A maldevelopment of whatever cause should be present at birth and remain stable thereafter, that is, be nonprogressive, in contrast to the majority of metabolic diseases of infancy discussed in the preceding chapter. However, this principle requires qualification: The abnormality may have affected parts of the brain that have not matured at birth, so that an interval of time must elapse postnatally before the defect can express itself.
Many of the teratologic conditions that cause birth defects pass unrecognized because they end in spontaneous abortions. For example, defects caused by chromosomal abnormalities occur in approximately 0.6 percent of live births, but such defects are found in more than 5 percent of spontaneous abortuses at 5 to 12 weeks’ gestational age.
Regarding the genetic causes of malformations and developmental delay, much has been learned but a full picture of the genetic influences on these conditions remains incomplete. Whole chromosome karyotyping allowed the recognition of conditions such as Down syndrome and its association with triplication of the entire chromosome 21. As more refined techniques became available, such as high-resolution banding, subtle changes such as small deletions in chromosomal architecture became apparent, as occur in Angleman and Prader-Willi syndrome and fragile-X syndrome. What followed, by the use of linkage analysis and other genetic techniques, was the elucidation of single gene mutations that were obligatorily associated with malformations or developmental delays; most of the inherited metabolic disorders of infancy and childhood discussed in Chap. 36 are of this type but also certain gross malformations of the brain such as lissencephaly, discussed further on.
These were the forerunners of a completely different category of technical innovations, anchored by the original method of sequencing short lengths of part of a gene by the Sanger method and its derivatives. With the development of the polymerase chain reaction and automated methods, longer and longer sequences of genes could be studied. This has allowed large population studies, merged with statistical techniques that expose genes in affected individuals that may be responsible for disease and are not present in high frequency in the general populations. From there, the rapid evolution of technology able to analyze thousands of portions of DNA in parallel and compare numerous sequences to a reference library of DNA has revealed variants at the resolution of single base pairs, single nucleotide polymorphisms (SNPs). Most exploration of human disease has been, until recently, based on the “common disease–common variant” model, in which a disease is attributable to limited number variants that exist in more than 1 to 5 percent of a population. For example, five polymorphisms are each responsible for doubling or tripling the risk of macular degeneration. However, most of these variants are probably not themselves responsible for the disease.
These types of genetic changes do not appear to explain the majority of the various developmental diseases. The relatively novel concept of duplication or deletion of portions of genes, copy number variation, emerged as explanatory of some proportion of diseases such as autism as discussed further on. What is interesting about copy number variation is that they may give rise to several phenotypes of similar disorder, quite unlike conventional mendelian mutations. This indicates that copy number variants, like SNPs, probably are not usually directly causative of a condition but instead modulate other functions that express proteins. This is the situation for many of the forms of developmental abnormalities such as generic cognitive developmental delay, autism, and certain psychiatric diseases.
Continued advances in molecular diagnostic techniques have allowed for sequencing of the whole exome as a means of assessing the genetic code for mutations or other irregularities associated with neurodevelopmental diseases. These techniques and their utility in clinical practice are reviewed by Sherr and colleagues, Srivastava and colleagues, and by Fogel. In parallel, investigations into epigenetic phenomena, that is, heritable alterations to DNA or RNA that do not affect the genetic code itself (i.e., DNA methylation, histone modifications, non-protein-coding RNA) are shedding new light on the mechanisms of a variety of neurodevelopmental and neurodegenerative diseases (see Klein and Benarroch).