Preface to the Fifth Edition

Roger N. Rosenberg

Juan M. Pascual, Editors

We are publishing the fifth edition of the Molecular and Genetic Basis of Neurological and Psychiatric Disease. The first edition appeared in 1993 followed by editions in 1997, 2003, and 2008. We are most grateful for the foresight, dedication, and authorship of our former editors for the success of the first four editions. They are Stanley B. Prusiner, Salvatore DiMauro, Robert L. Barchi, Louis M. Kunkel, Henry L. Paulson, Louis Ptáček and Eric J. Nestler. The fifth edition is edited by Roger N. Rosenberg and Juan M. Pascual.

There are several major new aspects to the fifth edition: The text now includes well over 100 chapters and 200 contributors. Every chapter has been thoroughly updated either by previous contributors or by new experts in the field, all of which are of international renown. A standard, unified chapter format has been followed as much as possible. Most illustrations are new or have been newly drawn, and color has been used wherever helpful throughout the text. The book is available both in print and in up-to-date electronic format. Additional new chapters in this edition cover the following topics: DNA sequencing and other methods of exonic and genomic analysis; pharmacogenomics; causation and association; stem cells and therapeutic development; neuroimaging; genetic counseling; the ethics of cognitive enhancement and mental impairment; cerebral malformations; global developmental delay and intellectual disability; neurodegeneration with brain iron accumulation; pantothenate kinase deficiency; Wilson disease; Menkes disease and other ATP7A disorders; disorders of manganese transport; aceruloplasminemia; neurotransmitter disorders; frontotemporal dementias; dystonia; glioblastoma; tuberous sclerosis; von Hippel–Lindau disease; Sturge–Weber syndrome; incontinentia pigmenti; channelopathies; vanishing white matter disease; pyruvate metabolism and Krebs cycle disorders; pain; vasculopathies; coagulopathies; sickle cell disease; and autism. Clearly, neurogenics/neurogenomics has advanced rapidly and is now poised to develop in the next decade effective targeted neurotherapeutics.

In the 21 years spanning the five editions of our book, molecular genomic analyses of the human genome have been implemented seeking the genetic basis for natural selection providing biological fitness and also risk of developing disease. Genome-wide association studies (GWAS) seeking gene variations, single nucleotide polymorphisms (SNP), causal of several human diseases have been conducted in recent years including autism, schizophrenia, obesity, diabetes and heart disease.

Several GWAS for risk association with neurological diseases, neuromic studies, have been reported. An increased risk for amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), restless leg syndrome (RLS), and multiple sclerosis have been associated with polymorphisms in specific genes. These observations have advanced an understanding of the causation of inherited, complex polygenetic, multifactorial neurological diseases. They have been made possible by the publication of the human genome and haplotype studies (HapMap analyses).

The hope with neurome-wide association studies has been that the complete complement of variant genes will be identified causal of the major neurodegenerative diseases. Then, pharmaconeuromic therapy would not be far behind. GWAS has provided new and important data of the major genes responsible for major human traits and common diseases. GWAS has provided insights into gene variations in low penetrant genes causal for polygenetic, multifactorial neurological disease, such as Alzheimer disease. Overall, about 400 genetic variants have been identified that contribute to human traits and diseases including neurological diseases.

Sequencing candidate genes for disease including their surrounding regions in thousands of people will be needed to discover more associations with disease. SNPs are turning out not to be a stringent enough level of analysis seeking genetic risks for disease. The change in mindset is going from seeking analyses of common, low-penetrance variants causal of common diseases to seeking rare low- or moderate-penetrance variants that have been missed by GWAS. It may be necessary to move beyond sequencing candidate genes and surrounding regions for disease association and begin sequencing whole genomes to find the missing heritability. Francis Collins, Director of the National Institutes of Health, has suggested that the 1000 genomes project, designed to sequence the genomes of at least 1000 people from all over the world, would provide a powerful approach to finding the hidden heritability.

