Clinical genetics is a relatively new discipline in medicine. Specialists exclusively practicing as geneticists began to appear in the 1960s. Slowly, the number of practicing clinical geneticists has risen to a little over 1000 by 2007. But this still only represents 0.18% of all practicing physicians in the United States. For much of the past five decades, the majority of the work done by genetic physicians has focused on diagnostics. Geneticists are skilled in the evaluation of individuals and families in an attempt to identify the etiology of a particular condition or set of symptoms. The identification of an etiology is a critical piece of the health care of an individual. For many people, simply knowing "why" is important for their own piece of mind and for dealing with the particulars of the condition. Knowing the cause can also help the family in many other ways such as identifying co-morbid conditions, defining prognosis, and for recurrence risk counseling.
In the realm of clinical genetics, therapeutics has always tended to lag behind diagnostics. Still, the role of the physician has traditionally focused not just on diagnostics, but on treatments. There are many reasons for this discrepancy. In Chapter 11 we discussed the amazing and rapid advances in genetic testing and screening. These advances continue to increase diagnostic yields and the amount of information that can be given to families. For the foreseeable future, clinical geneticists will continue to play a major role in the discovery of the causes of disease spurred by the ever-increasing number of powerful molecular tools that are constantly being introduced. In this section we will highlight the second aspect–therapeutics. The past 10 years has seen a dramatic rise in the number of therapeutic options that the geneticist has to work with. While the therapies employed by the geneticist may not be as tangible as the removal of an inflamed appendix, these are treatments all the same.
It is important to note that geneticists are not the only physicians who utilize genetic therapies. Oncologists, for example, have used genetic therapies for decades. Genotype information is routinely used to direct specific therapies, and DNA/RNA based tools are being increasingly used. With the continued advancements of genetic technologies, all health care providers will be using "genetic therapies" in the not so distant future (and in fact, the future may be now).
The past decade has seen a great emphasis placed on establishing the Family Centered Medical Home. Primary care physicians are trained to function as the center of a medical system of care where the medical home where all of the patient's information and care resides. In this regards, the medical genetics team can function as a Medical Home Neighbor, a professional partner of the medical home who works in collaboration to assure comprehensive and patient centered services. Many of the patients that the geneticist cares for have complex problems and require access to a plethora of specialists and services. Coordination of care is the key issue. Geneticists are not here to assume care, but to bring to the medical home expertise and information about genetic disorders that will complement the work being done in the primary care setting.
The mainstay of genetic therapies from the beginning has been to provide genetic counseling. Genetic counseling is the complex process of providing critical information about genetic conditions to a family in a process that is understandable, relevant, and sensitive. Medical geneticists work in collaboration with genetic counselors to provide this information. As with most medical practices, there are differences in the division of labor from practice to practice. Regardless of who does what part, the key element is that families get the information they need in a format that is both understandable and useful. A major challenge of genetic counseling is in the explanation of difficult concepts. Genetics is not typically a day-to-day conversation for most people. Of course, patients vary greatly in their level of understanding. In addition, the acute stress of the situation may cloud interpretation and retention. Also, as has been discussed throughout the last 13 chapters, current technology can be quite complicated.
Consider this scenario: You have a patient who is a 7-year-old boy who you have just diagnosed with fragile X syndrome (Figure 4-27). In order to inform the family of the type of inheritance that is seen in fragile X, you would want to tell the family: "your child has fragile X syndrome, which is an X-linked semi-dominant trait that shows genetic anticipation due to an expanding trinucleotide repeat in the FMR-1 gene." Presumably you, the reader, took a little while to grasp these concepts as you worked you way through Chapter 12. Think then about how you might explain the above information to the child's mother who has no medical background, did not finish high school, and, because she is a carrier of a fragile X expansion, has an IQ of 75 herself!
