A novel leukoencephalopathy described on the basis of characteristic MRI findings is variable called "CACH" (= childhood ataxia with central hypomyelination) or "Vanishing white matter". (1-4). Although the MRI findings were described for the first time, similar cases had already been described in the pathology literature (reviewed in 4).
Usually, the early development of patients with VWM is normal. The first clear signs of the disease may occur in infancy or early-childhood, but also in late-childhood, adolescence or adulthood. So, the age of onset is extremely variable. The course of the disease is chronic and progressive with additional episodes of more rapid and severe deterioration. These episodes are precipitated by infections with fever and minor head trauma. In particular, following an infection with fever, the patients may deteriorate for days with loss of motor skills, loss of vision, epileptic seizures, vomiting, irritability, depressed consciousness and finally coma. Some patients die during the coma; others recover slowly, but never to the same level as before the coma. The motor signs consist of cerebellar ataxia and variable spasticity. Decreased vision due to optic atrophy occurs in some patients. The mental capacities are relatively preserved. The severity of the disease is highly variable. Some patients die in a couple of months; some patients become wheelchair-dependent in their thirties after many years of illness. A late onset does not guarantee a mild disease course.
The diagnosis of VWM is based on MRI findings. Other laboratory tests are not helpful in establishing a diagnosis. The MRI shows diffuse abnormalities of the cerebral white matter from early on, possibly from birth. We have had the opportunity of obtaining MRIs in presymptomatic patients and so far have always found diffuse cerebral white matter abnormalities. We did not see onset of the disease in siblings with a normal MRI. Over time, the abnormal white matter vanishes gradually, to be replaced by CSF or tissue water (figure 2). MRI may show other abnormalities, such as lesions in the basal ganglia, thalamus and brain stem. The cerebellar white matter may be involved and there may be cerebellar atrophy. However, these are not necessary to make the diagnosis.
At autopsy, a cystic leukoencephalopathy is found. Both axons and myelin sheaths disappear. It is a matter of debate which goes first: the myelin or the axon (4-7). The cerebral cortex remains normal. Within the abnormal white matter, an increased number of oligodendrocytes is consistently found, either because they are the only cells preserved or because they actually proliferate (4-6).
Figure A shows a transverse T2-weighted image of a patient with VWM; figure B shows the FLAIR image at the same level in the same patient. Figures C and D show the comparable T2-weighted and FLAIR images of a healthy child. The T2-weighted image demonstrates that the white matter is diffusely abnormal (white) in the VWM patient (A). Because CSF is always white on T2-weighted images, one cannot differentiate between abnormal white matter and tissue water or CSF. On FLAIR images, CSF is dark and abnormal white matter is white, making it possible to distinguish the two. The FLAIR image makes clear that part of the abnormal white matter has vanished and has been replaced by tissue water (B).
From the outset, it was evident that VWM is an inherited disease with an autosomal recessive mode of inheritance. Most patients are found in north west Europe and North America. In collaboration with Dr. S. Naidu from the Kennedy Krieger Institute we started to collect blood samples from families for a genetic linkage study. Many families generously donated blood samples. Firstly, we found linkage between the inheritance of VWM and chromosome 3q27. A Dutch "founder effect" helped us to narrow down the possible location of the gene. We noted that most Dutch families came from the Eastern part of The Netherlands and genealogical studies revealed that these families share a common ancestor, the "founder", who lived around the year 1800. This ancestor must have introduced the gene defect into the local population (8). The patients from these families all shared the same genetic markers on chromosome 3q27. We also found this combination of markers in some American patients, who must share an ancestor with the Dutch patients. Although the critical region was narrowed down with the genetic information from these families, there were still 25 candidate genes in this region. The 13th gene that we analyzed for mutations was EIF2B5 . We found 16 different mutations in 29 patients from 23 families, showing that EIF2B5 is a gene responsible for VWM (9).
In several families we did not find linkage with chromosome 3q27 nor mutations in EIF2B5 . EIF2B5 encodes the epsilon-subunit of the translation factor eIF2B (see below for more details). eIF2B consists of five different subunits and the logical next step was to see whether the other families would show linkage with the chromosomal region of the other eIF2B-subunit genes. Two Dutch families came from the Southern part of The Netherlands. Genealogical studies showed that they must have shared ancestors. These families showed linkage with chromosome 14q24, where the gene EIF2B2 is located. We found 6 different mutations in 5 patients from 5 families, showing that defects in EIF2B2 may also lead to VWM. We analyzed the remaining patients and found mutations in EIF2B1 in one patient, in EIF2B3 in 2 patients, and in EIF2B4 in 2 patients (10). We could not find mutations in 2 patients. Both were atypical from the clinical and MRI perspectives. They probably do not have VWM (10).
EIF2B1, EIF2B2 , EIF2B3 , EIF2B4 and EIF2B5 code for the alpha-, beta-, gamma-, delta- and epsilon-subunit of eIF2B, respectively. eIF2B is a factor that is essential in the production of all proteins in the body. DNA is transcribed into RNA; RNA is translated into proteins. eIF2B plays an essential role in the initiation of translation of all proteins. It is also important in the regulation of protein synthesis. In conditions of stress, such as fever, proteins may coagulate. One of the defense mechanisms of the cell is to decrease the production of proteins to prevent this abnormal coagulation of proteins. In febrile conditions, eIF2B may be the most important factor to decrease protein production.
With this information, there are now some features of the disease that we understand. So far, we did not observe patients with two mutations that would destroy the eIF2B activity completely. We always found one or, more often, two "mild" mutations. Life is only possible if some eIF2B activity remains. We also understand now more about the sensitivity of VWM patients to conditions of stress, such as fever, although we do not yet know the mechanism at a cellular level. Possibly, the mutated eIF2B has sufficient activity for normal conditions but fails to decrease the protein production under stress. If this is the case, the proteins that are still produced under stress could coagulate. Another possibility is that the mutated eIF2B is labile and that the recovery of protein synthesis after stress fails. It is difficult to understand why the patients only have a brain disease and why other organs are not involved. It may be that the structures most sensitive to the detrimental effects of protein plugs along the axons, the very long and very thin extensions of neurons. The research goes on. We have started cellular studies to try to find out what exactly goes wrong during and after stress.
The direct consequence of our findings is that we know now that certain stress conditions should be avoided in patients with VWM. It is important to keep the temperature down with medication, if necessary with cooling, and to be liberal with antibiotics. In children with frequent upper respiratory tract infections, one may consider daily low-dose antibiotics. Another option is the flu-vaccination. One patient reports that she is worse after sun bathing. Playing for a long time in the full sun during hot weather may be something to avoid. It is impossible to avoid the minor head traumas of daily life, but it is better to avoid certain types of physical contact sports. We now can offer prenatal diagnosis, meaning that families in which we have found mutations can also have healthy children. Some families have been waiting for this option for a long time. We cannot yet cure patients. We will try to find drugs to ameliorate the disease process, but this may take a long time.
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