Enzyme-based Diagnosis of Classical Late Infantile Neuronal Ceroid Lipofuscinosis: Comparison of Tripeptidyl Peptidase I and Pepstatin-insensitive Protease Assays

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative diseases that include infantile NCL (INCL; OMIM 256730, where the defective gene is CLN1 ), classical late infantile NCL (LINCL; OMIM 204500, where the defective gene is CLN2 ), two variant late infantile NCLs (OMIM 256731, where the defective gene is CLN5 ; and OMIM 601780, where the defective gene is CLN6 ), juvenile NCL (JNCL; OMIM 204200; defective gene, CLN3 ), a juvenile onset epilepsy with progressive mental retardation (EPMR; OMIM 600143; defective gene, CLN8 ), and adult NCL (Kufs disease; OMIM 204300; defective gene, CLN4 ) [reviewed in Ref. (1)]. Patients experience a progressive and profound loss of neurons in the central nervous system that generally is associated with increasingly severe epileptic seizures, visual failure, ataxia, mental deterioration, and early death. At the cellular level, the NCLs are characterized by accumulation of autofluorescent storage material in lysosome-like organelles in neurons and other cell types. Different forms of NCLs have traditionally been classified on the basis of age of onset of symptoms and cellular morphology and, more recently, by molecular criteria. Molecular analysis has revealed that different mutations in a given NCL gene can produce distinct clinical presentations [e.g., CLN2 deficiencies can lead to late infantile as well as juvenile onset disease (2), CLN1 deficiencies to infantile as well as late infantile and juvenile onset disease (3), and CLN3 deficiencies to juvenile as well as delayed onset disease (4)(5)]. Because of the existence of multiple NCL disease genes that can have overlapping clinical manifestations, simple clinical assays for NCL classification are useful before proceeding to DNA-based analysis. Enzyme-based assays are now available for diagnosis of CLN2 deficiencies. The CLN2 gene encodes a lysosomal protein (6) that has sequence similarity to bacterial pepstatin-insensitive endoproteinases (7). We …