AFG2A-related encephalopathy, expanding the neurodevelopmental and epileptic spectrum

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. 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. 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%). 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.