Showing posts with label common diseases. Show all posts
Showing posts with label common diseases. Show all posts
Thursday, February 1, 2018
Precision Medicine and the Reinvention of Human Disease (not just about genes)
If everything you know about Precision Medicine comes from the lay press, you may have an unrealistic notion of what's happening in this field. The news seems to stress the one gene -> one disease paradigm that is easy to understand, but largely irrelevant to all the common diseases that occur in humans.
The one gene -> one disease paradigm is this: the clinical expression of each disease is caused by a genetic mutation in a particular gene responsible for that particular disease, or a particular subtype of a disease, in a particular individual. By finding and targeting the gene responsible for an individual's disease, Precision Medicine will cure the patient.
This paradigm is short and sweet, and it is more or less true for a number of rare diseases; but it is wrong for just about every disease that occurs commonly in humans, and it serves to distract our attention from the medical revolution that Precision Medicine will bring.
The purpose of my new book, Precision Medicine and the Reinvention of Human Disease, discussed in previous blogs, is to explain how Precision Medicine is changing our fundamental understanding of the pathogenesis of disease (i.e., the biological steps that lead to the development of diseases), and how this new information is changing the way that we prevent, diagnose, and treat human diseases.
Precision Medicine is not about finding the right gene for the right patient. Precision Medicine is about finding the common events and metabolic pathways that account for the development and the expression of diseases; and using these insights to reduce the morbidity and mortality of disease in the population.
Google Books has a very good "look inside" for my book, and I hope that readers of this blog will take a few moments to see if they might be interested in the subject.
- Jules Berman
key words: precision medicine, jules j berman, Ph.D., M.D., disease biology, pathogenetic, monogenic, rare diseases, complex diseases, common diseases
Monday, February 29, 2016
Rare Disease Day is Here!
It's finally come; the rare day that comes every four years, Rare Disease Day. For the past several weeks, leading up to February 29, I've been blogging about rare diseases. The basic theme of all my blogs is that the rarity of rare diseases is not a numeric accident. The rare diseases form a distinct class of diseases having a distinct set of unifying biological properties that distinguish them from common diseases.
In the past 30 years, most of the great advances of medicine have been in the realm of the rare diseases; not the common diseases. In many cases, progress in the common diseases has come as a secondary gain from discoveries made in rare diseases (e.g., statins to prevent heart disease, new cancer therapies targeted against specific molecules).
You can reverse-page through my recent posts, beginning on this blog page, to get a sense of why the rare diseases deserve our attention. Also, please read my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, to learn why our best chance to eradicate the common diseases is by funding research in the rare diseases.
- Jules Berman
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, common diseases, complex diseases, medical research, funding for rare disease research,jules j berman
In the past 30 years, most of the great advances of medicine have been in the realm of the rare diseases; not the common diseases. In many cases, progress in the common diseases has come as a secondary gain from discoveries made in rare diseases (e.g., statins to prevent heart disease, new cancer therapies targeted against specific molecules).
You can reverse-page through my recent posts, beginning on this blog page, to get a sense of why the rare diseases deserve our attention. Also, please read my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, to learn why our best chance to eradicate the common diseases is by funding research in the rare diseases.
- Jules Berman
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, common diseases, complex diseases, medical research, funding for rare disease research,jules j berman
Sunday, February 28, 2016
Counting the Rare Diseases
"The beginnings and endings of all human undertakings are untidy."- John Galsworthy
In the U.S., as written in Public Law 107-280, the Rare Diseases Act of 2002, "Rare diseases and disorders are those which affect small patient populations, typically populations smaller than 200,000 individuals in the United States." (1). Since the population of the U.S. is about 314 million, in 2013, this comes to about 1 case for every 1,570 persons. This is not too far from the definition recommended by the European Commission on Public Health; fewer than 1 in 2,000 people. It is important to have numeric criteria for the rare diseases, because special laws exist in the U.S. and in Europe to stimulate research and drug development for diseases that meet the criteria for being "rare". Unfortunately, it is very difficult to know, with any certainty, the specific prevalence or incidence of any of the rare diseases. A certain percentage of the cases will go unreported, or undiagnosed, or misdiagnosed. Though it is impossible to obtain accurate and up-to-date prevalence data on every rare disease, the U.S. the National Institutes of Health has estimated that rare diseases affect, in aggregate, 25-30 million Americans (2).
There seems to be a growing consensus that there are about 7,000 rare diseases (3). Depending on how you choose to count diseases, this may be a gross underestimate.
There are several thousand inherited conditions with a Mendelian inheritance pattern (4). To the rare genetic diseases, we must add the different types of cancer. Every cancer other than the top five or ten most common cancers, occurs with an incidence much less than 200,000 and would qualify as a rare disease. There are more than 3,000 named types of cancer, and many of these cancers have well-defined subtypes, with their own morphologic, clinical or genetic characteristics. Including defined subtypes, there are well over 6,000 rare types of cancer (5), (6), (7), (8).
Regarding the infectious diseases, well over 1,400 different infectious organisms have been reported in the literature (9). I've looked at several popular microbiology textbooks, and each seems to cover at most 300 organisms, and many of the textbook organisms would be considered rare. Hence, it's reasonable to assume that there are well over 1000 well-documented infectious diseases. This number is growing all the time, as we uncover new species of pathogenic organisms.
If we focus our attention on just one type of infectious disease, the fungal infections, we can see immediately why it is impossible to get a meaningful count of the number of rare diseases produced by microorganisms.
As the number of immune-compromised patients increases, due to transplants, AIDS, cancer treatment, long-term steroid use; and with the proliferation of medical devices that provide potential entry points for fungi, the number of newly recognized fungal pathogens will increase. It is estimated that there are about 20 new fungal diseases reported each year (10). If the number of diseases caused by other types of organisms (i.e., bacteria, protists, animals, viruses and prions) remains steady, then it will not be long before the number of different fungal diseases exceeds the number of different diseases produced by all other organisms, combined.
The increase in newly recognized fungal pathogens is partly credited to technical advances. It is now possible to identify heretofore undiagnosed cases of pathogenic species (11). In the past, when clinical mycology laboratories had fewer available tests, it was common to lump fungal pathogens under a commonly encountered species or genus. For example, Aspergillus fumigatus is a common cause of severe pulmonary infections in immune-compromised patients. With advanced typing techniques, an additional 34 species of Aspergillus have been isolated from clinical specimens (10).
In the absence of advanced fungal typing techniques, it can be difficult to correctly assign a fungal species name to a clinical specimen. Pathogenic fungi grow within human tissues vegetatively, as an expanding colony of hyphae or yeasts. The vegetative growth phase observed in tissues lacks the characteristic morphologic traits observed in sexually or asexually fungal reproduction. The pathologist who observes fungal infections in human tissues reaches a diagnosis on clinical presentation and on the somewhat non-specific morphologic features of the fungus in biopsied tissue (i.e., length and thickness of hyphae, presence or absence of septations, angularity of branches, etc.). Adding to the general confusion, fungal specimens grown in culture may have a different morphology from that of the same fungus growing in human tissue. This situation is very different from that of bacterial infections, which have the same morphology in tissues as they have in the culture dish. Consequently, a rare type of fungal infection can be misdiagnosed as a common fungal infection; unless an adequate tissue specimen is delivered to a well-equipped microbiology laboratory.
Sometimes, one clinical disease can be produced by any number of different fungal organisms. Mycetoma, also known as Madura foot and as maduromycosis, occurs most often in India, Africa, and South America. It presents as a slowly growing, fungating mass arising in the subcutaneous tissues, usually on the foot. As the mass grows, draining sinuses discharge fluid and hard grains (white, white-yellow or black grains). The may become superinfected, making it very difficult to determine the primary pathogen that caused the disease. More than thirty different species of fungi, and several bacteria, have been grown from these lesions. It has been claimed that black grain mycetomas is caused by Leptosphaeria senegalensis, Madurella grisea, Madurella mycetomatis, or Pyrenochaeta romeroi. White grain mycetomas are reputedly caused by Acremonium species, Aspergillus nidulans, Neotestudina rosatii, or Pseudallescheria boydii. White-yellow grain mycetomas are said to be caused by: Actinomadura madurae, Nocardia asteroides, and Nocardia brasiliensis. Brown-red grain mycetomas are said to be caused by: Actinomadura pelletieri or Streptomcyes somaliensis. Taken at face value, these claims would indicate that many different organisms, both bacterial and fungal, can produce a disease of remarkably specific, even unique clinical features. Suffice it to say that clinical science has much to learn about mycetoma.
It is worthy to note that many fungal organisms are unknown; we simply do not know the full list of potential fungal pathogens that live on earth. Furthermore, many of the known fungal organisms are unnamed. Fungi are classified based on the morphologic features of sexual growth in culture. If a fungal organism cannot be cultured, or if it does not display sexual reproduction in culture, then it cannot be classified with certainty. A special pseudoclass of fungi, deuteromycetes (spelled with a lowercase "d", signifying its questionable validity as a true biologic class) has been created to hold these indeterminate organisms until definitive classes can be assigned. At present, there are several thousand such fungi sitting in a taxonomic limbo (10).
A fungal infection with a single organism may produce many different clinical presentations. One or more of the following clinical scenarios may unfold, when a human is exposed to a fungus. These scenarios are listed in order of increasing morbidity:
A single species of fungus may manifest itself by any and all of these clinical manifestions (i.e., diseases). How shall we count the ways?
Likewise, many infectious organisms may manifest as several different named conditions, each with its own distinctive clinical features. For example, Leishmaniasis, an infectious disease that is common in Africa but rare in Europe, may present in one of four different forms (cutaneous, visceral, diffuse cutaneous, and mucocutaneous).
Now, if you are brash enough to think that all these "counting" issues could be resolved, with diligent effort, then please take a moment to consider the rare diseases caused by environmental agents. Depending on the toxin (which no doubt number in the thousands and greater), level of exposure, type of exposure, individual who is exposed (i.e., age, genetics, nutritional status), and admixture with other toxins (e.g., alcohol plus barbiturates, methamphetamine plus heroine), there are an uncountable number of rare diseases that may result.
Nonetheless, even the low-ball "7,000" number tells us that there are many rare diseases; way too many for any individual to fully comprehend.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, number of rare diseases, how many rare diseasesjules j berman
References:
[1] Rare Diseases Act of 2002, Public Law 107-280, 107th U.S. Congress, November 6, 2002.
[2] FAQ about rare diseases. National Center for Advancing Translational Sciences. National Institutes of Health. http://www.ncats.nih.gov/about/faq/rare/rare-faq.html, viewed on October 24, 2013.
[3] Field MJ, Boat T. Rare Diseases and Orphan Products: Accelerating Research and Development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. 2010. The National Academics Press, Washington, D.C. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56189/
[4] Omim. Online Mendelian Inheritance in Man. Available from: http://omim.org/downloads, viewed June 20, 2013.
[5] Berman JJ. Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches. BMC Cancer 5:100, 2005. Available from: http://www.biomedcentral.com/1471-2407/5/100, viewed on Jan. 1, 2015.
[6] Berman JJ Tumor taxonomy for the developmental lineage classification of neoplasms. BMC Cancer 4:88, 2004. http://www.biomedcentral.com/1471-2407/4/88, viewed Jan. 1, 2015.