Often, genetic diagnoses are made and discussed under extremely stressful conditions. For example, there are few situations that are more intense than the discovery of an unanticipated congenital anomaly in the delivery room. The birth of a child with congenital anomalies represents a loss of the perceived "normal" child. Parents in these situations will experience the typical stages of grieving. Likewise simply having a child with special needs adds another level of pressure to the already difficult task of raising a child. Persons with Special Health Care Needs (SHCN) present added stresses to parenting in many ways including financial, loss of insurance, time off work (multiple specialists), fear or jealousy of siblings, need for respite, and the unfortunate discomfort associated with public curiosity and meddling. In addition, the diagnosis of a genetic disorder in a family often exacerbates pre-existing conflicts and tension. The current divorce rate in the United States is a little over 50%. For families with special needs children the estimates are 85%! It is here that the genetic counselor or other psychosocial ancillary care person can be useful. Working with families in these situations and helping them maneuver the complex process of dealing with often overwhelming circumstances is why the discipline exists.
Think for a moment about the example of a child born with a cleft lip and palate (Figure 10-8). An initial assumption would be that child with a cleft would need a surgeon to repair the cleft, and that would pretty much take care of the situation. In reality, there are multiple possible medical complications and extenuating conditions of oro-facial clefting. Current health care standards now recommend that all children with clefts, be evaluated and have their care coordinated through a cleft team. The ideal team that provides care for children with clefts is comprised at least 14 different specialists! A list of specialists that might participate in a cleft lip and palate team is provided in Table 14-5. Granted, not every child will need to see every specialist on every visit. Still, in order to achieve optimal outcomes, children with clefts and other craniofacial malformations need access to such a team. Just imagine what it would mean for the family if they had to make visits to all of these specialists independently. Interdisciplinary services, such as a cleft team, epitomize family-centered services. Not only are all of the specialists under one roof at one time–"one stop shopping"–but communication is optimized. The team can make coordinated treatment plans and recommendations that will optimize the outcomes for each patient. As noted in the first section of this chapter, many different types of interdisciplinary teams exist. Table 14-1 lists some of the more common types of teams in which participation by the clinical geneticist is particularly helpful.
Table 14-5.List of Specialties on a Cleft Lip and Palate Team |Favorite Table|Download (.pdf) Table 14-5. List of Specialties on a Cleft Lip and Palate Team
|Primary team members |
|Dentistry (pediatric and adult) |
|Clinical genetics |
|Genetic counseling |
|Plastic surgery |
|Speech pathology |
|Accessible specialists |
|Behavioral psychology |
|Oral maxillofacial surgery |
Treatment of inborn errors of metabolism
The earliest true treatments for genetic disorders were those for metabolic disorders. The development of a modified formula low in phenylalanine that was effective in treatment of phenylketonuria (PKU) was reported by Professor Horst Bickel around 1955 (see Table 8-11). This therapy prevented the mental retardation and high likelihood of death in infants with untreated PKU. Since that time the treatment of PKU has become quite sophisticated (refer to the Clinical Correlation Section of Chapter 8). The treatment of PKU stands as the premier example of successful treatment of inborn errors of metabolism. Multiple, often combined, therapies are now available for many metabolic disorders. Primary treatment options include dietary modifications, cofactor replacement, administration of detoxifying agents, enzyme replacement therapies, and tissue transplantation (see Clinical Correlation section).
The first mass produced pharmaceutical manufactured using genetic engineering was human insulin produced from altered Escherichia coli bacteria in 1982. Over the last 30 years many such drugs have been developed (Table 14-3). The development of these drugs has greatly enhanced medical treatment for many disorders. Currently the vast majority of persons treated with insulin now use a form made by genetic engineering rather than extraction from bovine or porcine sources–as was the case into the 1970s.
One particularly fascinating story in this regards is that of growth hormone therapy. Human growth hormone deficiency (GHD) was discovered in the 1920s. Shortly thereafter, attempts to treat GHD began. Early strategies used growth hormone (GH) extracted from cattle–as was the case with insulin. In the 1950s the first treatments with GH extracted from human (cadaver) pituitary began. In 1960, the federal government established the National Pituitary Agency to centralize and administer the distribution of pituitary-source GH. The need for such an agency was that this source of GH was quite limited and needed to be rationed and prioritized for dissemination—only the most severe GHD children could be treated. The use of human pituitary GH extracts was halted in 1985 when several children receiving this therapy were found to have a lethal neurodegenerative disorder known as Creutzfeldt-Jakob disease. (Creutzfeldt-Jakob disease is part of a family of disorders known as transmissible spongiform encephalopathies. One such condition that you may be familiar with is the so called "mad cow disease.") Fortunately, at around the same time that CJD was reported in these patients, genetically engineered human growth hormone (hGH) was in the final stages of development. Currently there are several companies that now make hGH by genetic engineering techniques. This technology has resulted in an adequate, uninterrupted supply of GH for all persons needing the drug. Also, the risk of biological contamination—as in the pituitary source GH—has been eliminated.
