Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency

The infantile form of neuronal ceroid lipofuscinosis (NCL) has been well st udied in Finland, where there is a high carrier frequency (1:70) for a sing le mutation in the causative gene, CLN1, or PPT. We have recently studied a group of 29 NCL subjects in the United States with palmitoyl-protein thioe sterase (PPT) deficiency and described 19 different CLN1/PPT mutations in o ur population. In this report, we present a review of our previous findings , including a more detailed analysis of phenotype-genotype correlations, an d present previously unpublished data concerning the clinical manifestation s of the disorder in children of families with multiple affected members. O ur studies indicate that about half of PPT-deficient patients in the United States are very similar to Finnish infants with INCL, but that a different mutation (R151X) accounts for 40% of U.S. alleles, The Finnish mutation (R 122W) is rare in the United States. The other half of U.S. PPT-deficient pa tients develop symptoms after the age of 2 years, much later than Finnish p atients. One common mutation (the "Scottish" allele, T75P) accounts for 13% of alleles and results in a juvenile-onset phenotype that is clinically in distinguishable from JNCL with CLN3 mutations. Other rare mutations were al so associated with JNCL phenotypes, such as D79G and G250V. A preliminary e xpression study of two of these mutant enzymes supports the conclusion that juvenile-onset NCL (JNCL with GROD) is caused by missense mutations in the PPT gene that result in mutated enzymes with residual PIPT enzyme activity . (C) 1999 Academic Press.