GAD1 – Developmental and epileptic encephalopathy 89

Developmental and epileptic encephalopathy 89 (DEE89) is a rare autosomal recessive disorder characterized by profound neurodevelopmental delay, refractory seizures, and congenital anomalies such as cleft palate or omphalocele. GAD1 encodes glutamate decarboxylase 67 (GAD67), the rate-limiting enzyme for GABA synthesis; deficiency of GAD67 underlies DEE89 (GAD1 / Developmental and epileptic encephalopathy 89). Whole-exome sequencing in a single patient identified a novel homozygous variant, c.850C>T (p.Leu284Phe), presenting with severe neurodevelopmental delay, seizures, microcephaly, and toe clonus (PMID:37029735).

Molecular docking and dynamics simulation demonstrated that p.Leu284Phe disrupts the structural stability and function of GAD67, consistent with loss of enzymatic activity. However, only one unrelated proband and in silico data are available, with no reported segregation or biochemical assays, limiting current evidence. Additional unrelated cases, segregation studies, enzymatic functional assays, and animal models are required to confirm pathogenicity. Key Take-home: Consider biallelic GAD1 screening in infants with early-onset epileptic encephalopathy to enable accurate diagnosis and genetic counseling.

References

• Epilepsia open • 2023 • Developmental and epileptic encephalopathy 89: A novel bi-allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile. PMID:37029735

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