The story of the development of genetically engineered hGH is a fascinating one. There are many intriguing facets of this story if you find yourself inclined to search for more information. Likewise, there are other examples of other conditions in which treatment has been revolutionized by the development of similar therapies. It is, however, important to point out that things are not always as simple as they first appear. While genetically engineered drugs are wonderfully exciting and helpful, their development has not been without complications. Several important issues have emerged that are clinically relevant in their use.
Cost is a significant issue in the use of genetically engineered drugs. The research and development (R&D) costs of bringing these drugs can be staggering. In the case of human insulin, these costs can be shared across a large population–with almost 10% of the US population developing diabetes mellitus sometime in their life. Thus most people with diabetes can take engineered human insulin at a very affordable cost. However, this is not the case with other, less common disorders. Take for instance the example above of hGH. Currently an annualized cost of treatment is around $20,000-40 000 per year depending on the age and size of the patient. For conditions that are even less common the costs can be staggering. Current annualized cost estimates for the treatment of some of the lysosomal storage disorders are: Gaucher disease (~ $150,000 per year), Fabry disease (~ $250,000 per year), or Hunter syndrome (~ $500,000 per year). As one might imagine, payment for drugs this expensive is a very difficult problem to deal with. Some of the more critical issues along these lines include:
Who will pay for the drug?
Life-time maximum payments (ceilings) even if there is payment coverage.
When does the treatment become standard therapy instead of investigational?
Is there such a thing as a cost:benefit ratio that can be objectively applied?
Other problems that have been encountered with such therapies have included problems with the product development and manufacturing. There are also fiscal considerations from the manufacturer's side. What if the drug is not fiscally sound, i.e., what if it is not worth making? If the decision is made to stop production, what about the patients who were dependent on the pharmaceutical? On the other end of the spectrum, there are potential problems with expanded use/abuse. Going back to our example of hGH, there have been significant issues raised regarding its potential uses. Originally hGH was used solely for treating patients with complete growth hormone deficiency (GHD). Over time, with abundant supplies, its use has been expanded to partial GHD. In addition, the use of hGH has been expanded to a variety of other conditions (Table 14-6). Note the last indication listed in Table 14-6. The FDA has now approved the use of hGH therapy for normal variant short stature! A very long, intense ethical discussion can ensue over the pros and cons of treating "normally short" children. It is beyond the scope of this chapter to do so. However, you are encouraged to simply ponder what potential issues such a usage of hGH raises. Yet another possibility is the abuse of hGH as a performance enhancing drug. Many recent stories about high profile athletes and "doping" charges highlight the potential for abuse of such therapies.
Table 14-6.Licensed Indications for the Use of Human Growth Hormone Therapy |Favorite Table|Download (.pdf) Table 14-6. Licensed Indications for the Use of Human Growth Hormone Therapy
|Growth hormone deficiency (complete and partial) |
|Turner syndrome/SHOX gene mutations |
|Chronic renal failure |
|Prader-Willi syndrome |
|Intrauterine growth retardation (without catch-up growth by age 2 years) |
|Normal variant (idiopathic) SS |
The final conclusion of all of this is simple. Genetically engineered pharmaceuticals are truly amazing in their potential to treat human disease. They often present the first method ever developed for treating certain complex and rare disorders. Still, caution has to be maintained. While the science may be straightforward, the practical application (getting the drug to the patient) may be fraught with many unanticipated complications.