[7] Berman JJ. Tumor classification: molecular analysis meets Aristotle. BMC Cancer 4:10, 2004. Available from: http://www.biomedcentral.com/1471-2407/4/10, viewed Jan. 1, 2015.
[8] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.
[9] Berman JJ. Taxonomic Guide to Infectious Diseases: Understanding the Biologic Classes of Pathogenic Organisms. Academic Press, Waltham, 2012.
[10] Guarro J, Gene J, Stchigel AM. Developments in fungal taxonomy. Clinical Microbiology Reviews 12:454-500, 1999.
[11] Pounder JI, Simmon KE, Barton CA, Hohmann SL, Brandt ME. Petti CA. Discovering potential pathogens among fungi identified as nonsporulating molds. Journal of Clinical Microbiology 45:568-571, 2007.
In the U.S., as written in Public Law 107-280, the Rare Diseases Act of 2002, "Rare diseases and disorders are those which affect small patient populations, typically populations smaller than 200,000 individuals in the United States." (1). Since the population of the U.S. is about 314 million, in 2013, this comes to about 1 case for every 1,570 persons. This is not too far from the definition recommended by the European Commission on Public Health; fewer than 1 in 2,000 people. It is important to have numeric criteria for the rare diseases, because special laws exist in the U.S. and in Europe to stimulate research and drug development for diseases that meet the criteria for being "rare". Unfortunately, it is very difficult to know, with any certainty, the specific prevalence or incidence of any of the rare diseases. A certain percentage of the cases will go unreported, or undiagnosed, or misdiagnosed. Though it is impossible to obtain accurate and up-to-date prevalence data on every rare disease, the U.S. the National Institutes of Health has estimated that rare diseases affect, in aggregate, 25-30 million Americans (2).
There seems to be a growing consensus that there are about 7,000 rare diseases (3). Depending on how you choose to count diseases, this may be a gross underestimate.
There are several thousand inherited conditions with a Mendelian inheritance pattern (4). To the rare genetic diseases, we must add the different types of cancer. Every cancer other than the top five or ten most common cancers, occurs with an incidence much less than 200,000 and would qualify as a rare disease. There are more than 3,000 named types of cancer, and many of these cancers have well-defined subtypes, with their own morphologic, clinical or genetic characteristics. Including defined subtypes, there are well over 6,000 rare types of cancer (5), (6), (7), (8).
Regarding the infectious diseases, well over 1,400 different infectious organisms have been reported in the literature (9). I've looked at several popular microbiology textbooks, and each seems to cover at most 300 organisms, and many of the textbook organisms would be considered rare. Hence, it's reasonable to assume that there are well over 1000 well-documented infectious diseases. This number is growing all the time, as we uncover new species of pathogenic organisms.
If we focus our attention on just one type of infectious disease, the fungal infections, we can see immediately why it is impossible to get a meaningful count of the number of rare diseases produced by microorganisms.
As the number of immune-compromised patients increases, due to transplants, AIDS, cancer treatment, long-term steroid use; and with the proliferation of medical devices that provide potential entry points for fungi, the number of newly recognized fungal pathogens will increase. It is estimated that there are about 20 new fungal diseases reported each year (10). If the number of diseases caused by other types of organisms (i.e., bacteria, protists, animals, viruses and prions) remains steady, then it will not be long before the number of different fungal diseases exceeds the number of different diseases produced by all other organisms, combined.
The increase in newly recognized fungal pathogens is partly credited to technical advances. It is now possible to identify heretofore undiagnosed cases of pathogenic species (11). In the past, when clinical mycology laboratories had fewer available tests, it was common to lump fungal pathogens under a commonly encountered species or genus. For example, Aspergillus fumigatus is a common cause of severe pulmonary infections in immune-compromised patients. With advanced typing techniques, an additional 34 species of Aspergillus have been isolated from clinical specimens (10).
In the absence of advanced fungal typing techniques, it can be difficult to correctly assign a fungal species name to a clinical specimen. Pathogenic fungi grow within human tissues vegetatively, as an expanding colony of hyphae or yeasts. The vegetative growth phase observed in tissues lacks the characteristic morphologic traits observed in sexually or asexually fungal reproduction. The pathologist who observes fungal infections in human tissues reaches a diagnosis on clinical presentation and on the somewhat non-specific morphologic features of the fungus in biopsied tissue (i.e., length and thickness of hyphae, presence or absence of septations, angularity of branches, etc.). Adding to the general confusion, fungal specimens grown in culture may have a different morphology from that of the same fungus growing in human tissue. This situation is very different from that of bacterial infections, which have the same morphology in tissues as they have in the culture dish. Consequently, a rare type of fungal infection can be misdiagnosed as a common fungal infection; unless an adequate tissue specimen is delivered to a well-equipped microbiology laboratory.
Sometimes, one clinical disease can be produced by any number of different fungal organisms. Mycetoma, also known as Madura foot and as maduromycosis, occurs most often in India, Africa, and South America. It presents as a slowly growing, fungating mass arising in the subcutaneous tissues, usually on the foot. As the mass grows, draining sinuses discharge fluid and hard grains (white, white-yellow or black grains). The may become superinfected, making it very difficult to determine the primary pathogen that caused the disease. More than thirty different species of fungi, and several bacteria, have been grown from these lesions. It has been claimed that black grain mycetomas is caused by Leptosphaeria senegalensis, Madurella grisea, Madurella mycetomatis, or Pyrenochaeta romeroi. White grain mycetomas are reputedly caused by Acremonium species, Aspergillus nidulans, Neotestudina rosatii, or Pseudallescheria boydii. White-yellow grain mycetomas are said to be caused by: Actinomadura madurae, Nocardia asteroides, and Nocardia brasiliensis. Brown-red grain mycetomas are said to be caused by: Actinomadura pelletieri or Streptomcyes somaliensis. Taken at face value, these claims would indicate that many different organisms, both bacterial and fungal, can produce a disease of remarkably specific, even unique clinical features. Suffice it to say that clinical science has much to learn about mycetoma.
It is worthy to note that many fungal organisms are unknown; we simply do not know the full list of potential fungal pathogens that live on earth. Furthermore, many of the known fungal organisms are unnamed. Fungi are classified based on the morphologic features of sexual growth in culture. If a fungal organism cannot be cultured, or if it does not display sexual reproduction in culture, then it cannot be classified with certainty. A special pseudoclass of fungi, deuteromycetes (spelled with a lowercase "d", signifying its questionable validity as a true biologic class) has been created to hold these indeterminate organisms until definitive classes can be assigned. At present, there are several thousand such fungi sitting in a taxonomic limbo (10).
A fungal infection with a single organism may produce many different clinical presentations. One or more of the following clinical scenarios may unfold, when a human is exposed to a fungus. These scenarios are listed in order of increasing morbidity:
1. The fungus grows in the external environment, usually in soil or on plants, never interacting in any way with humans.
2. Spores and asexual reproductive forms are emitted into the air. In warm and tropical locations, fungal elements are the predominant particulate matter found in air samples. Humans are exposed constantly to a wide variety of fungi just by breathing (spores and conidia), by ingestion (fungi grow on the plants we eat), and by direct skin contact with fungal colonies in soil and airborne organisms.
3. After exposure, fungi may leave, without colonizing (e.g., you inhale them, and then you exhale them, and they're gone).
4. After exposure, fungi may transiently colonize a mucosal surface, such as the oral cavity, the nose, the gastrointestinal tract, the respiratory tract, or the skin. Once on a mucosal surface, an acute allergic response may occur (e.g. sneezing). After a time, the colony fails to thrive due to an inhospitable environment (e.g., insufficient food, poor ionic milieu, effective host immune response).
5. After exposure, fungi permanently colonize the mucosal surface, with no clinical effect. Candida species commonly colonize the mouth and the vagina. Aspergillus species may colonizes the respiratory surfaces (e.g. bronchi). In many cases, we simply carry fungal colonies as commensals (organisms that live within us, without causing disease).
6. Colonies persist, but the host reacts with an acute or chronic immune response. Chronic allergic aspergillosis of the bronchi is a good example. The patient may have a chronic cough. Microscopic examination of bronchial mucosa may reveal some inflammation, the presence of eosinophils, and the occasional hypha. Sometimes the host response is granulomatous, producing small nodules lining the bronchi, containing histiocytes and lymphocytes. A truce between the fungal colony and the host response is sometimes attained, in which the fungus colonies never leave, the inflammation never regresses, but the fungus does not invade into the underlying mucosa.
7. Fungi invade through the mucosa into the submucosa and underlying tissue. These locally invasive infections often manifest as a fungal ball, consisting of varying amounts of inflammatory tissue, necrosis, and fungal elements.
8. Fungal elements invade into lymphatics, traveling with the lymph fluid, and producing regional invasive fungal disease along the route of lymphatic drainage. The prototypical example of this process is found in infections with Sporothrix schenckii, which typically gains entrance to the skin, from the soil, through abrasions. Infection yields multiple skin papules, emanating from the point of primary infection (usually the hand or the foot), and following the line of lymphatic drainage.
9. Fungal elements invade into blood vessels.
10. Fungal elements grow in the blood and disseminate throughout the body.
11. Fungal elements spread throughout the body to produce invasive fungal infections in multiple organs.
A single species of fungus may manifest itself by any and all of these clinical manifestions (i.e., diseases). How shall we count the ways?
Likewise, many infectious organisms may manifest as several different named conditions, each with its own distinctive clinical features. For example, Leishmaniasis, an infectious disease that is common in Africa but rare in Europe, may present in one of four different forms (cutaneous, visceral, diffuse cutaneous, and mucocutaneous).
Now, if you are brash enough to think that all these "counting" issues could be resolved, with diligent effort, then please take a moment to consider the rare diseases caused by environmental agents. Depending on the toxin (which no doubt number in the thousands and greater), level of exposure, type of exposure, individual who is exposed (i.e., age, genetics, nutritional status), and admixture with other toxins (e.g., alcohol plus barbiturates, methamphetamine plus heroine), there are an uncountable number of rare diseases that may result.
Nonetheless, even the low-ball "7,000" number tells us that there are many rare diseases; way too many for any individual to fully comprehend.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, number of rare diseases, how many rare diseasesjules j berman
References:
[1] Rare Diseases Act of 2002, Public Law 107-280, 107th U.S. Congress, November 6, 2002.
[2] FAQ about rare diseases. National Center for Advancing Translational Sciences. National Institutes of Health. http://www.ncats.nih.gov/about/faq/rare/rare-faq.html, viewed on October 24, 2013.
[3] Field MJ, Boat T. Rare Diseases and Orphan Products: Accelerating Research and Development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. 2010. The National Academics Press, Washington, D.C. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56189/
[4] Omim. Online Mendelian Inheritance in Man. Available from: http://omim.org/downloads, viewed June 20, 2013.
[5] Berman JJ. Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches. BMC Cancer 5:100, 2005. Available from: http://www.biomedcentral.com/1471-2407/5/100, viewed on Jan. 1, 2015.
[6] Berman JJ Tumor taxonomy for the developmental lineage classification of neoplasms. BMC Cancer 4:88, 2004. http://www.biomedcentral.com/1471-2407/4/88, viewed Jan. 1, 2015.
[7] Berman JJ. Tumor classification: molecular analysis meets Aristotle. BMC Cancer 4:10, 2004. Available from: http://www.biomedcentral.com/1471-2407/4/10, viewed Jan. 1, 2015.
[8] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.
[9] Berman JJ. Taxonomic Guide to Infectious Diseases: Understanding the Biologic Classes of Pathogenic Organisms. Academic Press, Waltham, 2012.
[10] Guarro J, Gene J, Stchigel AM. Developments in fungal taxonomy. Clinical Microbiology Reviews 12:454-500, 1999.
[11] Pounder JI, Simmon KE, Barton CA, Hohmann SL, Brandt ME. Petti CA. Discovering potential pathogens among fungi identified as nonsporulating molds. Journal of Clinical Microbiology 45:568-571, 2007.
Saturday, February 27, 2016
Rare Disease Clinical Trials: Fast, Small and Decisive
"The subphenotyping of COPD [chronic obstructive pulmonary disease] into separate groups based on mechanism sets the stage for the rational development of therapeutics."
- Stephen Rennard (1)
Modern clinical trials had great success in late 1960s and early 1970s, when highly effective chemotherapeutic agents were found to be effective against a wide range of rare, childhood cancers. The prospective randomized control trial, performed on children with cancer, was so very successful that it served as a requirement and a standard for drug testing, for the past half-century.
Today, large, randomized prospective clinical trials are the standard for common diseases, such as cancer. The problem has been that none of the drugs tested on adults with cancer have had the kind of curative successes that we saw with the childhood tumors. Larger, longer and increasingly expensive studies were conducted to demonstrate incremental improvements in chemotherapeutic regimens. Though there have been successes in clinical trials for the common cancers occurring in adults, no trial on common cancers has yielded the spectacular successes witnessed for the rare childhood cancers.
Modern clinical trials are long and expensive. It takes about 10 to 15 years for an experimental drug to be developed (2). Only 5 in 5,000 compounds that have preclinical testing will enter clinical trials (2). The cost of developing a drug and bringing it to market is about $1 billion (3).
Clinical trials can be very large. In the realm of cancer trials, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, NIH/NCI trial NO1 CN25512) serves as an example. The PLCO is a randomized controlled cancer trial. Between 1992, when the trial opened, and 2001, when enrollment ended, 155,000 participants were recruited (4). The study will end in 2016.
It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial (5). Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials (5).
Overall, about 95% of drugs that move through the clinical trial gauntlet will fail (6). Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error (7), (8), (9). Like any human endeavor, clinical trials need to be validated in clinical practice (3). It may take years or decades to determine whether a treatment that demonstrated a small, but statistically significant effect in a clinical trial, will have equivalent value in everyday practice.
Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed to advance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.
The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail (6).
Rare diseases often have a single genetic aberration, driving a single metabolic pathway, that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are obvious, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease (6).
Consider the following story:
It is easy to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminates the hit-or-miss accrual activities that characterize clinical trials for common diseases.
In an effort to increase the scientific and clinical value of clinical trials, trialists often include ancillary studies in their trial designs. These ancillary studies may consist of molecular studies on tissue biopsies obtained from trial subjects. Using biopsy samples, different responses to a treatment can be correlated with a genetic marker or a genetic profile measured on tissues. In instances for which rare disease organizations collect and store biopsies obtained from their registered members, ancillary studies for orphan drug trials can be performed quickly, and with less expense than comparable studies on common diseases.
In the U.S. several laws have been passed to encourage and facilitate clinical trials for the rare diseases:
Thee U.S. Food and Drug Administration, is poised to provide guidance to organizations and corporations conducting clinical trials on orphan drugs (14). It is crucial that trial sponsors stay in close touch with FDA staff during the planning stages of drug trials. A little advice from a regulator can avoid the heartbreak that comes when an effective drug fails approval due to poor trial design.
Trials on orphan drugs commonly accrue human subjects from vulnerable populations (e.g., children, mentally impaired subjects, subjects with multiple life-threatening conditions). In such cases, human subjects may not be able to provide informed consent, and a parent or guardian will need to be consulted (See Glossary item, Informed consent). Trialists must be sensitive to the special needs of their subjects and their families. Recruiting an independent clinical safety board or institutional review board, with no financial ties to the trialists or their sponsors, is a prudent measure (14).
A recurring theme in these blogs is that common diseases are collections of genotypically distinct diseases that share a common phenotype and common disease pathways (1), (15), (16). If there is some reason to expect a drug to be particularly effective against a defined subset of individuals with a common disease, it may be worthwhile to design the trial for these individuals. The pharmaceutical company Genentech employed this strategy when it developed the breast cancer drug trastuzuab (trade name herceptin). Trastuzumab is a monocloncal antibody against the HER2 receptor ). In this case, preclinical evidence indicated that trastuzumab might be effective against breast cancers that had high levels of HER2. By limiting their study to individuals with HER2-positive breast cancers, the company achieved success, with a relatively small number of trial participants (6).
It is easy to find rare diseases that pose as variant subsets of common diseases (e.g., B-K mole syndrome patients composing a subset of individuals at high risk of developing melanoma; BRCA gene positive individuals as a subset of individuals at high risk of breast cancers; patients with alpha-1-antitrypsin deficiency as a subset of emphysema cases). A clinical trial specifically aimed at a rare subset of a common disease might facilitate later trials directed at other subsets of the same disease.
Such clinical trials are in progress. The I-SPY 2 trial matches treatments against subgroups of breast cancer patients whose tumor cells match particular molecular profiles (6). In the I-SPY 2 trial, multiple drugs are tested on relatively small, selected subgroups of cancer patients. As results are collected, unsuccessful drugs are phased out and replaced by other drug candidates, all within the same trial (6).
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, clinical trials, improving clinical trials, ancillary clinical trials, jules j berman
References:
[1] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[2] Orphan Drugs in Development for Rare Diseases; 2011 Report. America's Biopharmaceutical Research Companies. Available from http://www.phrma.org/sites/default/files/pdf/rarediseases2011.pdf, viewed July 14, 2013.
[3] Berman JJ. Principles of Big Data: Preparing, Sharing, and Analyzing Complex Information. Morgan Kaufmann, Waltham, MA, 2013.
[4] Prostate, lung, colorectal & ovarian cancer screening trial (PLCO) Available from: http://prevention.cancer.gov/plco, viewed August 22, 2013.
[5] English R, Lebovitz Y, Griffin R. Forum on Drug Discovery, Development, and Translation. Institute of Medicine, 2010.
[6] Leaf C. Do clinical trials work? The New York Times. July 13, 2013.
[7] Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem 49:7-18, 2003.
[8] Ioannidis JP. Why most published research findings are false. PLoS Med 2:e124, 2005.
[9] Ioannidis JP. Some main problems eroding the credibility and relevance of randomized trials. Bull NYU Hosp Jt Dis 66:135-139, 2008.
[10] Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 15:00124-00125, 2015.
[11] Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Grone HJ, et al. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum Molec Genet 13:1249-1255, 2004.
[12] Donovan S. Dying baby cured in world first. ABC News 5 Nov 5, 2009.
[13] Field MJ, Boat T. Rare Diseases and Orphan Products: Accelerating Research and Development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. 2010. The National Academics Press, Washington, D.C. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56189/
[14] Wizemann T, Robinson S, Giffin R. Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies Workshop Summary. National Academy of Sciences, 2009.
[15] Crow YJ. Lupus: how much "complexity" is really (just) genetic heterogeneity? Arthritis and Rheumatism 63:3661-3664, 2011.
[16] Wade N. Many Rare Mutations May Underpin Diseases. The New York Times May 17, 2012.
Modern clinical trials had great success in late 1960s and early 1970s, when highly effective chemotherapeutic agents were found to be effective against a wide range of rare, childhood cancers. The prospective randomized control trial, performed on children with cancer, was so very successful that it served as a requirement and a standard for drug testing, for the past half-century.
Today, large, randomized prospective clinical trials are the standard for common diseases, such as cancer. The problem has been that none of the drugs tested on adults with cancer have had the kind of curative successes that we saw with the childhood tumors. Larger, longer and increasingly expensive studies were conducted to demonstrate incremental improvements in chemotherapeutic regimens. Though there have been successes in clinical trials for the common cancers occurring in adults, no trial on common cancers has yielded the spectacular successes witnessed for the rare childhood cancers.
Rule - Clinical trials are the best method ever developed to determine whether a drug is safe and effective for a particular purpose, in a particular target population. Nonetheless, aazzclinical trials cannot provide the clinical guidance we need to develop all of the new medications that will be needed to conquer the common diseases.zzaa
Brief Rationale - We simply do not have have the money, time, and talent to perform all the anticipated clinical trials for the common diseases.
Modern clinical trials are long and expensive. It takes about 10 to 15 years for an experimental drug to be developed (2). Only 5 in 5,000 compounds that have preclinical testing will enter clinical trials (2). The cost of developing a drug and bringing it to market is about $1 billion (3).
Clinical trials can be very large. In the realm of cancer trials, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, NIH/NCI trial NO1 CN25512) serves as an example. The PLCO is a randomized controlled cancer trial. Between 1992, when the trial opened, and 2001, when enrollment ended, 155,000 participants were recruited (4). The study will end in 2016.
It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial (5). Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials (5).
Overall, about 95% of drugs that move through the clinical trial gauntlet will fail (6). Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error (7), (8), (9). Like any human endeavor, clinical trials need to be validated in clinical practice (3). It may take years or decades to determine whether a treatment that demonstrated a small, but statistically significant effect in a clinical trial, will have equivalent value in everyday practice.
Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed to advance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.
Rule - Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.
Brief Rationale - Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.
The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail (6).
Rule - Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases.
Brief Rationale - Common diseases are heterogeneous and produced a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are homogeneous, thus producing a uniform effect in the trial population, and lowering the number of trial participants required to produce a statistically convincing result.
Rare diseases often have a single genetic aberration, driving a single metabolic pathway, that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are obvious, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease (6).
Consider the following story:
Molybdenum cofactor deficiency type A is a metabolic disorder leading to seizures and progressive brain damage in affected infants. There was no known treatment, and about 100 babies died of this disease, worldwide, each year. Gunther Schwarz, a plant biologist in Germany, developed a compopund which could, in theory, compensate for the cofactor deficiency. The compound had been successfully tested in mice, but not in humans. When a an infant with the disease was born in Australia, Dr. Scwharz sent all his avaialable compound to the baby's doctor, Alex Veldman, at Monash Medical Center. Taking into consideration the infant's worsening condition, the bioethical board approved the experimental treatment. Within minutes of treatment, the baby's condition greatly improved (10), (11), (12).
It is easy to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminates the hit-or-miss accrual activities that characterize clinical trials for common diseases.
In an effort to increase the scientific and clinical value of clinical trials, trialists often include ancillary studies in their trial designs. These ancillary studies may consist of molecular studies on tissue biopsies obtained from trial subjects. Using biopsy samples, different responses to a treatment can be correlated with a genetic marker or a genetic profile measured on tissues. In instances for which rare disease organizations collect and store biopsies obtained from their registered members, ancillary studies for orphan drug trials can be performed quickly, and with less expense than comparable studies on common diseases.
