A novel homozygous missense variant in the GAMT gene causing cerebral creatine deficiency syndrome 2 in an Iranian patient: molecular dynamics insights and literature review

Cerebral creatine deficiency syndrome 2 (CCDS2; OMIM #612,736) is a rare autosomal recessive neurometabolic disorder caused by variants in the GAMT gene, leading to deficient creatine synthesis in the brain. Here, we report a 17-year-old Iranian Fars female patient from a consanguineous marriage presenting with severe intellectual disability, inability to walk, muscle atrophy, and epileptiform EEG activity. Whole-exome sequencing identified a previously unreported homozygous missense variant in GAMT (NM_000156.6: c.326A > G, p.Lys109Arg), classified as likely pathogenic according to ACMG guidelines. The affected lysine residue at position 109 is highly conserved across species. Molecular dynamics (MD) simulations over 100 ns revealed that the p.Lys109Arg substitution induces a more compact global conformation (lower RMSD and Rg) but drastically alters the dynamic coupling network. Compared to wild-type, the mutant exhibited a substantially higher standard deviation in the cross-correlation matrix (0.323 vs. 0.236) and a markedly increased number of both strongly positive (4,006 vs. 1,574) and strongly negative (3,326 vs. 576) correlated residue pairs, indicating the emergence of extensive long-range allosteric perturbations that may disrupt functional dynamics and stability. Our report highlights the value of MD simulations as a tool to evaluate the structural consequences of genetic variants.