From the Guidelines
Betagalactocerebrosidase enzyme deficiency is the primary cause of Krabbe disease, and normal enzyme activity is crucial for preventing the toxic accumulation of galactosylceramide and psychosine in the brain and other tissues. The enzyme betagalactocerebrosidase, also known as galactosylceramidase or GALC, plays a vital role in breaking down galactolipids, particularly galactosylceramide, in the myelin sheath of nerve cells 1. In normal individuals, this enzyme functions properly, preventing the toxic accumulation of galactosylceramide and psychosine, which are toxic to myelin-forming cells. However, in Krabbe disease, mutations in the GALC gene result in reduced or absent enzyme activity, leading to the accumulation of these substances and causing progressive damage to the nervous system.
The clinical presentation of Krabbe disease can vary, with four subtypes based on the age of onset and clinical presentation, including infantile-onset, late-onset, and other forms 1. The infantile-onset form is characterized by rapid neurodegeneration and early death, while patients with the late-onset type exhibit ataxia, weakness, vision loss, and psychomotor regression. Hematopoietic stem cell transplantation is the only treatment available for patients with Krabbe disease and is shown to be effective, particularly when initiated before symptom onset 1. Early diagnosis through enzyme activity testing and genetic analysis is crucial for identifying patients who may benefit from this treatment.
Key characteristics of Krabbe disease include:
- Autosomal recessive inheritance pattern
- Deficiency in galactocerebrosidase (GALC) activity
- Estimated frequency of 1 in 400,000
- Four subtypes based on age of onset and clinical presentation
- Progressive damage to the nervous system due to toxic accumulation of galactosylceramide and psychosine
- Hematopoietic stem cell transplantation as the only available treatment 1.
From the Research
Krabbe Disease and Betagalactocerebrosidase Enzyme
- Krabbe disease, also known as globoid cell leukodystrophy, is a genetic disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC) 2, 3, 4, 5, 6.
- The GALC enzyme is responsible for degrading galactosylceramide and galactosylsphingosine (psychosine), a toxic glycolipid that accumulates in the absence of GALC activity 2, 3.
- The accumulation of psychosine leads to the death of oligodendrocytes and Schwann cells, resulting in demyelination and neurodegeneration 2, 3, 5, 6.
Normal Function of Betagalactocerebrosidase Enzyme
- The betagalactocerebrosidase enzyme, also known as GALC, plays a crucial role in the lysosomal hydrolysis of galactosylceramide, an important component of myelin 4.
- The enzyme is necessary for the maintenance of normal myelination and the prevention of toxic glycolipid accumulation 2, 3, 4, 5, 6.
Krabbe Disease Treatment and Management
- Currently, there is no cure for Krabbe disease, but hematopoietic stem cell transplantation can slow the progression of the disease 2, 3, 4.
- Recent studies have shown that intrathecal gene therapy using AAV9 encoding canine GALC can improve myelination, attenuate inflammation, and prevent clinical neurological dysfunction in a canine model of Krabbe disease 6.
- Other therapeutic approaches, such as enzyme replacement therapy, autophagy activators, and inhibitors of the Pyroptosis process, are being explored 5.