INTRODUCTION: Krabbe disease (also called globoid cell leukodystrophy) is an autosomal recessive, degenerative disorder that affects the nervous system. It is caused by the deficiency of an enzyme called galactosylceramidase which in humans is encoded by the GALC gene. This enzyme removes galactose from ceramide derivatives (galactocerebrosides)and its deficiency impairs the growth and maintenance of myelin, the protective covering around certain nerve cells that ensures the rapid transmission of nerve impulses. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). This disorder is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that usually have more than one nucleus.It is caused due to a dysfunctional metabolism of sphingolipids.
CAUSE: Mutations in the GALC gene cause Krabbe disease. These mutations cause a deficiency of the enzyme galactosylceramidase. This deficiency leads to a progressive loss of myelin that covers many nerves. Without myelin, nerves in the brain and other parts of the body cannot function properly, leading to the signs and symptoms of Krabbe disease.
Among the genetic leukodystrophies known to occur in man, the fundamental genetic defects have been clarified in two disorders, metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe's disease). Globoid cell leukodystrophy manifests itself almost exclusively as disease of the myelin sheath is relatively easy to understand because it is caused by genetic abnormalities in the metabolism of the characteristic constituents of myelin, sulfatide and galactosylceramide. The presence of the abnormal and characteristic globoid cells in the white matter of Krabbe's disease patients appears to be due to a unique property of galactosylceramide in that, when present in free form in the brain, it elicits infiltration of macrophages which transform themselves to globoid-like cells. No other lipids, including sulfatide, are known to induce similar tissue reactions. The most conspicuous difference between the two diseases is the presence or absence of abnormal accumulation of the substrates, the degradation of which is genetically blocked in the respective diseases. In Krabbe's disease, galactosylceramide is always much less than normal despite the genetic block in its catabolic pathway.
Krabbe disease can develop at various ages: 1)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. 2)Late-onset Krabbe disease begins in late childhood or early adolescence. Krabbe disease is inherited, which means it is passed down through families. If both parents carry the nonworking copy of the gene related to this condition, each of their children has a 25% (1 in 4) chance of developing the disease. This condition is very rare. It is most common among people of Scandinavian descent.
SYMPTOMS: The majority of cases of Krabbe Disease appear within the first year of life. The patients rapidly regress to a condition with little to no brain function, and generally die by age 2, though some have lived longer. Death generally occurs as a result of a respiratory infection or brain fever. Symptoms that might be encountered in the infantile form of Krabbe Disease include:
-Developmental delay -Seizures -Limb stiffness -Optic atrophy: wasting of a muscle of the eye, resulting in vision diffculties -Neurosensoral deafness -Extreme irritability -Spasticity: presence of spasms -Ataxia: loss of the ability to control muscular movement -Progressive psychomotor decline: progressive decline in the coordination of movement
Although the majority of Krabbe Disease patients show symptoms within the first year of life, there have been cases diagnosed at all ages, through late adulthood. In general, the earlier the diagnosis, the more rapid the progression of the disease. Those who first show symptoms at ages 2-14 will regress and become severely incapacitated, and generally die 2-7 years following diagnosis. Some patients who have been diagnosed in the adolescent and adult years have symptoms that remain confined to weakness without any intellectual deterioration, while others may become bedridden and deteriorate both mentally and physically.
TESTS AND DIAGNOSIS: An exam of the retina in the eye may show damage to the optic nerve. There may be signs or deafness and abnormal posturing (rigid body movements and holding one's body in abnormal positions) in the late stages of the disorder.
Tests that may be done include:
-Blood test to look for galactosylceramidase levels in white blood cells -CSF total protein - tests the amount of protein in cerebrospinal fluid (CSF) -Genetic testing- 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. -MRI of the head -Nerve conduction velocity -Testing for the GALC gene defect- Krabbe Disease can be diagnosed by a biochemical assay that measures the GALC activity from a blood sample or skin biopsy. 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.
TREATMENT: Most treatment of Krabbe Disease is supportive. However, one medical treatment that has been demonstrated to have some effect is 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. 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.
Krabbe Disease is unique in that it has three animal models of disease that can be 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 genetic 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.
PROGNOSIS When untransplanted, and in the case of a failed transplant, generally fatal before age 2 for infants.
THE TWITCHER MOUSE: A MODEL FOR KRABBE DISEASE AND FOR EXPERIMENTAL THERAPIES
The twitcher, a neurological mouse mutant originally discovered at the Jackson Laboratory (Bar Harbor, Maine) in 1976, is an enzymatically authentic model of one of the classical human genetic leukodystrophies, Krabbe Disease or globoid cell leukodystrophy (GLD).Since the first clinico- pathological documentation and the identification of the genetic defect of a lysosomal hydrolase, galactosylceramidase, it has been widely used as a convenient and useful experimental tool for investigations of the pathogenesis of and therapeutic approaches for GLD. Despite the large number of known neurological mouse mutants, the twitcher remains the only naturally-occurring genetically authentic mouse model of human sphingolipidoses. Although the lack of authentic models for human sphingolipidoses among small laboratory animals has been alleviated recently with the increasing number of murine models artificially generated by the homologous recombination and transgenic technology, the twitcher mutant is the most thoroughly characterized and most extensively utilized model because of its 15-year history. A series of attempts at treating the disease by bone marrow transplantation was definitely but only partially effective. The recent successful cloning of the human galactosylceramidase gene has lead to identification of the mutation in the twitcher mutant.
CASE REPORTS