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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 
Genetic Insights
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.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.
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
Genetic Insights
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.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.
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
Genetic Insights
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.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.