The neuronal ceroid-lipofuscinoses.

The neuronal ceroid-lipofuscinoses, a group of progressive neurodegenerative diseases in children and in adults, have now been recognized for some 90 years, and the childhood forms represent one of the largest groups of progressive neurodegenerative diseases in children. Apart from a core group of major clinical forms-the infantile, the late-infantile, the juvenile, and the adult forms--numerous atypical patients afflicted with neuronal ceroid-lipofuscinosis have now been identified, constituting 10% to 20% of all patients with neuronal ceroid-lipofuscinosis. These "atypical" patients have, over the past 10 years, prompted the suggestion of 15 atypical variants or minor syndromes, many of them displaying the lipopigments of classic curvilinear and fingerprint ultrastructure, but others displaying granular osmiophilic deposits. The former lipopigments contain the subunit C of the mitochondrial adenosine triphosphate synthase, but lipopigments of the granular osmiophilic deposits including the classic infantile type Santavuori-Haltia, apparently do not, the latter type exhibiting sphingolipid activator proteins. The nosologic significance of both the subunit C of the adenosine triphosphate synthase and the sphingolipid activator proteins, although they make up a considerable amount of the crude auto-fluorescent lipopigments in neuronal ceroid-lipofuscinosis, is still unclear. In spite of numerous pathogenetic principles invoked, such as a defect in lipid peroxidation, abnormalities of dolichols and dolichol phosphates, and defects in protease inhibitors, precise pathogenesis and etiology of the neuronal ceroid-lipofuscinoses remain elusive. Recent promising molecular genetic studies have, however, revealed the gene for infantile neuronal ceroid-lipofuscinosis, CLN1, on chromosome 1p32; the gene for juvenile neuronal ceroid-lipofuscinosis, CLN3, on chromosome 16p12.1-11.2; and the gene for a Finnish variant of late-infantile neuronal ceroid-lipofuscinosis, CLN5, on chromosome 13q31-32. The genes for classic late-infantile neuronal ceroid-lipofuscinosis, CLN2, and for adult neuronal ceroid-lipofuscinosis, CLN4, have not been located, the former having been excluded from chromosomes 1 and 16. However, the gene products of the normal allelic forms have not yet been identified. A considerable number of sporadic animal models is now available, largely equivalent to the juvenile and infantile forms of neuronal ceroid-lipofuscinosis, with those of the English setter and the South Hampshire sheep evaluated best. Recently, several mouse models have been added to this list of autosomal-recessive models, again the one most thoroughly studied being the motor-neuron disease mouse. Progress has also been made in the prenatal diagnosis of neuronal ceroid-lipofuscinosis: now the infantile, late-infantile, and juvenile forms can be recognized prenatally by a combined genetic and electron microscopic approach.