Krabbe disease

Krabbe disease is a lysosomal demyelinating disorder confined to the nervous system, without visceromegaly. Two principal phenotypes form a clinical continuum. Historically, 85-90% of symptomatic individuals present with infantile-onset disease, marked by extreme irritability, spasticity, and developmental delay before age 12 months; the remaining 10-15% present from age 12 months up to the seventh decade with later-onset disease. Infantile-onset disease follows a rapidly progressive course with severe neurological deterioration, decorticate posturing including opisthotonus, absent tendon reflexes, optic atrophy, and sluggish pupillary responses. Later-onset disease shows variable progression and substantial inter- and intra-familial variability. Peripheral neuropathy affects nearly all individuals with infantile-onset disease but only about half of those with later-onset disease.

The estimated prevalence is 1:100,000.

Krabbe disease is caused by biallelic germline pathogenic variants in GALC (14q31.3). The encoded enzyme galactocerebrosidase (galactosylceramidase) normally degrades galactosylceramide and psychosine within lysosomes; loss-of-function variants result in severe enzyme deficiency, leading to accumulation of cytotoxic psychosine in oligodendrocytes and Schwann cells and to progressive demyelination of the central and peripheral nervous systems. Rarely, a Krabbe disease-like phenotype may result from biallelic pathogenic variants in PSAP (10q22.1), causing saposin A deficiency. Saposin A functions as an essential activator of galactocerebrosidase-mediated degradation of galactosylceramide. Deficiency of saposin A impairs this lysosomal degradation pathway despite an intact GALC enzyme, resulting in a clinically overlapping leukodystrophy characterised by progressive demyelination and neurological deterioration. This condition is genetically distinct from classic GALC-related Krabbe disease but may be considered in individuals with a compatible clinical phenotype.

Krabbe disease is inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers; each pregnancy of two carrier parents carries a 25% risk of an affected child, a 50% chance of a heterozygous carrier, and a 25% chance of an unaffected non-carrier. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Biochemical diagnosis rests on biochemical demonstration of markedly reduced galactocerebrosidase enzyme activity (0-5% of normal) in leukocytes or cultured skin fibroblasts and markedly elevated psychosine concentration in dried blood spots. Identification of biallelic pathogenic variants in GALC establishes the diagnosis on a molecular basis.

Main differential diagnoses include:

• Metachromatic (arylsulfatase A deficiency): subtypes resembling later-onset Krabbe disease, with sulfatide rather than psychosine accumulation; ARSA
• X-linked adrenoleukodystrophy: cerebral form with cognitive, behavioural, and motor decline plus adrenocortical involvement absent in Krabbe disease; ABCD1
• Canavan disease: developmental delay, hypotonia, and macrocephaly from infancy, with subcortical (not periventricular) white-matter MRI pattern; ASPA

• Establishing the diagnosis: confirms the underlying molecular cause, supports clinical decision-making, and concludes the diagnostic pathway.
• Specific and individualised surveillance: enables disease-specific monitoring, early detection of complications, and timely interventions, and is a prerequisite for targeted medical care; the precise programme is determined by the treating physicians in consultation with the affected individual.
• Family member testing: enables identification of at-risk relatives who carry the familial pathogenic variants, supporting informed reproductive and predictive decisions.

Orsini JJ, Escolar ML, Wasserstein MP, Caggana M. Krabbe disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .