Vanishing White Matter Disease

Vanishing white matter disease 1 (VWM) is a puzzling leukoencephalopathy caused by mutations in any of the five genes encoding eukaryotic translation initiation factor 2B (eIF2B), an ubiquitously expressed protein complex with a crucial role in initiation of mRNA translation for virtually every protein in the human body. VWM is one of the most prevalent inherited childhood white matter disorders 6 , but the disease may occur at all ages. 7,8 Most patients with VWM show signs of progressive neurologic deterioration with predominantly signs of motor dysfunction. In the past years it has become known that the clinical spectrum is extremely wide with, for example, migraines, psychiatric symptoms and presenile demen-tia as start of the disease at older age. In some patients the disease also affects other organs, especially the ovaries. Only in patients with the most severe variant of the disease, the antenatal onset variant, other organs can be affected as well. 7-12 The list of known VWM causing mutations is still expanding. 8,13 The disease is fatal. There is no specific treatment for VWM. Management is at present supportive. 8 Typical findings on MRI are symmetrical diffuse abnormality of the cerebral hemispheric white matter with rarefaction and cystic degeneration in a " melting-away " pattern. 1,7 Neuropathologi-cal findings show a cavitating white matter disease with meagre reactive gliosis and involvement of the glial lineage with a maturation defect of astrocytes and oligodendrocytes. The link between the selective vulnerability of the white matter of the brain and the mutated eIF2B protein complex is not understood. The main goal of this thesis was to increase our understanding of the phenotypic variation and the correlation between genotype and phenotype in VWM. The disease onset, clinical severity and disease course of VWM patients vary greatly. 7-12 Large studies on phenotypic variation in VWM are scarce. Chapter 2 provides data collected and analyzed from our VWM patient database, the largest cohort so far, to gain more systematic knowledge on the clinical variation in VWM. Data were collected on prevalence and characteristics of subgroups of patients defined by age of onset. The large clinical spectrum of VWM was confirmed in the dataset. The VWM disease spectrum consists of a continuum of phenotypes with extremely wide variability. The spectrum continues to expand on both extremes suggesting that even more extreme phenotypes are currently missed. The division in certain age of onset groups is arbitrary, though …