In the U.S. several laws have been passed to encourage and facilitate clinical trials for the rare diseases:
Public Law 105-115, FDA Modernization Act of 1997, grants an exemption for orphan drugs from drug approval application fees that would otherwise apply (13). Amendments to the Act, in 2007, include the Best Pharmaceuticals for Children Act (Public Law 110-85), which encourages the recruitment of children into clinical trials.
Public Law 111-80, the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010zzaa authorized the FDA to appoint a review group to recommend design improvements for preclinical and clinical trials aimed at preventing, diagnosing and treating rare diseases (13).
Thee U.S. Food and Drug Administration, is poised to provide guidance to organizations and corporations conducting clinical trials on orphan drugs (14). It is crucial that trial sponsors stay in close touch with FDA staff during the planning stages of drug trials. A little advice from a regulator can avoid the heartbreak that comes when an effective drug fails approval due to poor trial design.
Trials on orphan drugs commonly accrue human subjects from vulnerable populations (e.g., children, mentally impaired subjects, subjects with multiple life-threatening conditions). In such cases, human subjects may not be able to provide informed consent, and a parent or guardian will need to be consulted (See Glossary item, Informed consent). Trialists must be sensitive to the special needs of their subjects and their families. Recruiting an independent clinical safety board or institutional review board, with no financial ties to the trialists or their sponsors, is a prudent measure (14).
Rule - Clinical trials on common disease can be reduced to one or more trials of a subtype of the disease.
Brief Rationale - The heterogeneity of populations with a common disease allows trialists the freedom to design small trials, for subsets of individuals who have a particular genotype (i.e., a gene marker or a gene expression profile), a particular mode of inheritance (i.e., Mendelian), or a distinguishing clinical phenotype (e.g., early onset disease).
A recurring theme in these blogs is that common diseases are collections of genotypically distinct diseases that share a common phenotype and common disease pathways (1), (15), (16). If there is some reason to expect a drug to be particularly effective against a defined subset of individuals with a common disease, it may be worthwhile to design the trial for these individuals. The pharmaceutical company Genentech employed this strategy when it developed the breast cancer drug trastuzuab (trade name herceptin). Trastuzumab is a monocloncal antibody against the HER2 receptor ). In this case, preclinical evidence indicated that trastuzumab might be effective against breast cancers that had high levels of HER2. By limiting their study to individuals with HER2-positive breast cancers, the company achieved success, with a relatively small number of trial participants (6).
It is easy to find rare diseases that pose as variant subsets of common diseases (e.g., B-K mole syndrome patients composing a subset of individuals at high risk of developing melanoma; BRCA gene positive individuals as a subset of individuals at high risk of breast cancers; patients with alpha-1-antitrypsin deficiency as a subset of emphysema cases). A clinical trial specifically aimed at a rare subset of a common disease might facilitate later trials directed at other subsets of the same disease.
Such clinical trials are in progress. The I-SPY 2 trial matches treatments against subgroups of breast cancer patients whose tumor cells match particular molecular profiles (6). In the I-SPY 2 trial, multiple drugs are tested on relatively small, selected subgroups of cancer patients. As results are collected, unsuccessful drugs are phased out and replaced by other drug candidates, all within the same trial (6).
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, clinical trials, improving clinical trials, ancillary clinical trials, jules j berman
References:
[1] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[2] Orphan Drugs in Development for Rare Diseases; 2011 Report. America's Biopharmaceutical Research Companies. Available from http://www.phrma.org/sites/default/files/pdf/rarediseases2011.pdf, viewed July 14, 2013.
[3] Berman JJ. Principles of Big Data: Preparing, Sharing, and Analyzing Complex Information. Morgan Kaufmann, Waltham, MA, 2013.
[4] Prostate, lung, colorectal & ovarian cancer screening trial (PLCO) Available from: http://prevention.cancer.gov/plco, viewed August 22, 2013.
[5] English R, Lebovitz Y, Griffin R. Forum on Drug Discovery, Development, and Translation. Institute of Medicine, 2010.
[6] Leaf C. Do clinical trials work? The New York Times. July 13, 2013.
[7] Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem 49:7-18, 2003.
[8] Ioannidis JP. Why most published research findings are false. PLoS Med 2:e124, 2005.
[9] Ioannidis JP. Some main problems eroding the credibility and relevance of randomized trials. Bull NYU Hosp Jt Dis 66:135-139, 2008.
[10] Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 15:00124-00125, 2015.
[11] Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Grone HJ, et al. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum Molec Genet 13:1249-1255, 2004.
[12] Donovan S. Dying baby cured in world first. ABC News 5 Nov 5, 2009.
[13] Field MJ, Boat T. Rare Diseases and Orphan Products: Accelerating Research and Development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. 2010. The National Academics Press, Washington, D.C. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56189/
[14] Wizemann T, Robinson S, Giffin R. Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies Workshop Summary. National Academy of Sciences, 2009.
[15] Crow YJ. Lupus: how much "complexity" is really (just) genetic heterogeneity? Arthritis and Rheumatism 63:3661-3664, 2011.
[16] Wade N. Many Rare Mutations May Underpin Diseases. The New York Times May 17, 2012.
Friday, February 26, 2016
Rare Disease Versions of Common Diseases
"Mille viae ducunt homines per saecula Romam" (A thousand roads lead men forever to Rome) - Alain de Lille in Liber Parabolarum, circa 1175
It is almost impossible to study a rare disease without uncovering some fundamental cellular mechanism underlying a common disease (1). The reason is simple: there are a finite number of mechanisms whereby cells can malfunction, and most of these mechanisms are encountered, in pure form, in one or another rare disease. Furthermore, the best way to understand a complex disease often involves understanding the rare diseases that reproduce the common disease phenotype.
For example, consider the pathologic complexity of cancer. Every measured pathway, organelle, and biochemical process is altered in cancer cells. The history of cancer research is littered by theories of carcinogenesis based on observations of malfunctioning cellular components. Here is a small sampling of paraphrased hypotheses:
"Cancer cells have unchecked proliferation, accounting for the malignant phenotype."
"Cancer cells preferentially employ anaerobic metabolism, which accounts for the malignant phenotype."
"Cancer cells have dysfunctional mitochondria, accounting for the malignant phenotype."
"Cancer cells have lost programmed senescence; hence the non-dying cells account for the malignant phenotype."
"Cancer cells have lost cellular junctions cell membrane processes that control transmembrane homeostasis, giving rise to a malignant phenotype."
"The epigenome is ultimately responsible for the normal control of the genome; when the epigenome is sufficiently altered, cells cannot behave normally, and cancer results.
"Cancer cells are genetically unstable, resulting in the selection of cells with a malignant phenotype."
These theories and many others have helped fund generations of cancer researchers. All of these theories were based on valid observations. The problem has been that when everything is changed from normal in a cell, as it is in cancer, it becomes impossible to select those changes that are the underlying causes of disease (2).
What is true for cancer is true for every complex disease. We cannot determine the effects of one variable on another variable when all the variables are changing, all of the time. Under such circumstances, the most we can do is to describe the phenotype of the diseases during its development, and make a reasonable guess as to what seems to be the most important events that arise as the disease progresses. The monogenic rare diseases are much easier to study; one gene changes, and one disease phenotype emerges. A monogenic disease is something that scientists can understand.
The set of rare diseases covers all the bases, so that every pathological expression of every pathway is presumably represented by a rare disease. If this is the case, you might expect similarities between the clinical phenotypes of common diseases and of rare diseases.
We have observed that there are few common diseases, and that there are many different causes for the common diseases. If many different causes lead to a limited number of common phenotypes, can we not infer that many pathways lead to the common diseases, including the pathways found in rare diseases (3), (4)?
In point of fact, there are monogenic forms of most, if not all, of the common diseases.
In at least one polygenic disease, Williams-Beuren syndrome, a gene associated with the disease has been assigned a specific trait, essentially establishing a monogenic disease within a polygenic disease. Williams-Beuren syndrome is a microdeletion disorder caused by a deletion of about 26 genes on the long arm of chromosome 7. It is characterized by a striking facial morphism described as "elfin", developmental delays, transient hypercalcemia, and cardiovascular abnormalities. One gene, of the 26 deleted genes, seems to account for all of the cardiovascular abnormalities (10). Other feature of the syndrome are seem to arise collectively from the other deleted genes.
If common diseases are puzzles, then rare diseases are the pieces of the puzzle.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, phenocopy disease, phenocopies jules j berman
References:
[1] Jiang X, Liu B, Jiang J, Zhao H, Fan M, Zhang J, et al. Modularity in the genetic disease-phenotype network. FEBS Letters 582 (2008) 2549-2554, 2008.
[2] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.
[3] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[4] Crow YJ. Lupus: how much "complexity" is really (just) genetic heterogeneity? Arthritis and Rheumatism 63:3661-3664, 2011.
[5] Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 365:2225-2236, 2005.
[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.
[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.
[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.
[9] Glaser RL, Goldbach-Mansky R. The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep 8:288-298, 2008.
[10] Pober BR. Williams-Beuren syndrome. New England Journal of Medicine 362:239-252, 2010.
It is almost impossible to study a rare disease without uncovering some fundamental cellular mechanism underlying a common disease (1). The reason is simple: there are a finite number of mechanisms whereby cells can malfunction, and most of these mechanisms are encountered, in pure form, in one or another rare disease. Furthermore, the best way to understand a complex disease often involves understanding the rare diseases that reproduce the common disease phenotype.
Rule - We know more about the pathogenesis of rare diseases than we know about the pathogenesis of common diseases.
Brief Rationale - Each common disease has many causes and many pathways that contribute to the fully developed clinical phenotype. Because many cellular events are happening at once, there really is no way to design a controlled experiment that can determine the consequences of altering a single component of the system. Hence, the common diseases are all somewhat inscrutable.
For example, consider the pathologic complexity of cancer. Every measured pathway, organelle, and biochemical process is altered in cancer cells. The history of cancer research is littered by theories of carcinogenesis based on observations of malfunctioning cellular components. Here is a small sampling of paraphrased hypotheses:
"Cancer cells have unchecked proliferation, accounting for the malignant phenotype."
"Cancer cells preferentially employ anaerobic metabolism, which accounts for the malignant phenotype."
"Cancer cells have dysfunctional mitochondria, accounting for the malignant phenotype."
"Cancer cells have lost programmed senescence; hence the non-dying cells account for the malignant phenotype."
"Cancer cells have lost cellular junctions cell membrane processes that control transmembrane homeostasis, giving rise to a malignant phenotype."
"The epigenome is ultimately responsible for the normal control of the genome; when the epigenome is sufficiently altered, cells cannot behave normally, and cancer results.
"Cancer cells are genetically unstable, resulting in the selection of cells with a malignant phenotype."
These theories and many others have helped fund generations of cancer researchers. All of these theories were based on valid observations. The problem has been that when everything is changed from normal in a cell, as it is in cancer, it becomes impossible to select those changes that are the underlying causes of disease (2).
What is true for cancer is true for every complex disease. We cannot determine the effects of one variable on another variable when all the variables are changing, all of the time. Under such circumstances, the most we can do is to describe the phenotype of the diseases during its development, and make a reasonable guess as to what seems to be the most important events that arise as the disease progresses. The monogenic rare diseases are much easier to study; one gene changes, and one disease phenotype emerges. A monogenic disease is something that scientists can understand.
