White Matter Diseases
Our research aim is to understand how translationally regulated processes impact health and disease in CNS white matter. We currently focus on preclinical studies and development of suitable in vitro models for the childhood white matter disorder vanishing white matter.
Childhood white matter disorders – MRI, genes, mechanisms and therapies
Childhood white matter disorders (CWMDs) constitute a large group of rare disorders. CWMDs are typically diagnosed by Magnetic Resonance Imaging (MRI) of the brain. Most CWMDs are genetic and lead to increasing motor difficulties, wheelchair dependency and early death. In more than half of the children, the cause for the white matter disease cannot be found.
Our group has been working on CWMDs since 1987. We have developed an MRI pattern recognition system that greatly facilitates the diagnostic process. Patients with the same disorder have a consistent and characteristic MRI pattern. Recognition of the pattern leads to a rapid diagnosis. The cause for the disease can then be found with a low number of tests, reducing emotional burden and costs. We also applied pattern recognition to a large set of MRIs of CWMD patients without a specific diagnosis and have identified multiple novel disorders by their characteristic and consistent MRI pattern.
After definition of a new disease, we start a search for its cause, most often a mutated gene. We have found the genes for several disorders. Our most exciting result was finding 5 genes for a disease called “vanishing white matter‚. We expect to find more genes. We also study the new disorders in detail clinically and look for genotype-phenotype correlations.
We investigate disease mechanisms in the newly defined disorders, for which we found the disease gene. We apply quantitative MRI techniques to obtain a better understanding of what is happening at tissue level. In addition, we use techniques, like histopathology and immunohistochemistry of brain tissue from deceased patients, cell culture and patch-clamp techniques. We have made multiple mutant mouse models for CWMDs. Our studies have demonstrated that the basic defect in vanishing white matter resides in mRNA translation and regulation of protein synthesis. The disease especially affects glia (astrocytes and oligodendrocytes), which have abnormal morphology and function. A defect in glial maturation appears to be part of the pathophysiology. Defects in protein synthesis as cause of CWMDs have become a special research focus.
The final goal of our studies is to use new insights into the disease mechanisms for development of treatment. Cell replacement therapy is being developed by Dr. Vivi Heine and her co-workers for vanishing white matter and perhaps other CWMDs. We will set up drug screening for a few CWMDs. The mouse models will be pivotal in the development and testing of such therapies. When treatment will be ready for human application, we will set up international trials. In the mean time, we optimize symptomatic treatment of patients with CWMDs. Treatment of spasticity is an important part of this.
Van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 2006; 5: 413-423
Scheper GC, van der Klok T, van Andel RJ, van Berkel CGM, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krägeloh-Mann I, Smeitink JAM, Florentz C, Van Coster R, Pronk JC, van der Knaap MS. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nature Genet 2007; 39: 534-539
Scheper GC, van der Knaap MS, Proud CG. Translation matters: inherited diseases that affect protein synthesis. Nature Rev Genet 2007; 8: 711-723