Clinical and molecular characterization of Krabbe disease in Iranian patients: case report and literature review

Krabbe disease (KD, OMIM #245200) is a rare autosomal recessive lysosomal storage disorder characterized by severe demyelination affecting both the central and peripheral nervous systems. Here we report the clinical and molecular findings of two unrelated Iranian patients with KD, originating from consanguineous families. Genetic analysis was initially performed using whole-exome sequencing (WES), then validated by Sanger sequencing. WES identified a novel homozygous variant in the GALC, c.836T > G (p.L279X), in patient-1. In patient-2, WES detected a previously reported homozygous variant, c.578T > C (p.I193T), in the GALC. Sanger sequencing confirmed homozygosity of these variants in the affected patients and heterozygosity in their parents. The affected brother of patient-2 was also homozygous for the variant c.578T > C. The pathogenicity of the detected variants was supported by various lines of evidence, including in silico predictive tools, segregation analysis, and population genetic databases frequency. Our findings expand the mutational spectrum of GALC and highlight the clinical heterogeneity of KD. Morover, these finding contribute to improved genotype-phenotype correlations, which are essential for accurate diagnosis, prognostic valuation, and genetic counseling.