Pheno/genotypic correlations of neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal rec essive lysosomal storage disorders with both enzymatic deficiency and struc tural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (IN CL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Mo st patients with NCL have progressive ocular and cerebral dysfunction, incl uding cognitive/motor dysfunction and uncontrolled seizures. After reviewin g 319 patients with NCL, the authors found that 64 (20%) did not fit into t his classification of NCL. With research progress, four additional forms ha ve been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with me ntal retardation. These eight NCL forms resulted from 100 different mutatio ns on genes CLN1 to CLN8 causing different phenotypes (http://www.ucl.ac.uk /ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioester ase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene- encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based o n C-P findings, enzymatic assay, and molecular genetic testing. Before bioc hemical and genetic tests are conducted, ultrastructural studies (i.e., blo od [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional em phasis on age-related NCL forms.