PubMed2000
Neuronal ceroid lipofuscinoses represent a group of diseases which has until quite recently resisted definite elucidation of the underlying defect(s) on the molecular level. The common feature of all the NCLs is a serious and progressive neurological disorder, accompanied, with only few exceptions, by retinal degeneration. Visceral symptoms, despite the presence of the storage process, are absent, or minimal. There are many clinical variants of the disease process, among which a set of standard, historical phenotypes exists found to be linked to specific genotypes. The disorder is inherited and transmitted as an autosomal recessive trait. At the cellular level, it is featured by lyzosomal storage of autofluorescent hydrophobic material, the substantial part of which consists of hydrophobic proteins and esterified dolichol. The dominant protein is the subunit c of mitochondria ATP synthase. In one NCL type (NCL1) the dominant proteins are saposins A and D. Ultrastructural appearance is membranous with several relatively specific patterns with some tendency to condensation or, namely in NCL3 to vacuolar distension. Amorphous appearance is associated with NCL1. The impact of the disease process on the cell biology differs substantially depending on the cell type. The brain neurons are most seriously affected and degenerate, whereas other cell types mostly survive without detectable deterioration. Pathogenesis at the molecular level is now being elucidated using the modern molecular biology techniques, which have already enabled unravelling of a set of genes controlling majority of the standard historical phenotypes. The original infantile form of NCL (NCL1) is now defined as palmitoyl protein thioesterase deficiency (gen at the 1p32 locus), the late infantile form (NCL2) as pepstatin resistant proteinase deficiency (gen at the 11p15.5 locus) and the original juvenile form (NCL3) as a defect of the specific gene (locus 16p11.2-12.3), the product of which, the NCL3 protein, still lacks functional characterization. Two gene loci have been identified in the so-called early juvenile, or variant late infantile NCL. One of them is in the 13q21 locus (NCL5 or Finnish variant late infantile form), the second is in the 15q21-23 one (NCL6). Kufs form remains the least defined form of NCL. Recently two novel NCL variants were described with specific loci. Thanks to introduction of molecular genetic based diagnosis it was possible to recognize, besides the standard phenotype, existence of further phenotypic variants. The phenotype based scheme of NCL has thus been definitely substituted by classification based on genotype and biochemistry.