Year: 2026
Type: article
Study design: Systematic Review
Abstract: OBJECTIVES: To expand the clinical features, epilepsy phenotype, and genotype in individuals with AFG2A-related encephalopathy (AFG2A-RE), previously known SPATA5-related encephalopathy, and to explore potential associations between genotype and epilepsy manifestations. METHODS: We conducted a systematic literature review focusing on AFG2A-RE publications (45 patients), also included 6 of our patients recently reported as the result of a multicentre, retrospective, observational, and descriptive study. Available clinical descriptions, electroencephalography and MRI data, metabolic screening, genetic findings, and treatment responses were assessed. RESULTS: A total of 51 individuals with AFG2A-RE were included, 29 males; mean age 8.35 years. The most frequently described clinical features included intellectual disability (97.92%), hearing loss (93.62%), microcephaly (85.71%), visual impairment (79.49%), hypotonia (71.74%), spasticity (60.87%), and movement disorders (36.96%). Epilepsy was present in 74.71% of cases, with seizures of generalized onset being the most common (70.83%), and infantile epileptic spasms syndrome (IESS) was the predominant epilepsy syndrome at onset (66.67%). Epilepsy was often drug-resistant (82.35%). Brain MRI abnormalities were frequently observed (68.29%), including hypomyelination (39.02%), brain atrophy (34.15%), and a thin corpus callosum (29.27%). SIGNIFICANCE: This review presents the largest cohort of individuals with AFG2A-RE reported to date. AFG2A-RE is an ultra-rare, recessive disorder, sometimes presenting as a developmental and epileptic encephalopathy (DEE), characterised by the triad of epilepsy, congenital microcephaly, and deafness, and typically associated with intellectual disability, spasticity, and movement disorders. The cardinal clinical features of AFG2A-RE may mimic those of a mitochondrial disease. No significant associations between genotype and epilepsy phenotype were observed.
Institutions: Hospital Sant Joan de Déu Barcelona, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, University of Duisburg-Essen, Hospital Infantil Universitario Niño Jesús, Hospital Universitario Virgen de las Nieves, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,990
OpenAlex ID: W7148726506