Abstract
(Englisch)
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During the last decade pivotal research in the neuronal ceroid-lipofuscinoses (NCL), the most frequent neurodegenerative diseases in children, achieved by mapping and cloning genes on six different chromosomes, i.e. CLN1, 2, 3, 5, 6, 8 and by excluding other patients and families with NCL from being related to any of these known loci, hereby identifying at least two if not more unknown genes, those referring to CLN4 (adult NCL) and CLN7 (prevailing in Turkish families with NCL). Based on this initial success in elucidating NCL, formation ot his Concerted Action on NCL (ECA-'NCL') by connecting research groups from the European Union - and three other European countries - proved most fruitful to continue and even accelerate research and research achievements. For instance, while at the beginning ot the ECA-'NCL', i.e. January 1996, three genes for CLN1 and CLN3 have been identified - over a time-period of more than six years since the first localization of the CLN3 gene on chromosome 16 in 1989 - four more genes on four different chromosomes referring to additional four different clinical types of NCL were identified within a three-year period, i.e. CLN2, CLN5, CLN6 and CLN8. A collaborative network of ECA-'NCL' participating research groups resulted in the formation of a European Clinical Registry on NCL where families provided by ECA-'NCL' participants in different countries contributed to establish documentation of genetic heterogeneity of late-infantile NCL, commonly associated with CLN2, and to separation of CLN6 as an early-juvenile/late-infantile variant form of NCL as well as proposing CLN7 for Turkish NCL families with an early-juvenile/late infantile type by excluding them from all hitherto identified NCL gene loci.
Breakthroughs in the genetic spectrum of the NCL enabled more refined genetic counselling and prenatal diagnosis of several types of NCL in affected families. It further led to the recognition of respective gene products, i.e. two lysosomal enzymes, protein palmitoyl thioesterase (PPT) in CLN1 and pepstatin-resistant protease in CLN2 of lysosomal enzymes, and two proteins of lysosomal membranes in CLN3 and CLN5 which actually respresented hitherto unknown proteins of so far unknown function. These research data also showed than the NCL are clearly lysosomal.
Another minor break-through in elucidating the NCL occurred, when, contrary to the earlier assumption that the NCL were a peculiar form ot lipidosis; the discovery of subunit c of mitochondrial ATP synthase (SCMAS) and of the sphingolipid activator proteins (SAPs), showed proteins rather than lipids being the major components of the lipopigments accruing in NCL and, thereby, identified the NCL as protein-storing disorders or proteinoses rather than lipidoses. However, the storage ot these proteins within lipopigment residual bodies did not prove to be causative or of the same nosological significance as the intralysosomal accumulating substrates were in other classic lysosomal diseases. Hence, accumulation of these proteins in NCL lipopigments, dividing the group of NCL into SCMAS-forming ones and SAPs-producing ones, is still unexplanined and their relationship to respectively mutated genes ist still unknown.
It was at this time, when it was decided to form a European Concerted Action on NCL (ECA-'NCL') which was to unite and link several research groups acting in different countries of the European Union. This initiative proved to be both fruitful and successful because major research achievements have been provided by participants of the ECA-'NCL', especially groups of molecular genetics in London and Helsinki and clinicians. Foremost neuropediatricians, but also neurologists, had already assembled large numbers of families with various clinical form of NCL among their patients. Moreover, numerous neuropathologists in different countries of the European Union had long-standing experience in diagnosing NCL by electron microscopy. All these clinicians, neuropathologists, biochemists, and geneticists had published extensively on the NCL during their past professional lives by writing original articles, reviews, and textbook chapters. Thus, the platform für the ECA-'NCL' appeared well and solidly founded.
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