Rule - Common diseases are aggregates of the individual pathogenic pathways that account for the rare diseases.
Brief Rationale - Because every pathway is a product of gene expression, and because virtually every gene of functional importance is a candidate for a rare disease, it is reasonable to assume that each of the many pathways that participate in the phenotypic expression of a common disease will be expressed, in one or more of the 7,000+ rare diseases.
The set of rare diseases covers all the bases, so that every pathological expression of every pathway is presumably represented by a rare disease. If this is the case, you might expect similarities between the clinical phenotypes of common diseases and of rare diseases.
Rule - Any polygenic disease can be replicated by a monogenic disease.
Brief Rationale - The phenotype associated with a polygenic disease converges toward a physiologically permissible outcome. Because there is a monogenic disease affecting virtually every pathway available to cells, it is likely that each common disease will be replicated by at least one monogenic disease that converges to the same clinical phenotype.
We have observed that there are few common diseases, and that there are many different causes for the common diseases. If many different causes lead to a limited number of common phenotypes, can we not infer that many pathways lead to the common diseases, including the pathways found in rare diseases (3), (4)?
In point of fact, there are monogenic forms of most, if not all, of the common diseases.
- MODY (Maturity onset diabetes of the young), also known as monogenic diabetes, refers to any of several hereditary forms of the disease. Despite its name, MODY develops in children, like most other rare diseases. The "Maturity onset" in its name refers to its common disease counterpart.
- Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a monogenic cause of autism.
- McKusick-Kaufman syndrome and Bardet-Biedl syndrome-6 are both diseases that include a monogenic form, that causes obesity.
- Monogenic emphysema due to alpha-1-antitrypsin deficiency (5).
- Monogenic gallstone disease due to a mutation in the ABCB4 gene.
- Monogenic cardiomyopathy due to a mutation in the ABCC9 gene.
- Monogenic cardiac arrhythmia due to monogenic mutations in ion channel genes
- Monogenic cause of migraine in familial hemiplegic migraine type 2 and familial basilar migraine, due to mutations in the gene encoding the alpha-2 subunit of the sodium/potassium pump.
- Monogenic osteoarthritis, as a component of familial osteochondritis dissecans, due to mutation in the ACAN gene.
- Familial Alzheimer disease type 1 due to a mutation in the gene encoding the amyloid precursor protein.
- Monogenic, Mendelian forms of hypertension associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules. Changes in electrolyte transport result in increased retention of sodium and to an increased volume of body fluid (6), (7), (8).
- Auto-inflammatory syndromes with monogenic subtypes, including familial Mediterranean fever caused by a mutation in the MEFV gene, encoding pyrin (9).
In at least one polygenic disease, Williams-Beuren syndrome, a gene associated with the disease has been assigned a specific trait, essentially establishing a monogenic disease within a polygenic disease. Williams-Beuren syndrome is a microdeletion disorder caused by a deletion of about 26 genes on the long arm of chromosome 7. It is characterized by a striking facial morphism described as "elfin", developmental delays, transient hypercalcemia, and cardiovascular abnormalities. One gene, of the 26 deleted genes, seems to account for all of the cardiovascular abnormalities (10). Other feature of the syndrome are seem to arise collectively from the other deleted genes.
If common diseases are puzzles, then rare diseases are the pieces of the puzzle.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, phenocopy disease, phenocopies jules j berman
References:
[1] Jiang X, Liu B, Jiang J, Zhao H, Fan M, Zhang J, et al. Modularity in the genetic disease-phenotype network. FEBS Letters 582 (2008) 2549-2554, 2008.
[2] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.
[3] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[4] Crow YJ. Lupus: how much "complexity" is really (just) genetic heterogeneity? Arthritis and Rheumatism 63:3661-3664, 2011.
[5] Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 365:2225-2236, 2005.
[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.
[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.
[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.
[9] Glaser RL, Goldbach-Mansky R. The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep 8:288-298, 2008.
[10] Pober BR. Williams-Beuren syndrome. New England Journal of Medicine 362:239-252, 2010.
Thursday, February 25, 2016
What are the diseases of Aging?
I've been having a running discussion with an old colleague over the designation: "Diseases of Aging." It would seem that the literature on the subject categorizes any disease that occurs exclusively or preferentially in the older population as a disease of aging. This, to me, is very very wrong. It is a mistake that has actually impeded much scientific advancement in the field of aging research; and it should be corrected.
The group of diseases that happen to occur in older individuals contain biologically unrelated diseases, many of which have nothing to do with the aging process. Furthermore, some of the most important intrinsic diseases of the aging process occur in children, and would not be included in listings of diseases that occur in the elderly.
I would divide age-related diseases into three biological categories:
1) Non-aging diseases that happen to occur in older people. These would include diseases that begin in youth, but which take many years to fully develop; hence occurring disproportionately in an older population. This category of disease would include most of the common types of cancers (e.g., squamous carcinoma of skin, lung cancer, colon cancer, prostate cancer). There is abundant evidence based on epidemiology and pathology evaluations, that these diseases begin to develop in young individuals, but become clinically manifest in older individuals.
2) Diseases that result from the normal aging process. These are common diseases that occur mostly in tissues that stop dividing after a certain age. Osteoarthritis is a good example. As chondrocytes (cartilage cells) stop dividing (a biological feature of aging), worn chondrocytes are no longer replaced by new cells, resulting in progressive damage to joint cartilage, leading to osteoarthritis in the elderly.
3) Intrinsic diseases of the aging process. These are the inherited progerias (discussed in detail in my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases). These diseases are exceedingly rare and occur in infancy and childhood.
Until we stop lumping biologically unrelated diseases of the elderly into the "diseases of aging" category, it is unlikely that we will make much progress in aging research.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, aging, ageing, diseases of aging, meaning of aging, jules j berman
The group of diseases that happen to occur in older individuals contain biologically unrelated diseases, many of which have nothing to do with the aging process. Furthermore, some of the most important intrinsic diseases of the aging process occur in children, and would not be included in listings of diseases that occur in the elderly.
I would divide age-related diseases into three biological categories:
1) Non-aging diseases that happen to occur in older people. These would include diseases that begin in youth, but which take many years to fully develop; hence occurring disproportionately in an older population. This category of disease would include most of the common types of cancers (e.g., squamous carcinoma of skin, lung cancer, colon cancer, prostate cancer). There is abundant evidence based on epidemiology and pathology evaluations, that these diseases begin to develop in young individuals, but become clinically manifest in older individuals.
2) Diseases that result from the normal aging process. These are common diseases that occur mostly in tissues that stop dividing after a certain age. Osteoarthritis is a good example. As chondrocytes (cartilage cells) stop dividing (a biological feature of aging), worn chondrocytes are no longer replaced by new cells, resulting in progressive damage to joint cartilage, leading to osteoarthritis in the elderly.
3) Intrinsic diseases of the aging process. These are the inherited progerias (discussed in detail in my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases). These diseases are exceedingly rare and occur in infancy and childhood.
Until we stop lumping biologically unrelated diseases of the elderly into the "diseases of aging" category, it is unlikely that we will make much progress in aging research.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, aging, ageing, diseases of aging, meaning of aging, jules j berman
Wednesday, February 24, 2016
Common Diseases Emerge from Rare Diseases
Rule - Every common disease was, at some point, a rare disease.
Brief Rationale - Every epidemic begins with a solitary case. Common diseases are equivalent to epidemics that settle in to stay.
Of course, this phenomenon of rare diseases becoming common diseases is something that happens all the time with infectious diseases. In a sense, we see this every year when a new strain of flu virus emerges as an epidemic. In a prior blog, we looked at several specific examples wherein environmental, and sociological factors played a role in transformaing a rare disease into a common disease. Specifically:
Heart disease. Increased availability of cheap fatty and sweet foods, combined with social factors that favor a sedentary life-style, raised the heart attack from a collection of rare, hereditary conditions to one of the most common causes of death in industrialized societies.
Colon cancer. Common in the United States, colon cancer has an incidence of 40/100,000. In Africa and some parts of Asia, colon cancer is a rare disease, with an incidence under 5/100,000 (2). Speculation abounds to explain why this is so, but the the issue of diet looms large. The low-fiber, low-vegetable, high-meat diet preferred in high-incidence societies, contrasted with the high-fiber, high-vegetable, low-meat diet in the low incidence societies provides a credible, if unproven, explanation.
AIDS. Late in 1981, a Haitian man presented at Jackson Memorial Hospital in Miami with a constellation of infectious diseases, a strange rash, and mouth lesions of an unfamiliar type. At the time, the attending physicians were baffled. Eventually, after a desperate review of the newest literature, a diagnosis of an extremely rare diseases tentatively named GRIDS (gay-related immune disease syndrome), was rendered. Today, GRIDS, now known as AIDS, is a diagnosis that can be rendered, without hesitation or error, by a first-year medical student. In 1981, there were about a dozen well-document cases in the U.S. In 2011, 1.7 million people died of AIDS worldwide (3).
Lung cancer. Prior to the popularization of cigarette smoking, lung cancer was extremely rare. Today, lung cancer is the leading cause of cancer deaths in every country where smoking is common.
Today, let's look at an inherited genetic condition that has morphed from a single case to a common disease, all within a half century.
There is an inherited immunodeficiency of cattle caused by a deficiency of leukocyte adhesion factor. Affected cattle are homozygous for a gene allele that codes for a substitution in a a single amino acid in its protein product. Heterozygotes (i.e., cattle with an unpaired mutant allele) are common in the U.S., with a carrier rate of about 10%. Every cattle with a mutant allele is a descendant from one bull, whose sperm was used to artificially inseminate cows in the 1950s and 1960s (1). A disease that was essentially non-existent in 1950 became a common scourge of the dairy industry within a half-century, all due to the founder effect amplified by modern animal husbandry
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, jules j berman
References:
[1] Kehrli ME, Ackermann MR, Shuster DE, van der Maaten MJ, Schmalstieg FC, Anderson DC, et al. Bovine leukocyte adhesion deficiency: beta(2) integrin deficiency in young Holstein cattle. Am J Path 140:1489-1492, 1992.
[2] World Cancer Research Fund and American Institute for Cancer Research Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC, American Institute for Cancer Research, 2007. Available at: http://www.aicr.org/assets/docs/pdf/reports/Second_Expert_Report.pdf, viewed August 13, 2015.
[3] Global Health Observatory. HIV/AIDS. World Health Organization. Available from http://www.who.int/gho/hiv/en/, viewed July 27, 2013.
Tuesday, February 23, 2016
Why do Common Diseases Typically Occur in Adults, while Rare Diseases occur in Children?
