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  • Updated 03.15.2023
  • Released 04.01.1997
  • Expires For CME 03.15.2026

Alexander disease



Alexander disease is a leukodystrophy that may present at any age. Following the identification of pathogenic variants in the glial fibrillary acidic protein (GFAP) gene as the cause of Alexander disease, an increasing number of 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 elevated 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. Although a commercial assay for GFAP exists, clinical testing is not currently available. 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 most often caused by de novo heterozygous pathogenic variants in the GFAP gene.

• In children in particular, seizures, developmental delay, macrocephaly, or an MRI with specific abnormalities typically involving frontal white matter should suggest the diagnosis.

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

• Disease progression is typically slow, with variable rates of disability accumulation and life expectancy.

• Antisense suppression of GFAP is currently being tested in clinical trials as a treatment for Alexander disease.

Historical note and terminology

The first reported case of Alexander disease 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.

Over time, additional phenotypes have been recognized. For many years, an age-based classification system was used to capture neonatal, infantile, juvenile, and adult-onset forms (42; 05; 02; 20; 38; 44; 22; 48; 29). Although these phenotypes have some differences in clinical and radiographic manifestations, all forms of the disorder are caused by heterozygous, dominant pathogenic variants in the gene for GFAP, a component of astrocytic intermediate filaments (06; 31; 41; 11; 34; 35). As such, the pathologic hallmark is the same for all phenotypes: the presence of widespread and abundant Rosenthal fibers.

The age-based classification system (defined by age at symptom onset) was defined prior to the identification of GFAP as the causative gene. Thus, a study used the age of symptom onset and the GFAP variant site to statistically identify only two clinical types of Alexander disease (39). Type I is characterized by early-onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later-onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features.

Concurrent with the Prust classification (type I vs. type II disease), Yoshida and colleagues proposed a 3-group system based on clinical and imaging features (57). The cerebral form presents with developmental delay, seizures, and macrocephaly with frontally predominant white matter T2 hyperintensities on MRI in addition to other MRI features, whereas the bulbospinal form presents with bulbar dysfunction and long-tract signs that reflect medullary signal abnormalities or atrophy. The authors also described an intermediate form that captures the core features of both the cerebral and bulbospinal forms.

In summary, typical and atypical cases have been reported for each of the classification systems.

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