PATHOGENIC GALC VARIANTS AND EPILEPSY: A FAMILY-BASED OBSERVATION

Krabbe disease is a rare and fatal neurodegenerative disease, described by demyelination and severe neurological decline, caused by the mutation in the GALC gene. Epilepsy specific symptoms are known to be present as an early or presenting feature of late-onset forms, including generalized tonic-clonic seizures and progressive myoclonic epilepsy, associated with cortical or subcortical abnormalities on neuroimaging. However, the clinical relevance of heterozygous GALC variants in epilepsy remains unclear.
Next-generation sequencing was performed in family with a history of epilepsy. The sequencing data were further analyzed using bioinformatics and annotated using ANNOVAR and public databases, like ClinVar and Franklin. Clinical phenotypes were reviewed and compared with available literature.
A heterozygous missense variant in GALC (rs138577661), classified as pathogenic, was identified in the mother and all three children. Epilepsy was diagnosed in one child, while the mother and the remaining two children had no neurological manifestations at the time of evaluation.
Epileptic seizures may represent an early or initial clinical manifestation of late-onset Krabbe disease, particularly in patients with biallelic GALC variants and cortical involvement. However, the findings from this family indicate that heterozygous GALC variants alone are not sufficient to cause epilepsy and may contribute only to disease susceptibility. Further studies in larger cohorts are necessary to clarify the role and related pathways in epilepsy and to improve early detection of Krabbe disease.
This research has been funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan (Program targeted funding No. BR27199879).