GALC

GALC, or galactosylceramidase, is a lysosomal enzyme encoded by the GALC gene on chromosome 14q31. It hydrolyzes galactosylceramide and psychosine, lipid substrates involved in myelin turnover. Deficiency of GALC causes Krabbe disease, a rare autosomal recessive lysosomal storage disorder.

Genetically, pathogenic variants in GALC lead to reduced or absent enzyme activity. More than a hundred disease-causing variants have been described, including missense, nonsense, frameshift, and splice-site mutations. The relationship between genotype and disease course is variable, with infantile and later-onset forms observed.

Pathophysiology stems from accumulation of psychosine and related lipids due to GALC deficiency. Psychosine is cytotoxic to oligodendrocytes and Schwann cells, leading to demyelination of the central and peripheral nervous systems and progressive neurodegeneration.

Clinical features of Krabbe disease vary by onset. The infantile form typically manifests within the first months of life with irritability, feeding difficulties, fever, progressive developmental delay, hypotonia evolving to spasticity, and limb weakness, followed by optic atrophy and rapid decline. Without treatment, affected individuals often die in early childhood. Later-onset forms present with motor and cognitive deterioration beginning in childhood or adulthood.

Diagnosis relies on reduced GALC enzyme activity in leukocytes, fibroblasts, or dried blood spots, complemented by genetic testing for GALC variants. Elevated psychosine levels support the diagnosis and imaging may reveal demyelination.

Treatment is limited to disease-modifying approaches such as hematopoietic stem cell transplantation, most beneficial when given presymptomatically or early in infancy, along with supportive care. Research into gene therapy and enzyme replacement continues. Newborn screening programs increasingly include GALC testing in some regions.