Zebra of the Week: Alexander disease

Alexander disease is an ultra-rare, progressive leukodystrophy caused by mutations in the GFAP (glial fibrillary acidic protein) gene. The disorder affects astrocytes, the supportive cells of the central nervous system, leading to accumulation of abnormal GFAP protein and the formation of characteristic Rosenthal fibers. Over time, astrocyte dysfunction contributes to damage of myelin and impaired neurologic function.

Although traditionally considered a pediatric disease, Alexander disease can present at virtually any age, from the neonatal period through late adulthood. Clinical manifestations vary according to age of onset. The infantile form, which accounts for many recognized cases, typically presents before age 2 years with megalencephaly, developmental delay, intellectual disability, seizures, and progressive spasticity. Neonatal disease is often severe, with hydrocephalus, profound developmental impairment, and refractory seizures.

Juvenile- and adult-onset disease may follow a different course. Common features include bulbar dysfunction with dysarthria and dysphagia, gait impairment, ataxia, spasticity, autonomic symptoms, and seizures. Because adult presentations can be heterogeneous and may mimic more common neurodegenerative or demyelinating disorders, diagnosis is frequently delayed.

MRI findings are often highly suggestive and may demonstrate frontal-predominant white matter abnormalities, brainstem involvement, and other characteristic features. Definitive diagnosis is generally established through identification of a pathogenic GFAP variant. Most cases arise from de novo mutations, although autosomal dominant inheritance has been reported.

Historically, management has been largely supportive and focused on symptom control, including antiseizure therapy, rehabilitation, nutritional support, and management of swallowing and respiratory complications. Given the disease's progressive nature and potential for substantial disability, multidisciplinary care is often required.

First FDA-approved treatment

On September 3, 2026, FDA approved Zanvastro (zilganersen), the first approved therapy for Alexander disease and the first treatment designed to target its underlying biology. Zilganersen is an antisense oligonucleotide administered intrathecally every 3 months that reduces production of GFAP, the protein central to disease pathogenesis. In a randomized controlled study, treated patients demonstrated improvements or stabilization in motor function compared with untreated controls, supporting its approval for both pediatric and adult patients. Common adverse effects include vomiting, back pain, cough, headache, and post-lumbar puncture syndrome; cases of aseptic meningitis have also been reported.

Sources:

NIH GARD. Alexander disease

Ionis Pharmaceuticals, Inc. (2026 Sep 3). Zanvastro (zilganersen) approved by the FDA as the first and only disease modifying treatment for Alexander disease (AxD) in pediatric and adult patients

US Food and Drug Administration. (2026 Sep 3). FDA Approves First Drug to Treat Alexander Disease