title: Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency.
abstract: The infantile form of neuronal ceroid lipofuscinosis (NCL) has been well studied in Finland, where there is a high carrier frequency (1:70) for a single 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 thioesterase (PPT) deficiency and described 19 different CLN1/PPT mutations in our population. In this report, we present a review of our previous findings, including a more detailed analysis of phenotype-genotype correlations, and present previously unpublished data concerning the clinical manifestations of the disorder in children of families with multiple affected members. Our 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 (R122W) is rare in the United States. The other half of U.S. PPT-deficient patients develop symptoms after the age of 2 years, much later than Finnish patients. One common mutation (the "Scottish" allele, T75P) accounts for 13% of alleles and results in a juvenile-onset phenotype that is clinically indistinguishable from JNCL with CLN3 mutations. Other rare mutations were also associated with JNCL phenotypes, such as D79G and G250V. A preliminary expression 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 PPT enzyme activity.
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
authors: S L
authors: SL
authors: Hofmann
authors: A K
authors: AK
authors: Das
authors: W
authors: W
authors: Yi
authors: J Y
authors: JY
authors: Lu
authors: K E
authors: KE
authors: Wisniewski
mesh_terms: D017668:Age of Onset; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D008854:Microscopy, Electron; D016297:Mutagenesis, Site-Directed; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D013869:Thiolester Hydrolases / Q000172:deficiency* / Q000378:metabolism; D014162:Transfection
chemical_list: D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase