Journal of Advances in Medicine and Medical Research

Alexander disease (AxD) is a rare, dominantly inherited astrocytopathy caused principally by heterozygous pathogenic variants in GFAP, the gene encoding glial fibrillary acidic protein. In children, the disorder spans a continuum from neonatal or early-infantile encephalopathy with severe cerebral white-matter disease, seizures, hydrocephalus and rapid developmental compromise to later childhood phenotypes with mixed cerebral, bulbar, pyramidal and autonomic involvement. The historical age-based categories of infantile, juvenile and adult disease are therefore increasingly complemented by clinically and radiologically grounded cerebral, intermediate and bulbospinal phenotypes. This critical narrative review integrates clinical natural-history data, magnetic resonance imaging patterns, GFAP genotype–phenotype evidence, mechanistic studies in human tissue, induced pluripotent stem cell models and animal models, and the translational development of GFAP-lowering therapies. Evidence published from January 2001 to 8 August 2026 was prioritised, with older foundational observations considered when necessary. The strongest mechanistic evidence supports a toxic gain-of-function model in which mutant GFAP misassembly and pathological accumulation amplify GFAP transcription, disturb proteostasis, activate stress and inflammatory pathways, alter astrocytic morphology and homeostatic functions, and secondarily impair neurons, oligodendrocytes and myelination. Genotype is informative but not deterministic: recurrent variants at residues such as Arg79 and Arg239 show meaningful differences in age at onset and survival, yet substantial within-variant variability limits individual prognostication. Fluid GFAP is a biologically direct target-engagement biomarker, but its value as an independent clinical outcome biomarker is constrained when GFAP itself is therapeutically suppressed. Antisense oligonucleotide-mediated GFAP reduction has reversed major pathological features in preclinical models and has progressed to a late-stage intrathecal clinical programme. The field is consequently shifting from diagnosis and supportive care towards mechanism-based intervention, but paediatric trial design still requires age-sensitive functional outcomes, validated surrogate markers, genotype-aware stratification and longer-term assessment of developmental trajectories and treatment safety.