Bi-allelic GAD2 variants cause a rare developmental encephalopathy with early-onset seizures.

GAD2

Biallelic loss of function of GAD2, encoding the GAD65 isoform of glutamic acid decarboxylase, impairing GABA synthesis; all variants produce a truncated protein

The two glutamic acid decarboxylase isoforms are encoded by GAD1, already implicated in severe developmental and epileptic encephalopathy, and by GAD2, never before linked to human disease. The authors report four individuals from three unrelated families carrying biallelic loss-of-function GAD2 variants. All presented with early-onset epilepsy, developmental delay, mild to moderate intellectual disability and autism spectrum disorder, with seizures most severe in infancy and diminishing with age; EEG showed preserved background activity without consistent epileptiform abnormalities and brain MRI only minimal structural changes. The viable GAD65 knockout mouse model develops spontaneous seizures as early as four weeks, increased susceptibility to pentylenetetrazole, repetitive and anxiety-like behaviours, social deficits and impaired spatial learning. Transcriptomic profiling reveals dysregulation of metabolic and mitochondrial pathways already implicated in epilepsy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Only four patients, but the concordance between the human phenotype and the knockout mouse model is complete enough to consider GAD2 an established disease gene. The target is already captured by any exome: the immediate priority is reanalysis of negative epileptic encephalopathy exomes carrying biallelic truncating variants classified as uncertain. The attenuation of seizures with age is a useful counselling point for families, even though it rests here on a very small sample.

Analysis by Dr Thibaut Benquey