Neuronal Ceroid Lipofuscinosis. Closing Chapter of a Long Story

Overview

Neuronal ceroid lipofuscinoses represent a group of diseases which has until quite recently resis-ted definite elucidation of the underlying defect(s) on the molecular level. The common feature ofall the NCLs is a serious and progressive neurological disorder, accompanied, with only fewexceptions, by retinal degeneration. Visceral symptoms, despite the presence of the storage pro-cess, are absent, or minimal. There are many clinical variants of the disease process, amongwhich a set of standard, historical phenotypes exists found to be linked to specific genotypes. Thedisorder is inherited and transmitted as an autosomal recessive trait. At the cellular level, it isfeatured by lyzosomal storage of autofluorescent hydrophobic material, the substantial part ofwhich consists of hydrophobic proteins and esterified dolichol. The dominant protein is thesubunit c of mitochondria ATP synthase. In one NCL type (NCL1) the dominant proteins aresaposins A and D. Ultrastructural appearance is membranous with several relatively specificpatterns with some tendency to condensation or, namely in NCL3 to vacuolar distension. Amor-phous appearance is associated with NCL1. The impact of the disease process on the cell biologydiffers substantially depending on the cell type. The brain neurons are most seriously affectedand degenerate, whereas other cell types mostly survive without detectable deterioration. Patho-genesis at the molecular level is now being elucidated using the modern molecular biology techni-ques, which have already enabled unravelling of a set of genes controlling majority of thestandard historical phenotypes. The original infantile form of NCL (NCL1) is now defined aspalmitoyl protein thioesterase deficiency (gen at the 1p32 locus), the late infantile form (NCL2) aspepstatin resistent 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 prote-in, still lacks functional characterization. Two gene loci have been identified in the so-called earlyjuvenile, or variant late infantile NCL. One of them is in the 13q21 locus (NCL5 or Finnish variantlate infantile form), the second is in the 15q21-23 one (NCL6). Kufs form remains the least definedform of NCL. Recently two novel NCL variants were described with specific loci. Thanks tointroduction of molecular genetic based diagnosis it was possible to recognize, besides the standard phenotype, existence of further phenotypic variants. The phenotype based scheme of NCLhas thus been definitely substituted by classification based on genotype and biochemistry.

Key words:
neuronal ceroid lipofuscinosis - lysosomal storage - molecular pathogenesis - classifica-