SCIENTIFIC BACKGROUND

GALC, PSAP

Krabbe disease is a rare, autosomal recessive lysosomal disorder characterized by demyelination in the central and peripheral nervous systems. It is caused by variants in the GALC gene, which is responsible for the enzyme galactocerebrosidase. If this enzyme is missing, toxic lipid metabolites accumulate in the nervous system, leading to damage. While the infantile form leads to rapid neurological deterioration and is often fatal before the age of 24 months, the late onset form is more variable. There are also PSAP gene variants that cause atypical Krabbe disease.

 

Autosomal recessive Krabbe disease (also called globoid cell leukodystrophy) is a rare lysosomal disorder that affects the white matter of the central and peripheral nervous systems and triggers demyelination. It is caused by variants in the GALC gene, which codes for the enzyme galactocerebrosidase. This enzyme, which is responsible for the lyosomal metabolism of certain galactolipids, is missing in patients with Krabbe disease. Normally, galactocerebrosidase breaks down both galactolipids (metabolic byproducts of myelin) in the central nervous system (CNS) into galactose and galactocerebroside, and psychosine, a toxic lipid metabolite of myelin. In the absence of enzyme activity, galactocerebroside and the toxic psychosine accumulate in the CNS, particularly in the multinucleated globoid cells. The accumulation of psychosine leads to progressive damage to the oligodendrocytes and, eventually, to demyelization of the nerve cells, an inflammatory reaction, and changes to the white matter (leukodystrophy).

 

A distinction is made between the classic infantile form and the later onset form. Phenotypically, the infantile form is characterized by initially normal development in the first months of life, followed by a rapid severe neurological deterioration, which manifests itself in restlessness, irritability and increasing limb stiffness. Epileptic seizures are possible. Clinically, 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 the age of one year up to the 7th decade of life) is much more variable in its course. However, the symptoms are basically the same. The prevalence of the disease in Europe is around 1:100,000 births, with 90% of these being the infantile form and 10% the late-onset form.

 

The disease cannot be cured; stem cell transplantation (bone marrow or umbilical cord blood) is the current standard therapy for pre-symptomatic children. Other possible treatment options (enzyme replacement therapy, substrate reduction therapies and chemical therapy using chaperones) are currently in various phases of clinical testing.

 

There are several indications of a genotype-phenotype correlation:

  • In the infantile form with almost complete loss of galactocerebrosidase activity, the frequent 30kb deletion is detected in homozygous form as well as in combined heterozygous form with mostly nonsense or frameshift variants
  • In the late onset form, missense variants tend to occur in homozygous and combined heterozygous form

 

Galactocerebrosidase activity should be measured in white blood cells or fibroblast cells in order to make a diagnosis.

 

In addition to variants in the GALC gene, variants in the PSAP gene are the cause of atypical Krabbe disease. PSAP codes for the enzyme prosaposin. Inheritance is also autosomal recessive.

 

References

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

GENES

GALC, PSAP

ASSOCIATED TESTS

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