The neuronal ceroid-lipofuscinoses: From past to present

The neuronal ceroid-lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of children's progressive encephalopathies. Most childhood forms of NCL are clinically characterized by progressive loss of vision as well as mental and motor deterioration, epileptic seizures, and premature death, while the rare adult forms are dominated by dementia. All forms of NCL share common pathomorphological features. Autofluorescent, periodic acid-Schiff- and Sudan black B-positive granules, resistant to lipid solvents, accumulate in the cytoplasm of most nerve cells, and there is progressive and remarkably selective neuronal degeneration and loss. For a long time, the NCLs were grouped under the heading of the “amaurotic family idiocies” and conceived as lipidoses. However, in the late 1980ies and 1990ies the NCL storage cytosomes were shown to consist largely of two hydrophobic proteins: either subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D. Since 1995 numerous mutations in at least seven different genes have been shown to underlie the multiple human and animal forms of NCL. This review discusses the historical evolution of the NCL concept and the impact of the recent biochemical and molecular genetic findings on our views on the classification and pathogenesis of these devastating brain disorders.