The genetic explanations that would be of primary interest to find the missing heritability for genetic neurological disease missed by GWAS include copy-number variation (CNV), epistatic effects, and epigenetics. CNV refers to regions of DNA that are up to hundreds of base pairs long that are deleted or duplicated between individuals. There are strong CNV associations between schizophrenics compared to normals and they may arise de novo in persons without a family history of the mutation. Epistasis, where one or more modifying genes reduce or enhance the effect of another gene, may be an important genetic mechanism at work to explain heritability not found by GWAS. Epigenetics is another vital area to be explored. It refers to changes in gene expression that are inherited but not caused by alteration in the sequence of the gene. We now know that gene expression is altered by methylation or acetylation, and also by inhibition of messenger RNA expression by iRNA or microRNA binding.

The 21,000 protein-coding genes in the human genome make up less than 1.2% of the human genome. Analysis of the remaining 98.8% of the human genome and its role in the causation of human neurological diseases, both inherited and acquired, is a formidable challenge yet unexplored to any degree. RNA transcripts and their effects on regulation and levels of gene expression is one of the next frontiers for neuromics.

Then there is the issue that natural selection only functions before or during the reproductive years and not afterwards, when Alzheimer disease and Parkinson disease occur. Natural selection has as its major biological function to select for fitness allowing for reproduction and maintenance of a lineage or species. Aging and neurodegenerative diseases seem to have escaped the forces of natural selection by occurring after the reproductive years. On the other hand, perhaps evolution has actually selected for aging and neurodegenerative diseases as a means to maintain the limits of a finite lifespan. Clearly, neuromics must address the molecular basis of brain aging and why the aging process provides a permissive environment to allow the opportunistic neuromic program causal of late-onset neurodegenerative diseases to be expressed.

The cause of Alzheimer disease is due both to genetic polymorphisms and environmental stimuli. In this view, environmental stimuli, to be determined, influence the production of an abnormal pattern of gene expression causal of Alzheimer disease. So, we will have to understand the process of natural selection in the context of the selection pressures from the environments that we inhabit. Darwin emphasized adaptation to a changing environment as the principal selective influence for evolution. This principle is valid studying the interaction of environmental stimuli and the genetic factors causal of neurodegenerative diseases.

Deriving induced pluripotential stem cells from late-onset Alzheimer disease patients and differentiating them into neuroblasts would be one way to screen compounds to see if an abnormal pattern of gene expression is produced compared to derived neuroblasts from normal controls. Here would be a method to link environment to the genetic program causal of Alzheimer disease. It would also be a means to screen potential therapeutic agents that correct an abnormal pattern of gene expression seen in AD patients as a prelude to a clinical trial.

The 200 years since Charles Darwin’s birth, 150 years since the publication of On the Origin of Species, and the 20 years of the publication of the four editions of this book, is a brief time in human experience. The fifth edition builds on the development of neurogenetics during the past 20 years and documents the advances in genome sequencing, CNV, epistasis, epigenetics, RNA regulation of gene expression, and stem cell applications to decipher how mutations in these genetic functions are causal of neurological diseases.

We look forward to future editions of the book and wish to express our gratitude to our many loyal colleagues who have participated in all five editions, and thank our new authors for their contributions to maintain the book’s scientific rigor and excellence. Whereas we have made every effort towards comprehensiveness and clarity, many omissions and imprecisions are bound to remain. To that effect, we will welcome comments and suggestions at Rosenberg5ed@gmail.com. We have retained the names of Hugo W. Moser and John H. Menkes through the kindness of their families to honor their memory. The outstanding editorial contributions of Kristi Anderson, project manager, Mica Haley, publisher for neuroscience, and Julia Haynes, book production project manager, are most gratefully acknowledged. We are also thankful to our families, patients, colleagues and trainees both for interactions and for lost time while we were working on the fifth edition. While a textbook on the human experience of...