The rare diseases are often inherited monogenic diseases. Consequently every cell in the body contains the causal gene, and the gene has the opportunity to exert its effect throughout the period of embryonic development, and into childhood. Hence, the rare diseases tend to occur in childhood. The common diseases are caused by multiple factors that accumulate throughout life. Hence, the common diseases tend occur in adults. In general, the incidence of common diseases steadily increases with age
There are exceptions to the "one peak" rule. Some diseases have a bimodal distribution (i.e., two peaks). Distributions with more than two peaks are likely to occur, but the peaks in polymodal graphs run into one another and cannot, in general, be distinguished with certainty. Our ability to tease out polymodal data peaks may be improved, somewhat, as we become more adept at collecting information on large number of individuals, with verified, detailed quantitative feature data (i.e., age of occurrence of disease, gene mutations present in lesions, gene expression profiles)
For example, Hodgkin lymphoma, a rare tumor, has two peaks of disease occurrence
What does it mean when a rare disease breaks the "one peak" rule and demonstrates a bimodal age distribution? Here are a few possibilities:
Occasionally, we can determine the biological mechanism that accounts for a bimodal age distribution. For example, Kaposi sarcoma, caused by human herpesvirus-8, has two peaks in occurrence. The first peak, in young people, occurs in individuals with AIDS-related Kaposi sarcoma. The second peak occurs in older men, was a recognized disease entity prior to the AIDS epidemic (i.e., prior to 1980s), and is often referred to as "classic" Kaposi sarcoma. Classic Kaposi sarcoma is slow-growing, arises on the skin, often on the leg, and does not metastasize. It tends to occur in individuals of Mediterranean descent.
Once you begin to think about diseases in terms of multimodality, there is a short leap to thinking that the common, complex diseases are composite entities, composed of small sets of separate diseases that share a clinical phenotype.
In a provocative journal article entitled,"The many 'small COPDs', COPD should be an orphan disease," Stephen Rennard argued that many chronic diseases are actually heterogenous groups of diseases that we are just now learning to distinguish from one another (1). When we begin the process of separating diseases into related but distinguishable subsets of disease, we can begin to see why the common diseases may be aggregates of less common diseases. For example, mutation in the BRCA2 gene account for some cases of breast cancer, but the percentage is small. In fact, all of the known breast cancer risk genes, in aggregate, account for under 10% of the incidence of breast cancer. The remaining 90% would qualify today as sporadic tumors.
Interestingly, the same BRCA2 gene that accounts for a subset of cases of breast cancer, also accounts for a miniscule subset of a rare disease: Fanconi anemia. Most cases of Fanconi anemia are caused by mutations in genes coding for protein components of the Fanconi anemia protein complex which, along with BRCA2, helps coordinate DNA repair (2). A small percentage of Fanconi anemia patients are caused by homozygous mutations in the BRCA2 gene.
Though a rare disease hidden within a common disease accounts for only a small proportion of the total number of disease cases, the genetic cause of the rare disease subset may be much easier to find than the genetic cause of the so-called sporadic cases (3). When one mutated gene fully accounts for a subset of cases of a disease, its statistical association with with the disease can be demonstrated with a relatively small number of cases (3).
A rare subset of lung cancers is caused by a rearrangement in the NUT gene. As in so many other rare diseases that have a germline, monogenic cause, these cancers tend to occur in a much younger age group than cancers caused by an environmental factor (i.e., smoking, in this case) (4). The same observation holds for secretory breast carcinoma, formerly known as juvenile carcinoma of breast, which occurs in a younger age group than classic ductal breast carcinoma, and which is characterized by a specific fusion gene (5). Similarly, myelodysplastic syndrome, a preleukemic condition for which the preponderance of casses occur in elderly individuals, is known to occur in children who inherit a predisposition to losing chromosome 7 in somatic blood forming cells (6), (7).
Every type of cancer that is curable at an advanced stage (i.e., having multiple and widespread metastases) is a cancer of childhood. All of the cancers that typically occur late in life are incurable when they progress to an advanced stage.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, monogenic disease, disease genetics, jules j berman
References:
[1] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[2] D'Andrea AD.Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362(20):1909-1919, 2010.
[3] Li B, Leal SM. Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies. PLoS Genet 5:e1000481, 2009.
[4] French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline Carcinoma of Children and Young Adults With NUT Rearrangement. J Clin Oncol 22:4135-4139, 2004.
[5] Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367-376, 2002.
[6] Lizcova L, Zemanova Z, Malinova E, Jarosova M, Mejstrikova E, Smisek P, et al. A novel recurrent chromosomal aberration involving chromosome 7 in childhood myelodysplastic syndrome. Cancer Genet Cytogenet 201:52-56, 2010.
[7] Shannon KM, Turhan AG, Chang SS, Bowcock AM, Rogers PC, Carroll WL, et al. Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7. J Clin Invest 84:984-989, 1989.
Rule - When you graph the frequency of occurrence of a rare disease against the age of the individuals that develop the disease, there is usually one clear peak.
Brief Rationale - Rare diseases often result from a single mutation that enters the germline at the time of conception. The process by which the gene mutation leads to a clinical disease will require roughly the same length of time, in most affected individuals, producing a smooth, single peak, when disease occurrences are graphed against age of occurrence.
There are exceptions to the "one peak" rule. Some diseases have a bimodal distribution (i.e., two peaks). Distributions with more than two peaks are likely to occur, but the peaks in polymodal graphs run into one another and cannot, in general, be distinguished with certainty. Our ability to tease out polymodal data peaks may be improved, somewhat, as we become more adept at collecting information on large number of individuals, with verified, detailed quantitative feature data (i.e., age of occurrence of disease, gene mutations present in lesions, gene expression profiles)
Rule - Bimodality, when it occurs, is more often observed in the rare diseases, than the common diseases.
Brief Rationale - Because there are many occurrences of a common disease, second peaks (i.e. subpopulations with separate peak occurrence with age), are likely to be masked by the large number of occurrences of the larger peak. Because the total number of individuals with a rare disease is small, a relatively small subpopulation, with its own specific age of disease occurrence, is likely to produce a visible second peak, when the data is graphed.
For example, Hodgkin lymphoma, a rare tumor, has two peaks of disease occurrence
Graph showing incidence of Hodgkin Lymphoma, by age of occurrence of disease. There are two peaks in the graph. The first peak occurs in the early 20s. After the first peak, there is a trough, in the mid 40s, after which incidence increases steadily with age, toward a second peak. The graph was generated at the National Cancer Institute's Surveillance, Epidemiology and End Results "Fast Stats" query site.
http://seer.cancer.gov/faststats/selections.php?series=cancer
What does it mean when a rare disease breaks the "one peak" rule and demonstrates a bimodal age distribution? Here are a few possibilities:
1. Two different diseases, presumably with overlapping phenotypes, occur in two peak age groups, and are mistakenly assigned the same name.
2. A population is exposed to two environmental disease-causing agents, one working slower than the other.
3. A subpopulation is exposed to a different concentration of disease-causing agent, or at a different age, either resulting in disease occurring at a different average age, for the subpopulation.
4. Two genetic causes for the same disease have different latencies (i.e., lengths of time for the disease to develop)
5. Two sub-populations have different disease modifiers (i.e., sets of genes that alter the pathogenesis of the disease).
6. Faulty or insufficient data. Bimodality may be a distortion due to poor data that does not adequately conform to the naturally occurring (unimodal) distribution.
7. False conclusions based on accurate data. The second peak may be caused by valid by "noisy" data. Scientists should not assume that statistical conclusions, based on a single set of data, are correct. All conclusions must be constantly re-examined in light of new findings.
8. Combinations of examples 1 through 7.
Occasionally, we can determine the biological mechanism that accounts for a bimodal age distribution. For example, Kaposi sarcoma, caused by human herpesvirus-8, has two peaks in occurrence. The first peak, in young people, occurs in individuals with AIDS-related Kaposi sarcoma. The second peak occurs in older men, was a recognized disease entity prior to the AIDS epidemic (i.e., prior to 1980s), and is often referred to as "classic" Kaposi sarcoma. Classic Kaposi sarcoma is slow-growing, arises on the skin, often on the leg, and does not metastasize. It tends to occur in individuals of Mediterranean descent.
Once you begin to think about diseases in terms of multimodality, there is a short leap to thinking that the common, complex diseases are composite entities, composed of small sets of separate diseases that share a clinical phenotype.
Rule - A disease that can be separated into biological subsets, based on a quantifiable trait, such as age, can be interpreted as an aggregate of separate diseases, each with a smaller occurrence rate than the original disease.
Brief Rationale - By definition, a disease is a pathological condition that is biologically distinct from other pathologic conditions.
In a provocative journal article entitled,"The many 'small COPDs', COPD should be an orphan disease," Stephen Rennard argued that many chronic diseases are actually heterogenous groups of diseases that we are just now learning to distinguish from one another (1). When we begin the process of separating diseases into related but distinguishable subsets of disease, we can begin to see why the common diseases may be aggregates of less common diseases. For example, mutation in the BRCA2 gene account for some cases of breast cancer, but the percentage is small. In fact, all of the known breast cancer risk genes, in aggregate, account for under 10% of the incidence of breast cancer. The remaining 90% would qualify today as sporadic tumors.
Interestingly, the same BRCA2 gene that accounts for a subset of cases of breast cancer, also accounts for a miniscule subset of a rare disease: Fanconi anemia. Most cases of Fanconi anemia are caused by mutations in genes coding for protein components of the Fanconi anemia protein complex which, along with BRCA2, helps coordinate DNA repair (2). A small percentage of Fanconi anemia patients are caused by homozygous mutations in the BRCA2 gene.
Rule - Single gene mutations may account for small subsets of common diseases, but they do not account for large subsets of common diseases.
Brief Rationale - All the single gene disease mutations are rare. If this were not so, we would expect to see Mendelian inheritance, typical for monogenic diseases, among the common diseases; but we do not.
Though a rare disease hidden within a common disease accounts for only a small proportion of the total number of disease cases, the genetic cause of the rare disease subset may be much easier to find than the genetic cause of the so-called sporadic cases (3). When one mutated gene fully accounts for a subset of cases of a disease, its statistical association with with the disease can be demonstrated with a relatively small number of cases (3).
Rule - Rare diseases that are subsets of common diseases often occur in a younger population than the cases occurring in the larger set of individuals with so-called sporadic disease.
Brief Rationale - Rare diseases are typically germline, monogenic diseases that occur in young individuals.
A rare subset of lung cancers is caused by a rearrangement in the NUT gene. As in so many other rare diseases that have a germline, monogenic cause, these cancers tend to occur in a much younger age group than cancers caused by an environmental factor (i.e., smoking, in this case) (4). The same observation holds for secretory breast carcinoma, formerly known as juvenile carcinoma of breast, which occurs in a younger age group than classic ductal breast carcinoma, and which is characterized by a specific fusion gene (5). Similarly, myelodysplastic syndrome, a preleukemic condition for which the preponderance of casses occur in elderly individuals, is known to occur in children who inherit a predisposition to losing chromosome 7 in somatic blood forming cells (6), (7).
Rule - In a bimodal disease wherein the disease occurs in two age groups: young and old, the strongest likelihood of finding an effective treatment resides in the younger age group.
Brief Rationale - The younger age group is more likely to have a monogenic or oligogenic cause of the disease, and this often translates into a targeted cure. The older age group is likely to develop disease after the accumulation of multiple epigenetic, genetic, and environmental alterations, making it difficult to find an effective treatment.
Every type of cancer that is curable at an advanced stage (i.e., having multiple and widespread metastases) is a cancer of childhood. All of the cancers that typically occur late in life are incurable when they progress to an advanced stage.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, monogenic disease, disease genetics, jules j berman
References:
[1] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.
[2] D'Andrea AD.Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362(20):1909-1919, 2010.
[3] Li B, Leal SM. Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies. PLoS Genet 5:e1000481, 2009.
