Gene Mapping Of The Adult-form Autosomal Dominant Inherited Neuronal Ceroid-lipofuscinosis

The neuronal ceroid-lipofuscinoses(NCLs) are a large group of progressive neurodegenerative diseases with high phenotypic and genotypic heterogeneity. NCLs have originally been classified clinically by age of onset and clinical course: infantile form (INCL), late infantile form (LINCL), juvenile form (JNCL), adult form (ANCL, Kufs disease) and Northern Epilepsy (NE). In most cases, NCLs are inherited in an autosomal recessive manner, although some adult form cases are inherited in an autosomal dominant manner. Because of poor understanding of the pathogenesis, the research on this group of diseases had been limited before 1990's. Along with the development of molecular biology, positional cloning strategy was used to reveal the genetic basis of the diseases with unknown biochemical defects. So far six genes associated with NCL have been isolated and characterized: CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8. The CLN1 gene encodes palmitoyl protein thioesterase 1 (PPT1) while the CLN2 gene encodes tripeptidyl peptidase 1 (TPP1), CLN3, CLN5, CLN6 and CLN8, which encode novel transmembrane proteins, mutation in any one of these genes results in phenotype of NCL-disease. However, the gene responsible for adult-form NCL has not yet been identified.In the present study, we describe an US family named Parry with Kufs disease, which was inherited as an apparently autosomal dominant trait with full penetrance.Twenty-two individuals (eight men, fourteen women) have been affected over seven generations. The clinical course was strikingly consistent with onset at around 31 years of age and an average duration of seven years. Affected...