Background: Glutaric acidemia type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in glutaryl-CoA dehydrogenase (GCDH), with variable clinical severity despite early biochemical detectability. Population-specific mutational spectra and genotype–phenotype correlations remain insufficiently defined in infantile-onset disease. Therefore, this study aimed to define the GCDH variant spectrum in GA1 patients with mild hepatopathy and assess genotype–phenotype correlations. Methods: We performed integrated clinical, biochemical, and molecular characterization of 15 unrelated patients with infantile-onset GA1. Whole-exome sequencing (WES) was performed for all participants, and the resulting data were compared with the reference sequence of the GCDH gene. Results: All patients presented within the first 6 months of life with macrocephaly, seizures, dystonia, and feeding difficulties. Neurological impairment and mild hepatopathy were variably observed, and one patient developed an acute encephalopathic crisis. Six homozygous GCDH variants were identified, predominantly missense. A common variant, c.541G>C (p.Glu181Gln), accounted for 73.3% of cases and defined a consistent phenotype of early macrocephaly and movement disorder with frequent mild hepatic involvement, suggesting regional enrichment and raising the possibility of a founder effect that warrants confirmation in future haplotype studies. A truncating variant, c.382C>T (p.Arg128Ter), was associated with severe early encephalopathy. Exon 6 represented a mutational hotspot. Biochemically, all patients showed elevated urinary glutaric and 3-hydroxyglutaric acids, increased glutarylcarnitine, and low-to-normal free carnitine, with higher metabolite levels in clinically more severe cases. All variants were pathogenic or likely pathogenic and extremely rare in population databases. Conclusions: This cohort reveals a striking predominance of the GCDH c.541G>C variant and establishes a clear biochemical signature with genotype-associated clinical patterns in infantile-onset GA1. These findings support a population-specific mutational spectrum, refine genotype–phenotype correlations, and underscore the importance of early molecular diagnosis to guide targeted neurological and hepatic monitoring as well as regional screening strategies.
Beyzaei et al. (Sat,) studied this question.