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Alexander disease is a rare leukodystrophy caused by heterozygous mutations in the glial fibrillary acidic protein gene (GFAP), which encodes a type III intermediate filament expressed predominantly in astrocytes. Clinically, it presents across a spectrum from infantile onset with macrocephaly, seizures, and psychomotor regression to juvenile and adult-onset forms characterized by bulbar dysfunction, spasticity, and ataxia. Neuropathologically, Rosenthal fibers—cytoplasmic aggregates containing GFAP, αB-crystallin, and HSP27—are diagnostic. MRI typically reveals frontal-predominant white matter abnormalities in infantile cases and distinctive “tadpole” brainstem and cervical spinal cord atrophy in adult-onset cases.
Inheritance is autosomal dominant with the vast majority of cases arising from de novo missense mutations in GFAP. In a cohort of 15 suspected infantile cases, 14 harbored de novo GFAP mutations (PMID:11567214), and in a prospective series of 13 patients, 12 had pathogenic GFAP variants confirmed by sequencing (PMID:12034785). Familial segregation has been observed, for example, in an asymptomatic family with the c.992T>C (p.Leu331Pro) mutation present in three heterozygotes across two generations (PMID:15465095).
Over 400 affected individuals carrying GFAP variants have been reported, with a total of 98 distinct mutations documented in juvenile and adult-onset cases and 53 variants in infantile-onset patients. Four recurrent arginine substitutions—p.Arg79His, p.Arg88Cys, p.Arg239Cys, and p.Arg239His—account for nearly half of infantile cases (PMID:34146839). The variant c.715C>T (p.Arg239Cys) is a paradigmatic example and has been repeatedly observed in de novo patients and familial adult-onset cases.
Experimental studies reveal a gain-of-function mechanism: mutations such as p.Arg239Cys disrupt filament assembly, increase GFAP insolubility, and sequester αB-crystallin and HSP27, driving Rosenthal fiber formation in astrocytes (PMID:15840648). The p.Arg416Trp mutation induces aberrant filament aggregation and chaperone recruitment in vitro and localizes to Rosenthal fibers in patient tissue (PMID:16826512). In vivo zebrafish assays demonstrate that p.Asp128Asn and common arginine mutants cause GFAP aggregation, supporting pathogenicity (PMID:28882119).
Rare conflicting evidence includes a homozygous p.Arg66Gln mutation causing recessively inherited adult-onset Alexander disease with rescued aggregation by wild-type GFAP coexpression (PMID:32374915) and a promoter SNP (rs2070935 C/C) that modifies age at onset and ambulatory decline in late-onset disease (PMID:23903069). However, no associations have been refuted.
In summary, GFAP has a definitive gene–disease relationship with Alexander disease, supported by hundreds of probands, de novo and familial segregation, and concordant functional data across cellular and animal models. GFAP sequencing is essential in patients with characteristic MRI and clinical signs, and identification of a pathogenic variant confirms the diagnosis. Key take-home: GFAP mutation analysis enables accurate molecular diagnosis and informs prognosis and genetic counseling in Alexander disease.
Gene–Disease AssociationDefinitiveOver 400 probands across infantile, juvenile, and adult cases with de novo and familial segregation, consistent MRI features, and Rosenthal fiber pathology Genetic EvidenceStrong12 of 13 patients with confirmed GFAP mutations ([PMID:12034785]) and multiple recurrent de novo variants in unrelated probands Functional EvidenceModerateIn vitro and in vivo studies demonstrate mutant GFAP aggregation, filament disorganization, chaperone sequestration, and Rosenthal fiber formation |