Crushing Krabbe Disease: A Look at Leukodystrophy
On November 5, 2008, the Aldrian family’s lives completely changed when they welcomed two children into their lives - fraternal twins Trevor and Tyler. It was a day filled with elation and joy following years of miscarriages and struggles with fertility treatments. Unfortunately, within the first few months following their discharge from the hospital, it was noted that one of their sons, Trevor, consistently struggled with feeding, acid reflux, and often had spasms. Almost a year later, following visits to multiple doctors, he joined the 1 in 100,000 children in the U.S. who are diagnosed with infantile Krabbe Disease (KD), an autosomal recessive disorder falling into a group of rare neurological diseases known as leukodystrophies.1
Leukodystrophy is characterized by the abnormal development and deterioration of white matter protecting neuronal axons in the nervous system. These special cells that form the myelin sheath are called glial cells. We primarily see oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. By wrapping around axons like the coating of a wire, myelin sheath provides insulation for electrical impulses, optimizing signal transduction. They are essential for normal neurophysiology, where any major impairment to these glial cells can result in a wide variety of symptoms. In leukodystrophies, it is common to observe symptoms like ataxia, which manifests as a struggle to produce voluntary movements, visual impairments and overall lack of coordination of fine motor skills.1 Patients with these rare diseases tend to also display behavioural problems and cognitive issues, whether they suffer from infantile, juvenile, or adult presentations.2
First described by neurologist Knud Krabbe in 1916, the most common phenotype of Krabbe Disease affects infants with onset at around six months of age.1 Beginning with symptoms like irritability and seizures, KD progresses in morbidity with time; these later stages are characterized by severe mental and motor impairments, major growth delays, and increasing stiffness.2 The average lifespan of affected children can range from 3-10 years, but is usually fatal at two years of age as individuals eventually enter a vegetative state triggered by severe neurological deterioration to the brainstem, vital for basic aspects of living.2 Other subtypes of the disease can appear later in adolescence or even adulthood; it should be noted that later onset forms are much more scarce, and are typically less severe, allowing for longer lifespans of affected individuals.
It is understood that Krabbe Disease results from a deficiency in lysosomal galactocerebrosidase (GALC) triggered by mutations in the human GALC gene. GALC is a protein important for the breakdown of substances that are toxic for glial cells, and genetic mutations can lead to GALC with reduced function, or complete loss of function altogether.3 Researchers have identified the buildup of a substance called psychosine (PSY) to be a harmful substance that is normally found in very low amounts in our cells. Resulting from the chemical processing of lipids called sphingolipids, which make up a large majority of our neural tissues, GALC’s job is to convert PSY back into a non-toxic form. However, when GALC function is inhibited, PSY tends to accumulate and trigger neuroinflammation, leading to glial cell degradation and death.4 For patients like Trevor, PSY buildup is the key factor causing damage to nervous tissue and is responsible for the hallmark characteristics we observe in KD.
How do we combat such a devastating disease and its effects? While there is no cure for Krabbe Disease at the moment, a variety of therapeutic options are actively being researched, ranging from the introduction of genes into the individual to drug development. In particular, uncovering and understanding the genetic basis of the disease via model organisms like mice have been an instrumental aspect of treatment development. For example, suppressing PSY and its toxic properties via sphingolipid synthesis inhibition has been considered.3 Additionally, the use of hematopoietic stem cells, particularly umbilical cord and bone marrow stem cell transplants from healthy, compatible donors, to restore some GALC function has become increasingly appealing.4 This type of therapy works by introducing donor-derived stem cells with normal GALC function into the patient, and encouraging the growth and proliferation of these cells, allowing for remyelination of the nervous system.3 However, aside from issues with potential for immune rejection, it has also been observed that successful transplant recipients still developed issues with motor skills, revealing the need for further investigation.
Gene therapy has also risen in interest. Viral adeno- and lentiviral-associated delivery methods of the GALC gene have shown moderate success in mouse models, prolonging lifespans of diseased mice by slowing down KD pathology through the inhibition of PSY accumulation.3 Other common treatments investigated involve using anti-inflammatories targeting PSY-induced neuroinflammation, which has proven promising as well.4 Overall, these therapies are continuously being researched, and show signs of increased efficacy when utilized together. For example, the combination of gene therapy and stem cells has shown to double the lifespan of KD affected mice via improved CNS and PNS myelination, potentially paving the way towards a cure.3
In his honour, Trevor’s family founded Peace, Love and Trevor in 2011 to raise awareness and provide funding for families in similar situations. The Aldrians quickly realized that oftentimes these families don’t have all the resources necessary to provide for the needs of their terminally ill children, highlighting the importance of community involvement in matters relating not only to KD and leukodystrophies but rare diseases in general. Trevor’s story, and the stories of children like him, are not just emotionally powerful, but also essential for bridging the gap between understanding the progression of rare neurological disorders, divulging effective treatment, and ways the public can be involved. While a cure for leukodystrophies like Krabbe Disease has yet to be fully uncovered, we can utilize our knowledge of the rare disease to better support affected families until then.
1. Barañano K. Leukodystrophies. Semin Neurol. 2016;36(04):362-366. doi:10.1055/s-0036-1585455.
2. Escolar M, West T, Dallavecchia A, Poe M, LaPoint K. Clinical management of Krabbe disease. J Neurosci Res. 2016;94(11):1118-1125. doi:10.1002/jnr.23891.
3. Won, J., Singh, A. K., & Singh, I. Biochemical, Cell Biological, Pathological, and Therapeutic Aspects of Krabbe’s Disease. J Neurosci Res. 2016;94(11):990-1006. doi: 10.1002/jnr.23873.
4. Potter G, Petryniak M. Neuroimmune mechanisms in Krabbe's disease. J Neurosci Res. 2016;94(11):1341-1348. doi:10.1002/jnr.23804.
Cite This Article:
Rong M., Chan G., Palczewski K., Lewis K., Ho J. Crushing Krabbe Disease: A Look at Leukodystrophy. Illustrated by H. Zhang. Rare Disease Review. December 2018. DOI:10.13140/RG.2.2.24888.60163.