Molecular biology of neurological diseases.

Picture the scene. Neurologist on the telephone to a Departmental Librarian on a Friday morning. The last 5 years have seen a major transformation in neurology, particularly in the understanding of those disorders where inheritance is either auto-somal dominant, recessive or X-linked. Collaboration between Departments of Molecular Genetics and Neurology has developed to a point where gene markers for many ofthese disorders have now been identified. Although inherited neurological diseases are by no means the commonest conditions seen in the average neurology clinic, the unravelling of the aetio-pathogenesis using the techniques of molecular biology"2 has been scientifically intriguing and exciting in its own right but also is offering clues to the basic mechanisms underlying neuro-logical3 and in particular neuromuscular disorders .4 As is usually the case, any sort of information explosion spawns its own literature and terminology which is often sufficient to frighten off even the most dedicated academic neurologist. Because the work is carried out in the field of basic science, information frequently appears as letters to Nature or Science and therefore to have any hope of keeping up to date, neurologists now have to have access to journals which they probably thought they would last consult when they were working for their M.D.! The steps involved are however quite simple, and are: (a) chromosome localization and linkage; (b) fine mapping; (c) identification ofgene mutation(s); (d) function of the gene and (e) rational therapy. For the majority of neurological disorders, studies are currently at phases (a) or (b); a few are getting towards (c); one is at (d) and potentially one is getting towards (e). Clearly localization of the abnormal chromosome is easy in the X-linked disorders (e.g. Duchenne/Becker disease); however , where does one start to look for the chromosome involved in, for example, myotonic dystrophy? Throughout the genome, there are well recognized fragments of DNA whose chromosome localization is precisely known (e.g. Duffy blood group, chromosome 1 and MHC on chromosome 6). Various other markers have been identified in the autosomes (about 700 to date) and the first step in analysis is to look for linkage between the known chromosome markers and the family in whom the disease has been inherited.5 Such linkage is said to be found when the LOD score (LOD being the logarithm of the probability ratio of the known marker co-segregating with the putative disease marker) is greater than 3 (or odds of …