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  • Updated 12.27.2019
  • Released 04.01.1997
  • Expires For CME 12.27.2022

Alexander disease

Introduction

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. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis. Cerebrospinal fluid GFAP levels are an important disease biomarker. Current therapeutic efforts are geared towards reducing the expression of the mutated GFAP allele by using antisense oligonucleotides.

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.

• Antisense suppression of GFAP is being developed as a treatment for Alexander disease.

Historical note and terminology

The disorder known as Alexander disease is a rare leukodystrophy that occurs in an infantile, juvenile, and adult onset form (43; 05; 02; 17; 39; 45; 20; 30). 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 (06; 32; 42; 11; 35; 36). The first reported case of this disorder was described as "progressive fibrinoid degeneration of fibrillary astrocytes" in an infant with mental retardation and hydrocephalus (01). 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 (10; 17; 45). 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 (33). 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 (36). A presentation with severe vocal cord paralysis during sleep has been described (16).

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