicine
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 .
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 . These terms are no longer used.
This topic will review the pathology, pathogenesis, clinical features, and diagnosis of Alexander disease.
Alexander disease was first described in 1949, when W. Stewart Alexander reported a 15-month-old child with megalencephaly, hydrocephalus, and psychomotor retardation . 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 . 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 . (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 . 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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- CLINICAL FEATURES
- Traditional classification
- - Neonatal
- - Infantile
- - Juvenile
- - Adult
- Revised classification
- - Type I
- - Type II
- Genotype-phenotype correlations
- Brain MRI
- - MRI criteria
- Atypical neuroimaging features
- Magnetic resonance spectroscopy
- Prenatal diagnosis
- Differential diagnosis
- SUMMARY AND RECOMMENDATIONS