Hereditary components in the neurodegerative diseases: Alzheimer's disease and myotonic dystrophy

Abstract

RECENT progress in molecular genetics has, in the case of many diseases, permitted detection of specific mutations preceding understanding of disease mechanisms. Diseases of the nervous system are now beginning to benefit from this progress and the complex roles of mutant genes in neurological disorders previously thought not to be hereditory are starting to come into focus. Appreciation of complex interactions between gene expression, cellular aging, and environmental factors may hold the key to our understanding of neurodegenerative disorders. Late age of onset and characteristic anatomic distribution of neuronal system involvement characterize neurodegenerative diseases. Clinical and pathologic signs and symptoms of specific neuronal families characterize motor neuron disease, basal ganglial diseases including Huntington's Disease and Parkinson's Disease, and diseases of cognition including Alzheimer's Disease. Most late-onset neurodegenerative diseases appear to be sporadic initially, rather than clearly segregating as classical Mendelian traits. The hereditable component may have been poorly recognized because of short life spans and before the advent of molecular genetic markers that could be tested in large families for statistical linkage calculations. The study of genes that can lead to early selective neuronal cell death have produced a wealth of candidates in simpler systems that await a definition of relevance to disease processes affecting man. During the past decade positional genetic strategies have led to the discovery of previously unknown genetic loci for classically inherited diseases such as Duchenne dystrophy (5), neurofibromatosis (5,14,15) cystic fibrosis (11), myotonic dystrophy (1,4), and many others. As comparative genetic maps become more complete, the location of particular candidate genes that could make sense for positionally localized diseases leads rapidly to direct testing for mutations. Recent examples of candidate gene testing include the Na ÷ channel gene mutations found in hyperkalemic periodic paralysis and paramyotonia (9), prion gene mutations associated with Creutzfeld-Jacob and Gerstmann-Straussler diseases (3), and specific mutations of the amyloid precursor protein associated with a rare form of early onset Alzheimer's Disease (APP770 TM) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (APP770693glu-) (2,6). The study of mechanisms of disease resulting from specific mutations has clearly lagged behind the discovery of the site of mutation. This, of course, is not a new phenomenon in medical science. The specific mutation causing sickle cell disease was known for years before the mechanism of sickling was studied fully.