Alexander Disease via the GFAP Gene

Alexander disease is a rare, and often fatal, disorder affecting the midbrain and cerebellum of the central nervous system. Based on age of onset, different forms of Alexander disease have been described: infantile, juvenile, and adult forms. Generally, earlier onset is associated with more severe and rapid disease course (Srivastava et al. 2002).

The infantile form is the most common form of Alexander disease. Typically, this form begins before age 2 with progressive psychomotor retardation and loss of developmental milestones. Some patients also show hyperreflexia and ataxia. Survival ranges from several weeks to several years.

Juvenile Alexander disease is characterized by talking and swallowing difficulty and inability to cough. Age of onset is usually between 4 and 10 years of age. Affected children survive 10-30 years.

Adult-onset Alexander disease is relatively rare, and variable compared to the other two forms. The adult-onset form is generally similar to the juvenile form, though the symptoms are milder. Some patients may also manifest difficulties in talking, swallowing and walking, sleep disturbance, and ataxia.

Alexander disease is inherited in an autosomal dominant manner, and GFAP is the only known causative gene for this disease (Messing et al. 2012). Most patients have a de novo pathogenic variant. Penetrance is very high (nearly 100%) in patients with the infantile and juvenile forms of Alexander disease (Li et al. 2002; Messing et al. 2003).

GFAP encodes glial fibrillary acidic protein, which is an intermediate filament protein mainly expressed in mature astrocytes of the central nervous system. GFAP is a cytoskeletal protein regulating the morphology and motility of astrocytes (Eng et al. 2000). To date, over 100 pathogenic variants have been identified in GFAP to cause Alexander disease. Of note, more than 90% of pathogenic variants (96/106) in GFAP are missense, suggesting a toxic gain of function mechanism (Human Gene Mutation Database); however, the exact mechanism underlying Alexander disease remains unclear. GFAP with pathogenic variants may impair the oligomerization or solubility of protein molecules synthesized from the normal allele (Hsiao et al. 2005; Der Perng et al. 2006).

The clinical sensitivity of this test is expected to be high. Based on published reports, about 98% of patients with a diagnosis of Alexander disease have a pathogenic variant in GFAP (Srivastava et al. 2002).

This test provides full coverage of all coding exons of the GFAP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).