Krabbe disease results from biallelic pathogenic variants in GALC, located on chromosome 14. ClinGen has classified the GALC–Krabbe disease gene-disease relationship as DEFINITIVE. The condition follows autosomal recessive inheritance. GeneReviews genotype-phenotype analysis indicates that infantile-onset disease most commonly results from homozygosity for the common GALC 30-kb deletion, compound heterozygosity for this deletion with a severe pathogenic variant (frequently nonsense, frameshift, or certain missense variants), or compound heterozygosity for two severe variants. Later-onset Krabbe disease has been associated with genotype combinations that preserve partial enzyme activity, typically involving missense variants with less severe biochemical consequences.

Diagnostic evaluation involves measurement of galactocerebrosidase enzyme activity and molecular genetic testing of GALC. GeneReviews identifies two diagnostic scenarios: the symptomatic proband presenting with characteristic neurologic features, and the asymptomatic neonate identified through population-based newborn screening. Krabbe disease is included on the HHS Recommended Uniform Screening Panel (RUSP) as a core newborn screening condition; implementation varies across state programs. GeneReviews describes post-diagnosis evaluation as encompassing neurologic and developmental examination, brain stem auditory evoked response testing to assess hearing, and neuroimaging. Biochemical confirmation of reduced or absent galactocerebrosidase activity, alongside identification of biallelic GALC pathogenic variants, is documented as the confirmatory approach.

No drugs with active FDA-approved market status for Krabbe disease are documented in this packet. GeneReviews describes hematopoietic stem cell transplantation (HSCT) as the intervention with the most documented clinical use, with evidence indicating benefit primarily for pre-symptomatic neonates identified through newborn screening before clinical deterioration occurs. For symptomatic infants in advanced stages of infantile-onset Krabbe disease, GeneReviews characterizes management as supportive, directed at maintaining quality of life and preventing complications. GeneReviews-documented supportive interventions address gastrointestinal manifestations including gastroesophageal reflux and vomiting, among other system-specific concerns. Multiple agents hold FDA orphan drug designation for Krabbe disease—including AAV-based gene therapy vectors (AAVrh10-GALC by Forge Biologics, and an AAVhu68-GALC vector by a separate sponsor), Gemfibrozil (Polaryx Therapeutics), and ibudilast (MediciNova)—but none holds FDA approval for this indication as of the packet date.

GeneReviews describes infantile-onset Krabbe disease as following a rapidly progressive course, with death typically occurring before age two years in the approximately 85–90% of symptomatic individuals presenting with infantile onset. Later-onset Krabbe disease follows a slower progressive trajectory, with variable course by subtype and genotype. GeneReviews notes that identification of affected neonates through newborn screening and subsequent HSCT in the pre-symptomatic period has been associated with modified disease trajectories relative to outcomes observed when diagnosis follows symptom emergence, underscoring the clinical significance of early identification.

Active clinical investigations documented in this packet include: NCT04693598, a Phase 1 gene transfer trial evaluating GALC delivery via AAVrh10 vector, sponsored by Forge Biologics (active, not recruiting; estimated completion November 2026); NCT02993796, the Krabbe Disease Global Patient Registry at the State University of New York at Buffalo (recruiting; estimated completion September 2026); NCT03655223, the Early Check expanded newborn screening study at RTI International (active, not recruiting); NCT00787865, a longitudinal diffusion tensor imaging neuroimaging study at the University of Pittsburgh (active; estimated completion April 2027); and NCT03333200, a longitudinal neurodegenerative disorder study. GeneReviews documents ongoing preclinical investigation into enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy. The Krabbeconnect patient advocacy organization is documented as active in this disease community.