The first thing that comes to mind for most people when genetic treatments are discussed is the term "gene therapy." Gene therapy may be defined in several different ways. Narrowly defined gene therapy could mean using DNA as a pharmacologic agent. Alternatively, one could define it as those therapies in which genes (more specifically runs of nucleic acids) are transported into a patient's body to effect a therapeutic outcome. The greatest hurdle in implementing gene therapy is the difficulty in transferring the normal gene sequence into a living organism without disrupting normal biological functions. Simply put, how do you get the correct gene into the correct place without producing unwanted problems? Many different techniques for gene transfer have been tried. Some of the more commonly employed strategies include viral vectors, plasmids, chemical methods, and antisense oligonucleotide strands.
One of the early success stories in human gene therapy was the treatment of severe combined immunodeficiency (SCIDS) in the 1990s. SCIDS as the name implies is an immunodeficiency disorder with symptoms in early childhood. The disorder is an autosomal recessive disorder caused by mutations in the gene adenosine deaminase (ADA). Inactivity of this enzyme renders white blood cells incapable of carrying out normal immunologic responses. The approach to treating SCIDS with gene therapy involved taking a bacterium carrying a plasmid that had the normal human ADA gene incorporated in it. The cloned ADA gene was transferred from the bacterium to an inactivated retrovirus. Bone marrow from the patient with SCIDS was then harvested and infected with the retrovirus, thus transferring a functional copy of the ADA gene into the T cells. The genetically altered T cells were then transplanted back into the patient (Figure 14-1). Using this approach, patients with SCIDS were effectively "cured" of their disease. As these patients have been followed, limitations in this treatment modality have been noted including a low level of the retroviral transduction (<1%) and difficulty in maintaining transformed cells in the periphery. Unanticipated "side effects" like an increased risk of developing cancer also complicate such therapies.
Schematic of gene therapy trials for severe combined immunodeficiency (SCID). (From Klug WS, Cummings MR, Spencer CA, et al: Concepts of Genetics, 10th ed. Benjamin Cummings, 2011.)
There is thus a balance between optimism and realism that must be communicated to patients and to the public at large. The potential of gene therapy literally to cure human disease cannot be overstated. However, as noted earlier, there are practical and technical issues that continue to impede the translation of preclinical studies into effective clinical protocols. There are also critical issues of safety and regulation. When discussing gene therapy as a possible treatment option for patients, the clinician must be honest about the practical reality of gene therapy.
Despite these limitations the science of gene therapy continues to advance. In recent years, gene therapy has emerged as a truly independent discipline. There are now even clinicians who work solely within this field. In fact, many clinical trials with gene therapy are currently underway (Table 14-7).
Table 14-7.Clinical Trials with Gene Therapy |Favorite Table|Download (.pdf) Table 14-7. Clinical Trials with Gene Therapy
|Adenosine deaminase deficiency |
|Coronary artery disease |
|Cystic fibrosis |
|Duchenne muscular dystophy |
|Growth hormone deficiency |
|Hemophilia B |
|Inborn errors of metabolism (multiple) |
|Parkinson disease |
As we noted earlier, people react emotionally to the term "cloning." Just the overall consideration of making a duplicate of one's self reaches down to some of the most basic edicts of humanity. Unfortunately, these initial reactions have greatly limited the public from an accurate understanding of the concept. Cloning simply means making an identical copy of something. It is important to emphasize that cloning in the medical arena can occur at any of several different levels—cells, tissues, organs, or organisms. The tremendous ethical concerns that are typically raised are usually focused on the latter. These concerns have likewise overshadowed the tremendous potential that cloning has for the treatment of human disease. At the level of cells, tissues, and organs, the potential benefits are staggering—and largely noncontroversial. Some specific examples might include:
Cloning of an individual's neuronal cells could generate therapies for problems like spinal cord injuries or neurodegenerative conditions (including potentially even normal aging).
Cloning of organs for auto-transplantation. For instance a person with 80% to 90% of total body surface area burns will be in need of large amounts of tissue for grafting. Using cloning techniques from the small amounts of non-affected skin could generate adequate supplies of the patient's own skin (which would also alleviate issues with graft rejection). In conditions such as hepatic or renal failure, cloning an entire replacement organ from an individual's own cells would again alleviate graft issues and also eliminate the need for cadaver-source donors.
