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Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive demyelinating leukodystrophy caused by deficiency of the lysosomal enzyme galactocerebrosidase, encoded by the GALC gene. Patients present across a spectrum from infantile-onset with rapid neurodegeneration to adult-onset forms with progressive spastic paraplegia, optic atrophy, dementia, peripheral neuropathy, and variable survival (PMID:1817026). Biochemical diagnosis is established by severely reduced GALC activity in leukocytes or cultured cells, and molecular analysis of GALC confirms pathogenic variants.
Extensive case series and family studies have reported biallelic GALC variants in over 60 unrelated probands, demonstrating autosomal recessive inheritance with consistent segregation in multiple pedigrees. A 53-year-old adult-onset patient was compound heterozygous for c.560A>T (p.Asp187Val) and c.334A>G (p.Thr112Ala), each private to his lineage (PMID:8687180). A 28-year-old woman homozygous for c.908C>T (p.Ser303Phe) exhibited partial residual GALC activity corresponding to her protracted clinical course (PMID:10448809). Infantile cases include a novel homozygous frameshift c.727delT (p.Ser243GlnfsTer7) associated with rapid progression and early mortality (PMID:23276707). Segregation of these variants in affected sibships further supports pathogenicity.
The GALC variant spectrum encompasses missense, nonsense, frameshift, and splice site changes. Founder and recurrent alleles have been described, such as the p.Gly41Ser substitution in Sicilian late-onset patients (PMID:17579360). Hypomorphic variants (e.g., p.Gly270Asp) confer residual enzyme activity (~17% of control) correlating with milder phenotypes (PMID:10477434). Deep-intronic and large-deletion alleles also contribute, underscoring the need for comprehensive molecular testing.
Functional studies demonstrate that GALC missense mutants express misfolded protein, fail to undergo proteolytic processing, or exhibit diminished lysosomal targeting. Expression of c.908C>T (p.Ser303Phe) in COS-1 cells yielded low but detectable activity, explaining adult-onset presentation (PMID:10448809). Humanized mouse models carrying adult-onset mutations recapitulate psychosine accumulation and demyelination, and enzyme-loaded nanoparticles restore GALC activity in brain tissue (PMID:31799395). These findings validate haploinsufficiency and misfolding as key mechanisms.
Therapeutically, hematopoietic stem cell transplantation in a 41-year-old adult-onset patient normalized peripheral GALC activity, halted neurological progression, and improved gait over 24 months (PMID:23430802). Early intervention before symptom onset remains critical, highlighting the value of newborn and carrier screening for GALC variants.
In aggregate, definitive clinical validity is supported by decades of case and functional data linking biallelic GALC variants to Krabbe disease. Autosomal recessive inheritance, extensive segregation, diverse variant spectrum, and concordant biochemical and animal model studies establish GALC as the causal gene. Key Take-home: molecular diagnosis of GALC variants enables timely intervention with enzyme-based or stem cell therapies to modify disease course.
Gene–Disease AssociationDefinitiveOver 60 unrelated probands reported over 25 years with consistent autosomal recessive segregation and functional concordance Genetic EvidenceStrongMultiple unrelated probands (n>60) with biallelic GALC variants and co-segregation in families [PMID:8687180] Functional EvidenceModerateCellular expression and processing assays show reduced GALC activity; nanoparticle and HSCT rescue studies in models and patients |