Krabbe disease is a condition which usually appears in the first year of life. The general progression of symptoms is irritability, increased muscle tone, and deterioration of motor and developmental function.
Cerebrospinal fluid (CSF) protein
The CSF fills the otherwise open spaces of the brain and spinal cord. CSF typically does not contain much protein. Elevated CSF protein is often seen in children with Krabbe disease whose symptoms begin before age three. Other individuals with Krabbe disease may or may not have increased protein in their CSF.
The EEG measures the electrical activity of the brain using flat, wire electrodes taped to the scalp. Individuals who have Krabbe disease may have normal EEG patterns at first, but they will eventually develop abnormal EEG patterns. Seizures are often associated with these types of EEG patterns.
Nerve conduction velocity studies
These are similar to an EEG but measure the amount of time it takes an artificial electrical stimulus to travel along the nerve. The stimulus is detected at a point further down the neuronal pathway. Nerve conduction velocities are often decreased in people with Krabbe disease. Other types of peripheral nerve function tests also show unusual patterns. Loss of myelin covering the peripheral nerve (demyelination) causes these findings. It takes more time for unmyelinated nerves to send electrical messages to and from the brain.
Computerized tomography (CT)
The CT scan is a series of X-ray pictures of adjacent slices of the brain. It allows visualization of the internal structures of the brain without having to do an invasive procedure like surgery. Results of a CT scan may be normal in the initial sages of Krabbe disease. As this condition progresses there will be characteristic changes in the white matter.
Magnetic resonance imaging (MRI)
Similar to a CT scan, MRI produces pictures of the inside of the brain without surgery. Instead of X-rays, a magnetic field is used to visualize the brain. MRI is more sensitive than the CT scan in detecting loss of or irregularities in the brain's white matter. Findings are like those seen with the CT scan. Individuals with Krabbe disease will eventually show white matter changes by MRI.
Histologic techniques use chemical stains to look at tissues under the microscope. Stained samples of Krabbe disease brain tissue show the presence of many globoid cells, demyelination and decreased numbers of myelin synthesizing cells (oligodendrocytes in the brain). Peripheral nerve tissue shows degeneration of axons and demyelination. Although no globoid cells are seen, small tubular structures, or inclusions, can be found in Schwann cells, the myelin synthesizing cells in the peripheral nervous system. These inclusions may be cerebroside deposits.
Biochemical enzyme assays
As previously mentioned, enzyme activity can be tested in the laboratory. The compound on which an enzyme acts is called a substrate. Cerebroside and psychosine are substrates for galactosylceramidase (GALC). Cells from skin (skin fibroblasts), amniocentesis samples (amniocytes), other tissues, or blood can be tested for GALC activity. The amount of cerebroside, or a similar man-made chemical, broken down by the GALC in these cells is measured.
In general the following results are found. Healthy people with two working GALC genes (GALC+/GALC+) have enzyme activities within a certain range. This represents 100% activity and is called the control range. Of note, the control range of GALC enzyme activity is very wide. A parent of a child with Krabbe disease, and others who carry one working GALC gene and one non-working gene (GALC+/GALC-), will have very little or no enzyme activity. So GALC is not available to break down cerebroside or psychosine. The accumulation of these lipids causes the demyelination, globoid cell formation and symptoms of Krabbe disease.
Because Krabbe disease is a genetic condition, healthy relatives of someone with Krabbe disease often wish to know their "carrier status", or if they carry one copy of a GALC- gene. Biochemical testing of their blood cells is the most common way of answering this question. If the person is a carrier, the enzyme activity seen in their cells is usually ~50% for the control range. However, carrier testing may be difficult due to the wide range for GALC activity seen in healthy people.
Prenatal diagnosis of Krabbe disease using a biochemical enzyme test is discussed below.
The instructions to make the components of our body are found in our DNA. These instructions are coded by four chemicals whose order, or sequence, along the DNA tells that cell how to make proteins.
The GALC+ gene has recently been isolated and the chemical code of the GALC+ gene determined. With additional research, direct analysis of DNA changes causing Krabbe disease my be found. This will lead to improved methods for diagnosis and carrier detection in the future.