Neuropediatrics 2006; 37 - CS1_6_3
DOI: 10.1055/s-2006-943558

PATHOGENESIS AND MOLECULAR BIOLOGY OF LEUKODYSTROPHIES

MS van der Knaap 1, PKI Boor 1, B van Kollenburg 1, JC Pronk 1, GC Scheper 1
  • 1VU University Medical Center, Amsterdam, The Netherlands

A leukodystrophy can be defined as a progressive disorder of the white matter of the brain caused by a genetic defect. In contrast to previous definitions, this definition does not request that myelin is primarily affected. The adapted definition takes into account the fact that leukodystrophies are primarily diagnosed by conventional MRI, which usually cannot distinguish between white matter abnormalities related to primary involvement of myelin and white matter abnormalities related to other processes.

There are many different genetic defects underlying leukodystrophies and their number is still growing. They involve very different aspects of cellular metabolism, including lipid metabolism, amino acid and organic acid metabolism, sugar and polyol metabolism, copper metabolism, protein synthesis and folding, energy metabolism, and DNA repair. The genetic defects of leukodystrophies may involve structural proteins like myelin proteins, intermediate filaments and members of the dystrophin-associated glycoprotein complex. Leukodystrophies may also be related to genetic defects that lead to vascular abnormalities.

In the context of this lecture, we will focus on the pathogenesis of recently detected leukodystrophies, including “vanishing white matter disease” (VWM) and “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). The genetic defect underlying VWM involves either of the five subunits of translation initiation factor eIF2B. Despite the fact that the basic defect resides in house-keeping genes, most organs of the body remain intact and astrocytes and oligodendrocytes are selectively affected. In MLC, the genetic defect involves MLC1, a membrane protein located in astrocytic endfeet as part of the blood-brain and CSF-brain barriers. A novel pathogenetic mechanism underlying the extensive cerebral white matter abnormalities in MLC will be discussed.