Krabbe disease

A distinction is made between the classic infantile form and the later-onset form. The infantile form is characterised by initially normal development during the first months of life, followed by rapid and severe neurological deterioration with restlessness, irritability and increasing limb stiffness; epileptic seizures are possible. MRI shows changes in the white matter. The average age of death in the infantile form is 24 months (range 8 months to 9 years).

The later-onset form (onset from one year of age up to the seventh decade of life) is much more variable in its course, although fundamentally the same symptoms occur. Accumulation of psychosine leads to progressive damage of oligodendrocytes, demyelination of nerve cell processes, inflammatory reactions and connective tissue remodelling of the white matter (leukodystrophy).

The prevalence in Europe is approximately 1:100,000 births. About 90% of cases correspond to the infantile form and 10% to the later-onset form.

Krabbe disease is caused by variants in the GALC gene, which encodes galactocerebrosidase, an enzyme responsible for lysosomal metabolism of certain galactolipids. Normally, galactocerebrosidase degrades galactolipids (metabolic products of myelin) into galactose and galactocerebroside and is involved in the metabolism of psychosine, a toxic lipid metabolite formed during myelin breakdown. In the absence of enzyme activity, galactocerebroside and psychosine accumulate in the central nervous system, particularly in multinucleated globoid cells.

Accumulation of psychosine causes progressive oligodendrocyte damage, demyelination, inflammatory reactions, and leukodystrophy.

Variants in the PSAP gene, which encodes prosaposin, can cause an atypical form of Krabbe disease.

Genotype–phenotype correlations have been observed:

• In the infantile form with almost complete loss of galactocerebrosidase activity, the frequent 30 kb deletion is detected in homozygous form or in compound heterozygous form with mostly nonsense or frameshift variants.
• In the later-onset form, missense variants are more commonly found in homozygous or compound heterozygous form.

Krabbe disease is inherited in an autosomal recessive manner. This also applies to atypical forms caused by variants in the PSAP gene.

For diagnosis, galactocerebrosidase activity should first be measured in white blood cells or fibroblasts. Molecular genetic testing of the GALC gene can confirm the diagnosis. Characteristically, there is markedly reduced or absent enzyme activity.

There is currently no curative therapy. The current standard treatment for presymptomatic children is stem cell transplantation (bone marrow or umbilical cord blood). Other therapeutic approaches, including enzyme replacement therapy, substrate reduction therapies, and chemical chaperone therapy, are currently under clinical investigation.

• Schöls L. et al., Leukodystrophien und hereditäre Leukenzephalopathien im Erwachsenenalter, S1-Leitlinie, 2022, in: Deutsche Gesellschaft für Neurologie, (Hrsg.), Leitlinien für Diagnostik und Therapie in der Neurologie
• Orsini JJ, Escolar ML, Wasserstein MP, et al. Krabbe Disease. 2000 Jun 19 [Updated 2018 Oct 11]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]
• Heller et al. 2022, Mol. Therapy, 31:7
• Vademecum metabolicum – Diagnose und Therapie erblicher Stoffwechselkrankheiten, J. Zschocke, G. Hoffmann, 5. Auflage, Thieme Verlag