[4] French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline Carcinoma of Children and Young Adults With NUT Rearrangement. J Clin Oncol 22:4135-4139, 2004.
[5] Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367-376, 2002.
[6] Lizcova L, Zemanova Z, Malinova E, Jarosova M, Mejstrikova E, Smisek P, et al. A novel recurrent chromosomal aberration involving chromosome 7 in childhood myelodysplastic syndrome. Cancer Genet Cytogenet 201:52-56, 2010.
[7] Shannon KM, Turhan AG, Chang SS, Bowcock AM, Rogers PC, Carroll WL, et al. Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7. J Clin Invest 84:984-989, 1989.
Monday, February 22, 2016
More on the Complexity of Rare Monogenic Diseases
In yesterday's blog, we saw how one gene can cause several phenotypically distinctive diseases. In this section, we shall review the mechanisms whereby one disease can be caused by any one of several different genes. When one clinical phenotype is caused by any one of several different genes, the phenomenon is referred to locus heterogeneity.
Here are a few examples wherein rare, monogenic diseases can be caused by errors in any one of several different genes:
- Tuberous sclerosis is an inherited monogenic rare syndrome that produces multiple benign hamartomas, as well as certain types of cancers. The genetic basis of tuberous sclerosis involves bi-allelic inactivation of either of two unlinked genes that seem to have equivalent pathogenic roles. The genes are TSC1 (encoding hamartin) and TSC2 (encoding tuberin). In this disease, the hamartin and tuberin genes lock together in a protein complex. A defect in either gene disrupts the same pathway (1).
- Bardet-Biedl syndrome is characterized by rod-cone dystrophy, obesity, polydactyly, and a variety of organ abnormalities. The various forms of Bardet-Biedl syndrome are accounted for by mutations in one of at least 14 different genes. Although the underlying pathogenesis of Bardet-Biedl syndrome is yet to be clarified, there is evidence to suggest that each of the gene mutations known to cause Bardet-Biedl produce a defect in the basal body of ciliated cells (2). Such defects produce the pleiotropic phenotype that characterizes Bardet-Biedl syndrome.
- Li-Fraumeni syndrome is an inherited cancer syndrome characterized by an increased risk of developing such common cancers as breast cancer, lung cancer, colon cancer, pancreatic cancer, and prostate cancer. Various types of rare cancers associated with the Li-Fraumeni syndrome include soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemias, adrenocortical carcinomas, Wilms tumor, and phyllodes tumor of breast. The observation that common cancers and rare cancers having a common underlying genetic cause would seem to indicate that a rare genetic cause of a common disease can sometimes occur within a gene that is known to cause a rare disease.
Li-Fraumeni syndrome was originally believed to be caused exclusively by mutations in the TP53 gene encoding protein p53. TP53 is an example of a tumor suppressor gene. The absence of a tumor suppressor reduces the cell's normal ability to suppress cellular events that increase the susceptibility of cells to cancer. In the case of the p53 gene, loss of activity reduces the ability of cells to undergo apoptosis, a process by which cells commit suicide following DNA damage. By continuing to survive and divide, damaged cells contribute to a subpopulation of cells at risk for progressing through the stages of carcinogenesis. As it turns out, mutations in genes other than TP53 can produce a syndrome similar to, if not indistinguishable from, Li-Fraumeni syndrome. In addition to TP53, the genes that produce forms of Li-Fraumeni syndrome include CHEK2 and BRCA1 (3). In all three cases, the resulting syndrome results in a very high risk for breast cancer (4). All three genes have similar functions: controlling whether cells live or die following DNA damage.
- Retinitis pigmentosa is a group of inherited conditions characterized by the progressive loss of photoreceptor cells in the retina. Rhodopsin consists of the protein moiety opsin and a reversibly covalently bound cofactor, retinal (5). More than 100 mutations in the rhodopsin gene account for about 25% of cases. About 150 mutations have been reported in the opsin gene. Other mutated genes causing variants of retinitis pigmenotosa involve pre-mRNA splicing factors, as well as post-translational errors in protein folding and other errors of chaperone proteins. Mutations in any one of more than 35 different genes can cause variant forms of retinitis pigmentosa. Retinitis pigmentosa is unusual for being a disease that can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Digenic and mitochondrial forms of retinitis pigmentosa have been described, and the disease can appear as a solitary disorder or as part of a multi-organ syndrome (e.g., NARP syndrome of neuropathy, ataxia, and retinitis pigmentosa caused by a mutation in the mitochondrial DNA gene MT-ATP6).
Why there are so many forms of retinitis, with such a large repertoire of disease-causing genes, is somewhat of a mystery. Most of the genes causing various forms of retinitis pigmentosa express constituents of specialized photoreceptors found exclusively in retinal photoreceptor cells (e.g., rhodopsin). Other genes that cause retinitis pigmentosa are active in many different cells (e.g., splicing factors). The outer segment of rod photoreceptors are continuously shed from the tips of cells and replaced by new segments. Rods are extraordinarily dependent on maintaining a high rate of self-renewal, and small deficiencies in cell synthesis may precipitate the loss of these cells (6), (7), (8).
- Epidermolysis bullosa is an inherited disease characterized by blistering of the skin and mucosal membranes (e.g., mouth). It is always caused by a defect causing the epidermis to be poorly anchored to the underlying dermis. Over 300 gene defects can result in epidermolysis bullosa. Depending on the variant form of the disease, any of several different genes may serve as the underlying cause (e.g., COL, PLEC, Desmoplakin genes). There is also an autoimmune form of epidermolysis bullosa acquisita, wherein antibodies target Type VII collagen, a component of the basement membrane glue that helps bind epidermis with dermis.
There are also instances in which a rare phenotypic condition occurs as a component of multiple syndromes, each caused by a different genetic mutation. For example, inherited hemophagocytic lymphohistocytosis is a component of Chediak-Higashi syndrome and of Griscelli syndrome. Hemophagocytosis is the pathological phagocytosis (i.e., engulfment) of red blood cells by macrophages. Acquired hemophagocytic lymphohistocytosis can occur in Letterer-Siwe disease (9). In all cases, the final pathogenetic steps of these phenotypically related diseases involves the hypersecretion of cytokines by lymphocytes and macrophages, precipitating a severe, and life-threatening, inflammatory response, that includes hemophagocytosis.
In instances where a combined gene deficiency is found, the root cause may be a microdeletion, that deletes multiple genes, at once. Alternately, a combined deficiency may be caused by a pleiotropic gene that controls the synthesis of several different proteins. In combined factor V and factor VIII clotting factor deficiency, a defect in either the LMAN1 OR MCFD2 genes results in deminished transport of factor V and factor VIII from the endoplasmic reticulum to the Golgi apparatus. Hence, the post-translational processing of both these factors is incomplete, and a combined deficiency results. The gene products of MCFD2 and LMAN1 form a cargo receptor complex that acts on a similar set of proteins. Hence, mutations in either gene can produce the same combined deficiency of factor V and factor VIII (10).
The number of rare genetic syndromes that can be caused by any one of several different genes is quite long. A few additional examples are listed here.
The diseases discussed in this section are examples of disease convergence, in which different underlying processes eventually converge to a common phenotype.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, monogenic disease, disease genetics, jules j berman
References:
[1] van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053-1057, 1998.
[2] Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628-633, 2003.
[3] Silva AG, Ewald IP, Sapienza M, Pinheiro M, Peixoto A, de N brega AF, et al. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion. BMC Cancer 12:237, 2012.
[4] Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-1388, 2006.
[5] Hubbard R, Wald G. The mechanism of rhodopsin synthesis. Proc Natl Acad Sci USA.37:69-79, 1951.
[6] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.
[7] Korenbrot JI, Fernald RD. Circadian rhythm and light regulate opsin mRNA in rod photoreceptors. Nature 337:454-457, 1989.
[8] Tanackovic G, Ransijn A, Thibault P, Abou Elela S, Klinck R, Berson EL, et al. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 20:2116-2130, 2011.
[9] Dufourcq-Lagelouse R, Pastural E, Barrat FJ, Feldmann J, Le Deist F, Fischer A, et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review). Int J Mol Med 4:127-133, 1999.
[10] Zhang B, McGee B, Yamaoka JS, Guglielmone H, Downes KA, Minoldo S, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 107:1903-1907, 2006.
Here are a few examples wherein rare, monogenic diseases can be caused by errors in any one of several different genes:
- Tuberous sclerosis is an inherited monogenic rare syndrome that produces multiple benign hamartomas, as well as certain types of cancers. The genetic basis of tuberous sclerosis involves bi-allelic inactivation of either of two unlinked genes that seem to have equivalent pathogenic roles. The genes are TSC1 (encoding hamartin) and TSC2 (encoding tuberin). In this disease, the hamartin and tuberin genes lock together in a protein complex. A defect in either gene disrupts the same pathway (1).
- Bardet-Biedl syndrome is characterized by rod-cone dystrophy, obesity, polydactyly, and a variety of organ abnormalities. The various forms of Bardet-Biedl syndrome are accounted for by mutations in one of at least 14 different genes. Although the underlying pathogenesis of Bardet-Biedl syndrome is yet to be clarified, there is evidence to suggest that each of the gene mutations known to cause Bardet-Biedl produce a defect in the basal body of ciliated cells (2). Such defects produce the pleiotropic phenotype that characterizes Bardet-Biedl syndrome.
- Li-Fraumeni syndrome is an inherited cancer syndrome characterized by an increased risk of developing such common cancers as breast cancer, lung cancer, colon cancer, pancreatic cancer, and prostate cancer. Various types of rare cancers associated with the Li-Fraumeni syndrome include soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemias, adrenocortical carcinomas, Wilms tumor, and phyllodes tumor of breast. The observation that common cancers and rare cancers having a common underlying genetic cause would seem to indicate that a rare genetic cause of a common disease can sometimes occur within a gene that is known to cause a rare disease.
Li-Fraumeni syndrome was originally believed to be caused exclusively by mutations in the TP53 gene encoding protein p53. TP53 is an example of a tumor suppressor gene. The absence of a tumor suppressor reduces the cell's normal ability to suppress cellular events that increase the susceptibility of cells to cancer. In the case of the p53 gene, loss of activity reduces the ability of cells to undergo apoptosis, a process by which cells commit suicide following DNA damage. By continuing to survive and divide, damaged cells contribute to a subpopulation of cells at risk for progressing through the stages of carcinogenesis. As it turns out, mutations in genes other than TP53 can produce a syndrome similar to, if not indistinguishable from, Li-Fraumeni syndrome. In addition to TP53, the genes that produce forms of Li-Fraumeni syndrome include CHEK2 and BRCA1 (3). In all three cases, the resulting syndrome results in a very high risk for breast cancer (4). All three genes have similar functions: controlling whether cells live or die following DNA damage.
- Retinitis pigmentosa is a group of inherited conditions characterized by the progressive loss of photoreceptor cells in the retina. Rhodopsin consists of the protein moiety opsin and a reversibly covalently bound cofactor, retinal (5). More than 100 mutations in the rhodopsin gene account for about 25% of cases. About 150 mutations have been reported in the opsin gene. Other mutated genes causing variants of retinitis pigmenotosa involve pre-mRNA splicing factors, as well as post-translational errors in protein folding and other errors of chaperone proteins. Mutations in any one of more than 35 different genes can cause variant forms of retinitis pigmentosa. Retinitis pigmentosa is unusual for being a disease that can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Digenic and mitochondrial forms of retinitis pigmentosa have been described, and the disease can appear as a solitary disorder or as part of a multi-organ syndrome (e.g., NARP syndrome of neuropathy, ataxia, and retinitis pigmentosa caused by a mutation in the mitochondrial DNA gene MT-ATP6).
