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What Causes Krabbe Disease?
Krabbe disease is an autosomal recessive disorder resulting from a deficiency in an enzyme known as galactocerebrosidase (GALC). GALC is an enzyme that breaks down molecules called galactolipids, which are heavily present in the brain. There are many different galactolipids, but the buildup of one in particular, called psychosine, appears to be responsible for a good deal of the pathology of Krabbe disease. In patients with Krabbe disease, psychosine can be at levels 100 times that of healthy individuals, and this buildup is thought to lead to the demyelination observed in Krabbe disease.
Another name for Krabbe disease is Globoid Cell Leukodystrophy. This name comes from a characteristic pathology of Krabbe disease, where a specific type of cell (called the macrophage) accumulates high levels of undegraded galactolipids as a result of the lack of GALC activity. These cells look different from healthy cells, and are termed globoid cells
What is infantile Krabbe disease, and what are the symptoms?
Classic-infantile Krabbe disease is the most severe form affecting ~85-90% of all cases.1 As with many lysosomal storage disorders, babies appear normal for the first few months of life then begin to develop noticeable symptoms. Cases of infantile Krabbe disease have reported an average onset of clinical deterioration between 3 to 14 months of age. Treatment for this form largely involves supportive medicine as most have irreversible brain damage at time of diagnosis, disqualifying them as a candidate for a hematopoietic stem cell transplant (HSCT). Some of the key characteristics associated with infantile Krabbe disease are:
- Extreme irritability; above and beyond colic
- Sensitivity to sound; easily startles
- Severe acid reflux; appears to not keep a majority of feedings down
- Significant decrease in daily consumption of formula\breast milk
- Loss of milestones; no longer tracks objects or giggles
1 Wenger DA. Krabbe Disease. 2000 Jun 19 [Updated 2011 Mar 31]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
What is late-onset Krabbe disease, and what are the symptoms?
In a relatively small number of patients, Krabbe disease does not appear until later in childhood, adolescence, or even in adulthood. There is a variable age when symptoms first appear, a variable degree of health problems that develop and a variable rate at which the disorder progresses. The course of late-onset Krabbe is mostly associated with clinical deterioration of 3 years or later. Children presenting with this form of Krabbe disease live for years especially when a hematopoietic stem cell transplant (HSCT) is performed. The clinical symptoms of late-onset Krabbe disease is quite varied but some notable characteristics are as follows:
- Loss of manual dexterity and fine-motor skills; unable to button a shirt
- Peripheral neuropathy; complaints about tingling or burning sensation in hands or feet
- Lower limb weakness; appears to trip over their feet or fall more
- Deceased mental acuity; trouble remembering people’s names or simple words
How is Krabbe disease diagnosed?
Krabbe disease can be diagnosed by a biochemical assay that measures the GALC activity from a blood sample. It should be noted that the absolute level of GALC activity is not an indicator of prognosis; that is, a particularly low GALC activity does not necessarily predict a more rapid progression of disease than a somewhat higher GALC activity.
The genetic basis for Krabbe disease is known, so it also may be possible to perform DNA sequencing of the gene in order to confirm the diagnosis of Krabbe disease. In conjunction with genetic counseling, this knowledge may also allow relatives of patients with Krabbe disease to be tested for the presence of the genetic mutation responsible, allowing them to make informed decisions about having children.
How is Krabbe disease treated?
The majority of cases of Krabbe are diagnosed already symptomatic. Palliative and supportive care is the only treatment available for these cases. Most treatment of Krabbe disease is supportive. Patients that are diagnosed before symptoms begin through newborn screening , previous family history or later onset of symptoms may be eligible for a hematopoietic stem cell transplant (HSCT). This method appears to be of some benefit in cases of later onset or in infantile patients who have been diagnosed before or at birth. The clinical course of patients who have received the transplants seems to be less severe, and an improvement in the pathology of the disease can be seen by MRI. HSCT has shown to stabilize the disease progression, given a better quality of life and extended the life of the treated patient. However, HSCT does not appear to be beneficial in the case of infantile patients who have already begun displaying the symptoms of Krabbe disease. HSCT has been attempted on three fetuses with Krabbe disease, and failed in all cases, presumably because the donor cells were not sufficiently engrafted.
How is research on Krabbe disease progressing towards better treatments?
Krabbe disease is unique in that it has three animal models of disease that have been studied: a mouse model, dog model, and a monkey model. The mouse model is sometimes referred to as the “twitcher” mouse, and carries the same genetic defect found in patients with Krabbe disease. Various treatments have been attempted on these animal models, with varying degrees of success. One promising treatment is gene therapy, where the deficient gene (GALC) is delivered in a harmless virus. Another promising method of treatment is stem cell therapy, which can provide healthy cells with GALC activity to allow for remyelination. However, none of these methods have yet been attempted on human subjects to date.
Other names for Krabbe disease:
- globoid cell leukodystrophy
- globoid cell leukoencephalopathy
- Galactosylceramide beta-galactosidase deficiency
- Galactocerebrosidase deficiency
- GALC deficiency