Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCLs) are a group of severe neurodegenerative diseases with onset usually in childhood and characterised by the intracellular accumulation of autofluorescent storage material. Within the last decade, mutations that cause NCL have been found in six human genes (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8). Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice. Approximately 160 NCL disease-causing mutations have now been described (listed and fully cited in the NCL Mutation Database, http://​www.​ucl.​ac.​uk/​ncl/​). Most mutations result in a classic morphology and disease phenotype, but some mutations are associated with disease that is of later onset, less severe or protracted in its course, or with atypical morphology. Seven common mutations exist, some having a worldwide distribution and others associated with families originating from specific geographical regions. This review attempts to correlate the gene, disease-causing mutation, morphology and clinical phenotype for each type of NCL.