A rare disease a day: Krabbe Disease

Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease and Sanfilippo syndrome it is now the turn of Krabbe Disease.

Krabbe disease (also known as globoid cell leukodystrophy or galactosylceramide lipidosis) is an often fatal degenerative disorder affecting the myelin sheath of the nervous system. A defect in the GALC gene causes Krabbe disease resulting in not being able to make enough galactocerebroside beta-galactosidase (galactosylceramidase). A crystal structure for the enzyme and substrate was recently published providing insights into the catalytic mechanism. This disease is inherited in an autosomal recessive pattern and occurs in about 1 in 100,000 births.

Krabbe disease can be characterized as early-onset Krabbe disease and late-onset Krabbe disease. Early-onset Krabbe disease appears in the first months of life. Most children with this form of the disease die before they reach age 2. Symptoms include changing muscle tone from floppy to rigid (decerebrate posturing), Hearing loss that leads to deafness, Failure to thrive, Feeding difficulties, Irritability and sensitivity to loud sounds, Severe seizures (may begin at a very early age), Unexplained fevers, Vision loss that leads to blindness and vomiting. In comparison late-onset Krabbe disease begins in late childhood or early adolescence and has the following symptoms including vision problems followed by walking difficulties and rigid muscles.

There is no treatment for the disease although bone marrow transplant (BMT) is partially effective. Enzyme replacement therapy (ERT) led to animal studies in 2005. More recent combinations of BMT and ERT in the Twitcher mouse model for Krabbe disease demonstrated increased life span. Recent lentiviral-mediated neonatal intracerebral gene therapy in the mouse model also suggest this may be an option for treatment in the future. A high throughput screening assay with patient fibroblasts was developed in 2013 and used to screen a small compound collection, identifying several chaperones. The crystal structure of the enzyme could also enable chaperone development. a-lobeline (an alkaloid with high affinity for nicotinic acetylcholine receptors, and candidate for addiction treatment) was found to be effective against the D528N mutant. The structure of this molecule (top right on image below) looks pretty simple and likely the pharmacophore is common in other drugs (see other molecules in figure from a similarity search in Approved Drugs app).

The most well known parent/patient led foundation is Hunter’s Hope Foundation (@HuntersHopeFDN) which has funded research and development of a patient registry.

compounds similar to a-lobeline

compounds similar to a-lobeline


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