Normal and defective neuronal membranes: Structure and function - Neuronallesions in peroxisomal disorders

Neuronal involvement in the peroxisomal disorders is divided into two main groups: developmental and postdevelopmental or degenerative. In the former the major lesions are neuronal migration abnormalities, which vary from sev ere in the cerebro-hepato-renal (Zellweger) syndrome (ZS) to mild in neonat al adrenoleukodystrophy. More common, but much less severe, are defects in neuronal differentiation or terminal migration, particularly involving the inferior medullary olives. Ultrastructural and neurochemical observations i n ZS suggest that the presence of abnormal cytosomes in migrating neurons a nd radial glia, probably the result of excessive very long chain fatty acid s, are responsible in part for its major neocortical migration defect, para sylvian pachygyria-polymicrogyria. The postdevelopmental neuronal lesions i nvolve specialized sensory neurons of the retina and the inner ear, resulti ng in atypical retinitis pigmentosa and its consequent visual defects and s ensorineural hearing deficits. Neuronal atrophy and/or loss is seen in both the dorsal-root ganglia of adrenomyeloneuropathy and the atrophic cerebell um of rhizomelic chondodysplasia punctata. The underlying pathophysiology o f these neuronal lesions is postulated to be caused by the incorporation of abnormal fatty acids into neuronal membranes, leading to an unresponsivene ss to neurotrophic factors necessary for normal function and survival or to increased permeability of calcium channels and cell death.