Hunting for genes and mutations

During the last 15 years, the identification of dozens or even hundreds of genes which, when mutated, cause inherited neurologic disorders has profoundly reshaped practically all areas of neurology. These discoveries have generated new classifications of heterogeneous “idiopathic” diseases, such as the spinocerebellar ataxias, the familial spastic paraplegias, and the hereditary neuropathies, based on the underlying genetic defects. They have provided unprecedented insight into the molecular pathogenesis, mostly through the study of transgenic animal models, and they have opened up new diagnostic possibilities, with all their promises and challenges.

Almost all of these discoveries rest on a statistical method called linkage analysis. Linkage analysis allows rough localization of the position of a gene, which is responsible for an observable, genetically determined trait (in this instance: the disease), which segregates in a family in a Mendelian (autosomal dominant, autosomal recessive, or X-linked) fashion, if a sufficient number of affected and unaffected family members are available for study.

Linkage analysis is based on the following observation: if two genetic loci are located on the same chromosome, the probability that they are passed on to the next generation together (“linked”) is inversely proportional to their distance …