John B. Bodensteiner, MD
Dr. Bodensteiner is Director of the American Board of Psychiatry and Neurology, Founding Editor and Senior Associate Editor of Seminars in Pediatric Neurology, and Senior Associate Editor of the Journal of Child Neurology.
The impetus for this article is the celebration of 25 years of publication of Neurology Reviews. Child Neurology has advanced so much in these years that it is hardly recognizable from the previous state of our understanding. Many components of the discipline include, but are not limited to, epilepsy, headache, demyelinating diseases, autoimmune diseases, neoplastic, neonatal, neuromuscular disease, and developmental conditions. My interest has been related to the neuromuscular diseases of childhood. Thus, I have chosen to describe some of the ways the advances in basic medical science and our understanding of the genetic and molecular mechanisms of disease have altered the way we think about these conditions. For the first time, this knowledge has allowed us to identify targets and techniques for effective intervention and disease modification.
Myotonic Muscular Dystrophy
One example of how the advancement in the discipline of genetics has changed our understanding of disease would be myotonic muscular dystrophy (MyoD1). When I started seeing patients in the mid 1960s, MyoD1, particularly as seen in children, was recognized as an example of autosomal dominant inheritance. The tendency for subsequent generations to be more severely affected than their parents is a phenomenon known as anticipation. Anticipation was recognized, though not explained, with the understanding of the genetic mechanisms of the time. The fact that when the disease affected an infant or newborn it was almost always inherited from the mother was also well established, though the reason for this was also not understood. Actually, during the late 1970s and early 1980s the existence of the phenomenon of anticipation was widely questioned and some publications proposed that anticipation was just an artifact of observation due to the fact that we (medical clinicians) were getting better and thus identifying the disease earlier than in past years. The recognition of the importance of repeated segments of DNA in the pathogenesis of human disease and the subsequent development of the technology to study the phenomenon allowed recognition of this previously unappreciated mechanism of genetic disease causation. This new genetic mechanism explained how anticipation could occur and confirmed it as a real phenomenon. Expanded numbers of tandem repeats probably allowed the explanation of the difference in gene transmission related to the parental gender as well.1
Advancements in the understanding of genetic mechanisms of disease have made it possible to begin to identify the molecular mechanisms operating in many previously incomprehensible diseases. The development of laboratory techniques necessary for the identification of these genetic abnormalities has brought the recognition of these disease mechanisms into clinical practice. Twenty-five years ago, the ability to identify alterations in DNA sequences, the presence of deletions/duplications and expansion of trinucleotide repeats, as well as the determination (and recognition of the significance) of gene copy number, was not available to the clinician. This advancement in genetic understanding has, in turn, allowed the identification of therapeutic targets in the hope of being able to moderate or eliminate the consequence of the defective gene.