Neurogenetics

On June 26, 2000, President Bill Clinton announced, “Today the world is joining us here in the East Room to celebrate the completion of the first survey of the entire human genome.” This date could be considered the beginning of a medical revolution. Since then, genomics has become affordable as a diagnostic tool, and high-resolution chromosomal arrays and next-generation sequencing methodologies are now routinely being used in clinical genetics practices. Large-scale genome-sequencing projects are ongoing worldwide. Saudi Arabia, the United Kingdom, and the United States have all launched projects that in total will sequence approximately 100,000 individuals' genomes. The number of central nervous system disease-associated genetic variants has grown exponentially over the last few years to several thousands, and is expanding on a daily basis. The application of transgenic technology in animal model systems has dramatically enhanced our insight into meticulously orchestrated molecular cascades and disease mechanisms. Although many neurologic diseases, such as intellectual disability, autism, and dystonia, were considered untreatable conditions just until a few years ago, it is certain that detailed clinical and molecular characterization of individuals affected by these conditions will allow us to discover novel therapeutic targets. In fact, close to 100 causes of intellectual disability and autism are already treatable if diagnosed early in life.

This utilization of large-scale gene-sequencing methods, such as whole exome sequencing, has not only drastically increased the yield for a molecular diagnosis in individuals with neurologic disease, but has also resulted in an expansion of the clinical phenotypes of monogenetic diseases. A prominent example of this expansion is the clinical spectrum of diseases associated with SCN1A gene mutations, which were first associated with Dravet syndrome and are now seen in individuals without epilepsy but with neurodevelopmental disabilities.

With this dramatic revolution in genomics, it is crucial that today's neurologist develops a systematic approach for the evaluation of patients that goes beyond anatomical localization, but also includes a molecular localization of disease-causing lesions. Although it is impossible to cover the thousands of genetic diseases that involve the central nervous system, the aim of this issue of Seminars is to provide the reader with a neurogenetic approach to diseases based on their clinical, neuroimaging, or biochemical patterns of presentation. We are honored that several world authorities in neurogenetics have provided these fantastic reviews, and would like to sincerely thank them for their contributions. The initial reviews focus on the genetic causes of various clinical presentations, including spastic paraplegia, dystonia, ataxia, epilepsy, and other paroxysmal disorders. Two articles focus on genetic diseases with characteristic neuroimaging features, followed by several articles on various categories of metabolic disorders. We believe that readers of Seminars in Neurology will benefit from these reviews in their clinical practice.