- 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 González-Scarano, MD
Francisco González-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].
- Barkovich AJ, Messing A. Alexander disease: not just a leukodystrophy anymore. Neurology 2006; 66:468.
- Russo LS Jr, Aron A, Anderson PJ. Alexander's disease: a report and reappraisal. Neurology 1976; 26:607.
- ALEXANDER WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 1949; 72:373.
- Rosenthal W. Über eine eigenthümliche, mit syringomyelie complicirte geschwulst des rückenmarks. Bietr Pathol Anat 1898; 23:111.
- Brenner M, Johnson AB, Boespflug-Tanguy O, et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001; 27:117.
- Fenichel GM. Clinical Pediatric Neurology: A Signs and Symptoms Approach, 5th ed, Saunders, Philadelphia 2005. p.133.
- Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE. Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. Cell 1989; 57:71.
- Tomokane N, Iwaki T, Tateishi J, et al. Rosenthal fibers share epitopes with alpha B-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold. Am J Pathol 1991; 138:875.
- Iwaki A, Iwaki T, Goldman JE, et al. Accumulation of alpha B-crystallin in brains of patients with Alexander's disease is not due to an abnormality of the 5'-flanking and coding sequence of the genomic DNA. Neurosci Lett 1992; 140:89.
- Head MW, Corbin E, Goldman JE. Overexpression and abnormal modification of the stress proteins alpha B-crystallin and HSP27 in Alexander disease. Am J Pathol 1993; 143:1743.
- Head MW, Goldman JE. Small heat shock proteins, the cytoskeleton, and inclusion body formation. Neuropathol Appl Neurobiol 2000; 26:304.
- Johnson AB, Brenner M. Alexander's disease: clinical, pathologic, and genetic features. J Child Neurol 2003; 18:625.
- Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 2000; 25:1439.
- Li R, Messing A, Goldman JE, Brenner M. GFAP mutations in Alexander disease. Int J Dev Neurosci 2002; 20:259.
- Nielsen AL, Jørgensen P, Jørgensen AL. Mutations associated with a childhood leukodystrophy, Alexander disease, cause deficiency in dimerization of the cytoskeletal protein GFAP. J Neurogenet 2002; 16:175.
- Srivastava S, Naidu S. Alexander disease. In: GeneReviews [Internet]. www.ncbi.nlm.nih.gov/books/NBK1172/ (Accessed on May 13, 2015).
- Garbern JY. Leukodystrophies. In: Neurogenetics: Clinical and Scientific Advances, Lynch DR (Ed), Taylor and Francis, New York 2005. p.469.
- Springer S, Erlewein R, Naegele T, et al. Alexander disease--classification revisited and isolation of a neonatal form. Neuropediatrics 2000; 31:86.
- Singh N, Bixby C, Etienne D, et al. Alexander's disease: reassessment of a neonatal form. Childs Nerv Syst 2012; 28:2029.
- Bassuk AG, Joshi A, Burton BK, et al. Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene. Neurology 2003; 61:1014.
- Kinoshita T, Imaizumi T, Miura Y, et al. A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation. Neurosci Lett 2003; 350:169.
- Van Poppel K, Broniscer A, Patay Z, Morris EB. Alexander disease: An important mimicker of focal brainstem glioma. Pediatr Blood Cancer 2009; 53:1355.
- Niinikoski H, Haataja L, Brander A, et al. Alexander disease as a cause of nocturnal vomiting in a 7-year-old girl. Pediatr Radiol 2009; 39:872.
- Franzoni E, Van der Knaap MS, Errani A, et al. Unusual diagnosis in a child suffering from juvenile Alexander disease: clinical and imaging report. J Child Neurol 2006; 21:1075.
- Stumpf E, Masson H, Duquette A, et al. Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol 2003; 60:1307.
- Martidis A, Yee RD, Azzarelli B, Biller J. Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease. Arch Ophthalmol 1999; 117:265.
- Sreedharan J, Shaw CE, Jarosz J, Samuel M. Alexander disease with hypothermia, microcoria, and psychiatric and endocrine disturbances. Neurology 2007; 68:1322.
- Pareyson D, Fancellu R, Mariotti C, et al. Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain 2008; 131:2321.
- Farina L, Pareyson D, Minati L, et al. Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol 2008; 29:1190.
- Okamoto Y, Mitsuyama H, Jonosono M, et al. Autosomal dominant palatal myoclonus and spinal cord atrophy. J Neurol Sci 2002; 195:71.
- Prust M, Wang J, Morizono H, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011; 77:1287.
- GFAP mutations associated with Alexander disease. Waisman Center, University of Wisconsin-Madison. www.waisman.wisc.edu/alexander-disease/mutation-table.pdf (Accessed on March 24, 2015).
- Rodriguez D, Gauthier F, Bertini E, et al. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet 2001; 69:1134.
- Gorospe JR, Naidu S, Johnson AB, et al. Molecular findings in symptomatic and pre-symptomatic Alexander disease patients. Neurology 2002; 58:1494.
- Meins M, Brockmann K, Yadav S, et al. Infantile Alexander disease: a GFAP mutation in monozygotic twins and novel mutations in two other patients. Neuropediatrics 2002; 33:194.
- Li R, Johnson AB, Salomons G, et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 2005; 57:310.
- van der Knaap MS, Naidu S, Breiter SN, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22:541.
- van der Knaap MS, Breiter SN, Naidu S, et al. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213:121.
- Vázquez E, Macaya A, Mayolas N, et al. Neonatal Alexander disease: MR imaging prenatal diagnosis. AJNR Am J Neuroradiol 2008; 29:1973.
- van der Knaap MS, Salomons GS, Li R, et al. Unusual variants of Alexander's disease. Ann Neurol 2005; 57:327.
- van der Knaap MS, Ramesh V, Schiffmann R, et al. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006; 66:494.
- Probst EN, Hagel C, Weisz V, et al. Atypical focal MRI lesions in a case of juvenile Alexander's disease. Ann Neurol 2003; 53:118.
- Romano S, Salvetti M, Ceccherini I, et al. Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord. Lancet Neurol 2007; 6:562.
- Duckett S, Schwartzman RJ, Osterholm J, et al. Biopsy diagnosis of familial Alexander's disease. Pediatr Neurosurg 1992; 18:134.
- Brockmann K, Dechent P, Meins M, et al. Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease. J Neurol 2003; 250:300.
- Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72:750.
- van der Knaap MS, Barth PG, Stroink H, et al. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37:324.
- van der Knaap MS, Boor I, Estévez R. Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol 2012; 11:973.
- van der Knaap MS, Smit LM, Barth PG, et al. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997; 42:50.
- Brockmann K, Meins M, Taubert A, et al. A novel GFAP mutation and disseminated white matter lesions: adult Alexander disease? Eur Neurol 2003; 50:100.
- Seil FJ, Schochet SS Jr, Earle KM. Alexander's disease in an adult. Report of a case. Arch Neurol 1968; 19:494.
- Schwankhaus JD, Parisi JE, Gulledge WR, et al. Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia. Neurology 1995; 45:2266.
- Sechi G, Matta M, Deiana GA, et al. Ceftriaxone has a therapeutic role in Alexander disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:416.
- Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005; 433:73.
- Lipski J, Wan CK, Bai JZ, et al. Neuroprotective potential of ceftriaxone in in vitro models of stroke. Neuroscience 2007; 146:617.
- 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