What is Krabbe Disease?
Another name for Krabbe Disease is Globoid Cell Leukodystrophy. (GLD) It is an autosomal, progressive, neurodegenerative, lysosomal disorder that impairs the protective white matter (myelin) around the sending arm of the neuron (axon). The myelin does not develop properly nor can it sustain itself. The result is a greatly shortened life span due to the damage caused to the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). Krabbe is pronounced as Crab-hey with the inflection on the “e” as an “a”.
What causes Krabbe?
A faulty or mutated GALC (Galactosylceramide) gene which is found on Chromosome 14 (14q31) causes Krabbe. This mutation causes a deficiency or shortage of the enzyme Galactocerebrosidase which then does not produce the correct amounts of Sulfatide and Galactosylceramide to ensure the functional healthy production of myelin. This dysfunction causes a build up of a Galactolipid (a fat) called Psychosine in extremely elevated levels in the Lysosome. This disorder is also characterised by the abnormal presence of globe-shaped cells that that has led to the term “Globoid” GLD is known as a “storage” disease as is another Leukodystrophy Metachromatic Leukodystrophy (MLD).
The Lysosome has been termed a “scavenger” cell or a “recycling” cell as its main function is to process unwanted material and redistribute for use in other parts of the cell. When, due a mutation it cannot do its job the unwanted material accumulates or stores itself in the cell which causes its malfunction.
Forms of Krabbe
This form which affects 90% of people with Krabbe appears in the first few months of life and causes such symptoms as:
- Developmental delay
- Limb stiffness
- Optic atrophy: wasting of a muscle of the eye, resulting in vision difficulties
- 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
- Feeding difficulties
- Unexplained crying
- Loss of head control
- Extreme irritability
- Changes in muscle tone (limb and muscle stiffness, poor coordination of movements)
- Progressive loss of hearing and sight
- Spasticity (presence of spasms or consistently contracted muscles)
- Loss of developmental milestones
Symptoms usually start at two to six months of age. Development may be normal up to that time. Eventually children lose mental and motor function, some may become deaf and blind, cannot move or speak, and typically must be fed through a tube. The average age of death is 13 months (ranging from 6 months to 5 years).
Many babies in this stage of Krabbe’s disease are misdiagnosed. It is common for parents of these babies to be told that their infant has colic, reflux, food/milk allergy, or even cerebral palsy.
Late Onset Infantile
When children have the late-onset form of the disease — which develops later in childhood or in adolescence — they may experience the signs and symptoms above, as well as other signs that may include:
- Visual impairment progressing to blindness, which may be the initial sign
- Difficulty walking (called ataxia or gait disturbances)
- Loss of manual dexterity
Adolescent – Very Rare
Onset of symptoms occurs between three and ten years of age. Loss of mental function and vision, paralysis on one side of the body, and difficulty in walking or other motor performance may be seen. Initially symptoms progress rapidly but then the rate of deterioration is much slower than for the infantile form. Symptoms may last five years or longer
Adult – Very Rare
Symptoms can appear as early as 10 years of age and as late as 45 years. These individuals may be learning disabled. Common first signs are loss of vision and deterioration in fine movements. Symptoms may last more than 20 years.
Krabbe disease is rare and is thought to affect 1 person in every 100,000 people in the general population. However, there is an unusually high incidence in the Israel Muslim community and particularly with the Druze community in Israel with 6 cases per 1000 live births being reported.
How is Krabbe diagnosed?
There are many methods used to positively determine a Krabbe diagnosis. They can involve all or some of the following:
- Measuring GALC activity in Leukocytes taken from a blood sample, chorionic villi or a fibroblast grown from a skin biopsy.
- Magnetic Resonance Imaging (MRI)
- Computerised Tomography (CT)
- Electroencephalograms (EEG)
- Measuring the protein in Cerebral Spinal Fluid (CSF)
- Genetic testing
- Nerve conduction velocity tests
New Born Screening:
Please be aware that there is a New Born Screening (NBS) test which is available in some parts of the world and it is very important to understand that this test does not diagnose Krabbe. It simply flag the possibility and further testing must be done to determine if it was a false positive or your child is only a carrier. The test that is used is the standard Guthrie or Heel Prick Test which also screens for many other diseases or disorders.
As mentioned a faulty or mutated GALC (Galactosylceramide) gene which is found on Chromosome 14 (14q31) causes Krabbe. It is an Autosomal recessive condition being that it is found on a non sex chromosome (an autosome) and both parents must have the mutation. The parents of a child with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. This means that there is a 1 in 4 chance (25%) chance that a child will be unaffected, there is a 2 in 4 chance (50%) that the child be a carrier and a 1 in 4 chance (50%) that child will be affected.
It is most important that all those families involved with GLD contact a genetic counsellor for a full explanation of its inheritance, consequences and of all the available options for having future children.
How is Krabbe treated?
Treatment for Krabbe is symptomatic and supportive. It is very important to fully explore with your medical team the option of undertaking hematopoietic (HSCT) or cord blood transplants as they can only be offered to pre-symptomatic infantile children and possibly mildly affected late-onset patients. These are only stabilising therapies and are not cures.
These transplants are Allogeneic not Autologous and involve chemotherapy some times with radiation and Graft versus Host (GVHD) complications. Autologous means the person is there own donor. It can be a long and stressful procedure and therefore needs careful consideration.
Gene therapy, enzyme replacement therapy and otr alternatives are currently being explored by research scientists.
Are there other names for Krabbe Disease?
Other names for Krabbe Disease include:
- globoid cell Leukodystrophy
- globoid cell Leukoencephalopathy
- Galactosylceramide beta-galactosidase deficiency
- Galactocerebrosidase deficiency
- GALC deficiency