Neuronal ceroid lipofuscinoses: research update

This study describes the phenotype/genotype analysis of 159 probands with n euronal ceroid Lipofuscinosis (37 CLN1, 72 classic CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research i n Developmental Disabilities (IBR). Phenotype/genotype comparison showed th at mutations in the CLN1 gene were associated with different phenotypes: in fantile, late infantile, and juvenile. Two common mutations (223A-->C and 4 51C-->T) were found in 26 of 37 CLN1 subjects (64% of alleles examined). A nonsense point mutation, 451C-->T, was the most common in CLN1 subjects wit h infantile onset at 0-2 years, accounting for 50% of alleles studied. A mi ssense point mutation, 223A-->C, was the most common among CLN1 subjects wi th juvenile onset older than 4 years, accounting for 45% of alleles examine d. Twenty-one other CLN1 mutations were identified in 4 of 37 subjects with infantile onset, 6 of 37 with late-infantile onset, and 6 of 37 with juven ile onset. All CLN1 probands were palmitoyl-protein thioesterase (PPT)-defi cient and showed granular osmiophilic deposits (GROD) at the electron micro scopic (EM) level. In the group of classic CLN2 (72 probands), two common m utations were found: an intronic 3556G-->C transversion in the invariant AG of 3' splice junction in 55% of probands, and a nonsense mutation 3670C--> T in 30% of probands. Classic late-infantile onset (2-4 years) was found in 68 of 72 (95%) cases, whereas juvenile onset (> 4 years) occurred only in 4 of 72 (5%) cases. All probands had deficiency of tripeptidyl-peptidase I (TPP1) activity and, at the EM level, curvilinear profiles. Ten probands wi th late-infantile onset did not show mutations in the CLN2 gene, had normal TPP1 activity, and at the EM level had mixed profiles. Further studies are in progress to identify genetic defect(s) in these subjects. The CLN3 grou p (40 probands) was divided into two categories: classic or typical present ation, and delayed classic or atypical presentation. All CLN3 patients had onset of symptoms after 4 years of age. In 40 probands, the 1.02-kb common deletion was found in one or two alleles of the CLN3 gene. Homozygotes for the common CLN3 deletion showed the classic phenotype. The phenotype in com pound heterozygotes was either the classic or the delayed classic or atypic al form. Thus, our study indicates that some mutations in the CLN1 and CLN2 genes may be associated with juvenile onset of the disease process and a m ore benign clinical course. Interfamilial and intrafamilial variations also were found, especially in the speed of becoming blind and neurologically d isabled.