Alexander disease

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released April 1, 1997; last updated December 2, 2016; expires December 2, 2019

This article includes discussion of Alexander disease, dysmyelinogenic leukodystrophy with megalobarencephaly, fibrinoid leukodystrophy, leukodystrophy with diffuse Rosenthal fiber formation, megalencephaly associated with hyaline pan-neuropathy, progressive fibrinoid degeneration of fibrillary astrocytes, adult Alexander disease, infantile Alexander disease, and juvenile Alexander disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Alexander disease is a leukodystrophy that may occur at any age. Following the identification of mutations in the glial fibrillary acidic protein (GFAP) gene as the cause of Alexander disease, an increasing number of adult patients have been identified. The disease is caused by a combination of the formation of characteristic aggregates, called Rosenthal fibers, and the sequestration of the protein chaperones alpha B-crystallin and HSP27 into Rosenthal fibers. GFAP levels are consistently in the CSF of patients with Alexander disease. Phosphorylated TPD-43 accumulates in astrocytes, suggesting a common mechanism with amyotrophic lateral sclerosis. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis. Cerebrospinal fluid GFAP levels are an important disease biomarker.

Key points

 

• Alexander disease is an autosomal dominant glial cell disease caused most often by de novo heterozygous mutations in the GFAP gene.

 

• Alexander disease is a leukodystrophy in young children but may present as a glial tumor in older patients and adults.

 

• In children in particular, a large head or an MRI with specific abnormalities, including spinal cord atrophy, should suggest the diagnosis.

 

• Based on the age of onset and the location of the GFAP mutation, one can divide Alexander disease in 2 subtypes with distinct average life expectancy.

 

• GFAP protein levels are elevated in the CSF of patients.

Historical note and terminology

The disorder known as Alexander disease is a rare leukodystrophy that occurs in an infantile, juvenile, and adult onset form (Russo et al 1976; Borrett and Becker 1985; Arend et al 1991; Howard et al 1993; Pridmore et al 1993; Schwankhaus et al 1995; Johnson 1996). For many years it was not clear whether all forms were manifestations of the same disorder, but today all 3 forms are believed to be caused by heterozygous, dominant mutations in the gene for GFAP, a component of astrocytic intermediate filaments (Brenner et al 2001; Messing et al 2001; Rodriguez et al 2001; Gorospe et al 2002; Namekawa et al 2002; Okamoto et al 2002). The first reported case of this disorder was described as "progressive fibrinoid degeneration of fibrillary astrocytes" in an infant with mental retardation and hydrocephalus (Alexander 1949). The disorder's defining feature has always been the widespread presence of abnormal astrocytic inclusions within the brain called Rosenthal fibers. The disorder has also been called "megalencephaly associated with hyaline pan-neuropathy," "fibrinoid leukodystrophy," "leukodystrophy with diffuse Rosenthal fiber formation," and "dysmyelinogenic leukodystrophy with megalobarencephaly.

An adult form of Alexander disease has been described (Duckett et al 1992; Howard et al 1993; Schwankhaus et al 1995). Its pathology closely resembles the pathology of Alexander disease in children, with widespread and abundant Rosenthal fibers. However, the adult disorder is rare, varied, and has been described in adults from their late teens up 82 years of age, both with and without clinical neurologic symptoms. The presentations are highly variable and sometimes resemble multiple sclerosis. The so-called adult Alexander disease patients present with later onset or longer survival than do individuals suffering from the juvenile form of this disorder. Among the adult patients, a much greater tendency toward familial incidence is observed than in those with childhood onset, and in some cases there may be autosomal dominant inheritance (Messing et al 2012). Three adult family members with palatal myoclonus and spinal cord atrophy, but without pathological evaluation, were all found to have the same heterozygous glial fibrillary acidic protein mutation (Okamoto et al 2002). A presentation with severe vocal cord paralysis during sleep has been described (Hida et al 2012).

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