Cloning of a specific anatomic structure would aid in reconstructive options for problems such as injury or congenital anomalies. For instance, cloning of an entire ear appears to be a reasonable expectation in the near future.
In a very real sense, all of these examples would fit our definition of "genetic therapies." Also, while these may seem somewhat dramatic and maybe a little too amazing to be true, they are none-the-less on the horizon. Despite the limitless potential that such interventions promise, the huge ethical issues associated with the cloning of individuals has largely overshadowed such promise in the eyes of the public. Deep concerns exist over the moral and ethical questions of cloning people—and even other animals. While final resolution on such issues will need careful consideration and discussions among all interested disciplines (ethics, politics, religion, law), certain principles are straightforward enough to discuss here.
One of the most misunderstood concepts of the cloning of individuals is the idea of making an exact duplicate of one's self. It is critical to recognize that our genetic code is not the sole determinant of who we are as individuals. As individuals we are products of not only our genetic make-up, but of environmental influences, experience and chance as well. One only has to think about the practical example of monozygotic (MZ) twins. Almost everyone has had the chance to know a set of siblings who are monozygous twins. Simple observation will quickly highlight the fact that those two persons, while similar, are not exactly the same. Simply put, although they are genetically identical they are not developmentally identical. Even the concept of being genetically identical is an oversimplification. While monozygotic twins start off genetically identical, genetic differences likely happen throughout gestation (see Chapter 7, Mutation).
Because of the rate of spontaneous mutations, MZ twins will almost certainly have several acquired genetic difference even by the time of birth. Likewise, MZ twins do not even share an identical in utero environment. Twins differ in their position in the womb and in blood flow in the womb. Clinical geneticists have long observed the not infrequent occurrence of discordant phenotypes in MZ twins (we refer you to similar discussions in Chapter 10 on "Concordance" and to Figure 10-5).
At the present time, the bulk of international law and consensus is on the side of extreme caution. A legal moratorium currently exists in the United States on the cloning of individual humans. Before this would ever become a sanctioned practice, many ethical and legal issues will have to be resolved. Several practical issues will have to be ironed out as well. For instance, the famous sheep Dolly (Figure 14-2) was conceived by a nuclear transplantation of the nucleus from a donor cell of an adult sheep. Thus even at the time of birth, Dolly possessed a mature genome and actually died a premature aging death. Thus, it is clear that careful oversight is needed in this realm. However, such caution should not stymie efforts for less controversial interventions that could greatly benefit our patients.
Dolly, the famous sheep (right) that was 'conceived' by nuclear transplantation producing a literal clone of the donor. (Courtesy of the Roslin Institute, The University of Edinburgh.)
The concept of personalized medicine was introduced in the Clinical Correlation section of Chapter 1 of this book. Personalized medicine may be defined as health care targeted to the inherent biology and physiology of an individual leading to improvements in their medical care. Simply, this is medicine tailored to the individual with direction coming from the person's own unique situation. As we have emphasized a number of times, a large contributor to individual diversity is one's own genomic constitution. Thus, the ultimate "genetic therapy" is that in which knowledge of an individual's genome directs their medical care. Personalized medicine can occur at several levels. In its simplest form it may be using the person's family history information to identify specific risks that warrant testing, screening or interventions hopefully to prevent disease. In Chapter 9 we emphasized the importance of having family history information on every patient. The well-trained modern health care professional should have a working knowledge of genetics to be able to review and accurately respond to a patient's family history. Even in this era of modern genetic diagnostics, the family history remains equally effective in identifying and diagnosing conditions in a family. This is indeed personalized medicine at its classic best!
Using any number of the remarkable molecular tools discussed in Chapter 11, personalized medicine can now be taken to the molecular level. The next 10 years will see the era of molecular-based personalized medicine ushered in. Currently there are just a few logistical hurdles, such as reimbursement and regulation, that need to be addressed. However, there is no question that direct clinical utility of such science will occur in the very near future (Table 1-5).