14800-DvRappard

15 General introduction 1 The cortex is usually spared from demyelination and oligodendrocyte loss. However, thinning of myelin, loss of neurons, reactive astrocytes and sulfatide containing granules have occasionally been observed. 15 MLD has always been seen as a primarily white matter disease. However, since sulfatide is a constituent of membrane lipid rafts, it is logical that its accumulation also affects neurons. The cerebral cortical gray matter (GM) and thalamic volume are already reduced at diagnosis, regardless of age at onset, inMLD patients compared to controls. 16 The neurons of the cerebral and cerebellar cortex hardly ever contain metachromatic materials with exception of the large pyramidal neurons. 17 At the end stage of the disease, especially in the adult onset type, patients suffer from dementia. Interestingly, in these patients the cortical neurons and axons are usually relatively spared, suggesting that the white matter degeneration is mainly contributing to the dementia. PATHOLOGY OF THE PERIPHERAL NERVOUS SYSTEM The accumulation of sulfatides in the PNS results in peripheral demyelinating neuropathy; characterized by severe slowing of motor and sensory conduction. Histopathology shows reduced density of large myelinated fibers and accumulation of sulfatides in macrophages and Schwann cells. 8 Disease mechanisms in the CNS and PNS have been hypothesized to be separable processes. The degree of damage to the PNS (as measured by nerve conduction velocity and sural nerve sulfatide levels) does not always correlate with CNS disease manifestations (degree of affected motor function or change in metabolite concentrations such as N-acetylaspartate (NAA) in the white matter measured by quantitative magnetic spectroscopy (MRS)). 18 Interestingly, the level of sulfatides in the cerebral spinal fluid (CSF) does not reflect the extent of central white matter injury, but is proportional to PNS damage. 19 The peripheral nerves are enlarged (and not thinned as a result of atrophy as would be expected in a neurodegenerative disease) on ultrasound in MLD, 20 probably as a result of the accumulation of metachromatic inclusions. STORAGE IN OTHER ORGANS The accumulation of sulfatides is not limited to the CNS and PNS, but also occurs in visceral organs, such as the gallbladder 21-23 which is further described in chapter 9 of this thesis. Other organs affected by the disease are intestines, adrenal glands, lymph