Why there are so many forms of retinitis, with such a large repertoire of disease-causing genes, is somewhat of a mystery. Most of the genes causing various forms of retinitis pigmentosa express constituents of specialized photoreceptors found exclusively in retinal photoreceptor cells (e.g., rhodopsin). Other genes that cause retinitis pigmentosa are active in many different cells (e.g., splicing factors). The outer segment of rod photoreceptors are continuously shed from the tips of cells and replaced by new segments. Rods are extraordinarily dependent on maintaining a high rate of self-renewal, and small deficiencies in cell synthesis may precipitate the loss of these cells (6), (7), (8).
- Epidermolysis bullosa is an inherited disease characterized by blistering of the skin and mucosal membranes (e.g., mouth). It is always caused by a defect causing the epidermis to be poorly anchored to the underlying dermis. Over 300 gene defects can result in epidermolysis bullosa. Depending on the variant form of the disease, any of several different genes may serve as the underlying cause (e.g., COL, PLEC, Desmoplakin genes). There is also an autoimmune form of epidermolysis bullosa acquisita, wherein antibodies target Type VII collagen, a component of the basement membrane glue that helps bind epidermis with dermis.
There are also instances in which a rare phenotypic condition occurs as a component of multiple syndromes, each caused by a different genetic mutation. For example, inherited hemophagocytic lymphohistocytosis is a component of Chediak-Higashi syndrome and of Griscelli syndrome. Hemophagocytosis is the pathological phagocytosis (i.e., engulfment) of red blood cells by macrophages. Acquired hemophagocytic lymphohistocytosis can occur in Letterer-Siwe disease (9). In all cases, the final pathogenetic steps of these phenotypically related diseases involves the hypersecretion of cytokines by lymphocytes and macrophages, precipitating a severe, and life-threatening, inflammatory response, that includes hemophagocytosis.
In instances where a combined gene deficiency is found, the root cause may be a microdeletion, that deletes multiple genes, at once. Alternately, a combined deficiency may be caused by a pleiotropic gene that controls the synthesis of several different proteins. In combined factor V and factor VIII clotting factor deficiency, a defect in either the LMAN1 OR MCFD2 genes results in deminished transport of factor V and factor VIII from the endoplasmic reticulum to the Golgi apparatus. Hence, the post-translational processing of both these factors is incomplete, and a combined deficiency results. The gene products of MCFD2 and LMAN1 form a cargo receptor complex that acts on a similar set of proteins. Hence, mutations in either gene can produce the same combined deficiency of factor V and factor VIII (10).
The number of rare genetic syndromes that can be caused by any one of several different genes is quite long. A few additional examples are listed here.
- Autosomal dominant cutis laxa can be caused by a mutation of the elastin gene or the fibulin-5 gene.
- Hypotrichosis simplex of the scalp can be caused by mutation in the CDSN gene or the KRT74 gene.
- Oguchi disease can be caused by a mutation oin the arrestin gene or the rhodopsin kinase gene.
- Autosomal dominant form of throbocytopenia can be caused by a mutation in the ANKRD26 gene, or the cytochrome c gene.
The diseases discussed in this section are examples of disease convergence, in which different underlying processes eventually converge to a common phenotype.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, monogenic disease, disease genetics, jules j berman
References:
[1] van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053-1057, 1998.
[2] Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628-633, 2003.
[3] Silva AG, Ewald IP, Sapienza M, Pinheiro M, Peixoto A, de N brega AF, et al. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion. BMC Cancer 12:237, 2012.
[4] Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-1388, 2006.
[5] Hubbard R, Wald G. The mechanism of rhodopsin synthesis. Proc Natl Acad Sci USA.37:69-79, 1951.
[6] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.
[7] Korenbrot JI, Fernald RD. Circadian rhythm and light regulate opsin mRNA in rod photoreceptors. Nature 337:454-457, 1989.
[8] Tanackovic G, Ransijn A, Thibault P, Abou Elela S, Klinck R, Berson EL, et al. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 20:2116-2130, 2011.
[9] Dufourcq-Lagelouse R, Pastural E, Barrat FJ, Feldmann J, Le Deist F, Fischer A, et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review). Int J Mol Med 4:127-133, 1999.
[10] Zhang B, McGee B, Yamaoka JS, Guglielmone H, Downes KA, Minoldo S, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 107:1903-1907, 2006.
Sunday, February 21, 2016
Monogenic Rare Diseases are Surprisingly Complex
"How is it that you keep mutating and can still be the same virus?" - Chuck Palahniuk, in his novel, Invisible Monsters
Monogenic diseases, caused by an aberration in a single gene, account for the majority of rare diseases. Monogenic diseases are the simplest diseases occurring in any organism, and one would think that once we identify the protein coded by the mutant gene, we would fully understand the disease. Nothing could be further from the truth. Knowing the gene, and its protein, may bring us to the root of the disease, but it does not explain how the disease develops; it does not explain the pathogenesis of the disease.
In point of fact, we know very little about the pathogenesis of most of the rare, monogenic diseases. When we try to study the pathogenesis of rare diseases, we quickly learn that they are much more complex than we had imagined. The complexity derives from the general biological properties of genes and of the cellular processes that influence the expression of genes. Let us examine a partial list of factors that add to the complexity of monogenic diseases.
1. A single gene may produce a protein product whose function varies depending on the specific site and type of mutation in the gene. Hence, variations in a gene can produce different diseases.
For example, different mutations of the same gene, desmoplakin, cause the following diseases:
- Arrhythmogenic right ventricular dysplasia 8
- Dilated cardiomyopathy with woolly hair and keratoderma
- Lethal acantholytic epidermolysis bullosa
- Keratosis palmoplantaris striata II
- Skin fragility-woolly hair syndrome
There are hundreds of examples of single genes that can produce more than one disease. Appendix I from my book, Rare Diseases and Orphan Drugs, contains a list of approximately 170 genes, with each gene known to be the underlying cause of more than one listed genetic diseases.
The disease caused by a gene may change depending on whether the gene is expressed as a germline mutation or a somatic mutation. In the case of the MYCN gene, a germline mutation resulting in MYCN gene haploinsufficiency (i.e., for which one gene is non-functional while the gene on its matching chromosome expresses a normal gene product) may produce Feingold syndrome, a developmental disorder characterized by microcephaly, limb malformations, esophageal and duodenal atresias, and other developmental alterations. The same gene, occurring in somatic cells (i.e., as new mutations in tissue cells of adult organisms), as an amplified gene, is associated with neuroblastoma formation.
In some cases, the diseases produced by a specific genetic mutation will change depending on the mutation's parental lineage. Prader-Willi syndrome is a genetic disease characterized by growth disorders (e.g., low muscle tone, short stature, extreme obesity, and cognitive disabilities). Angelman syndrome is a genetic disease characterized by neurologic disturbances (e.g., seizures, sleep disturbances, hand-flapping), and a typifying happy demeanor. Both diseases can occur in either gender and both diseases are caused by the same microdeletion at 15q11-13. When the microdeletion occurs on the paternally-derived chromosome, the disease that results is Prader-Willi syndrome. When the microdeletion occurs on the maternally-derived chromosome, the disease that results is Angelman syndrome.
In some cases, variation in the sites of mutations in a gene do not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott-Aldrich syndrome, mutations that truncate the protein product of the WAS gene will produce severe disease, while mutations that produce changes in single amino acids, without changing the length of the protein, will tend to produce mild disease (1).
In some cases, the gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, H19 differentially methylated region is a site on chromosome 11p15.5 in which microdeletions occur in some cases of Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Opposite methylation patterns in the H19 differentially methylated region will cause Beckwith-Wiedemann syndrome when there is gain-of-methylation and Russell-Silver syndrome when there is loss-of-methylation (2). Beckwith-Wiedemann syndrome is characterized by tissue overgrowth and tumor formation (3). Russell-Silver syndrome is characterized by dwarfism.
2. A single gene may encode a regulatory protein that effects many other proteins, to produce a disease that affects many different tissues, through unrelated mechanisms. It may be difficult or impossible to determine all the different proteins and pathways that are altered by a defective regulatory gene.
In general, diseases due to genes encoding transcription factors are characterized by multiple anomalies of development and growth. Transcription factors are proteins that bind to specific DNA sequences to control the transcription of DNA to RNA. A mutation in a single transcription factor can produce a phenotypically complex syndrome. For example a mutation in the gene encoding transcription factor TBX5 causes Holt-Oram syndrome, consisting of hand malformations, heart defects and other malformations.
3. A protein with a single function may exert a pleiotypic response in different types of cells and tissues, causing may different phenotypic changes in tissues, to produce a seemingly complex disease phenotype.
Consider the example of the rare disease, ligneous conjunctivitis. Ligneous conjunctivitis is caused by a deficiency of a single protein, plasminogen. Plasmin, the activated form of plasminogen, breaks down fibrin, a protein produced during coagulation and clot formation. In the absence of plasminogen, fibrin accumulates in various sites, and the accumulating fibrin dries out as a hard material. On the surface of the eyes, dried fibrin elicits inflammation, leading to a thick, hardened focus of conjunctivitis (i.e., ligneous conjunctivitis). Accumulating fibrin in the middle ear and the tracheo-bronchial mucosa (of the lungs), leads to inflammation at these sites. In the brain, an occlusive hydrocephalus may occur, due to fibrin deposits blocking the normal flow and clearance of cerebrospinal fluid in the brain ventricles. In retrospect, the pathogenesis of ligneous conjunctivitis is simple to understand. All of the pleiotrophic effects are the result of a deficiency of a single protein, with a single function, that happens to be expressed in several different organs to produce a variety of clinical conditions that are closely related to one another; but not obviously so. Ligneous conjunctivitis is an example of the simplest form of pleiotropism, wherein seemingly unrelated phenotypes result from an alteration in a single expressed protein, and a single functional pathway.
Another example of pleiotypia resulting from a gene with a single function is found in the WHIM syndrome. WHIM is an acronym for Warts, Hypogammaglobulinemia, Infections and Myelokathexis (congenital leukopenia and neutropenia). We now know that WHIM is a combined immunodeficiency disease caused by an alteration in the chemokine receptor gene CXCR4 (4). Warts result from a lowered immune repression of papillomaviruses. Likewise, the other phenotypic components of the disease arise from the aberrant chemokine. Though the altered CXCR4 gene produces a syndrome with a complex phenotype, it does so through the action of one protein with one function.
4. A protein with a single function may exert a single type of response, but that response may depend on the genetic and epigenetic conditions under which the protein is expressed. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration.
If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical, in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse. If the mouse homolog served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same, in man and mouse.
Lesch-Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphporibosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompany the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal (5). How can this be? A single gene cannot cause a disease, all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.
Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY. Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene (6).
Though there is often striking phenotypic homogeneity among humans with the same genetic defect, there are many exceptions. Modifier genes can influence the time of onset of disease, the severity of disease, and the clinical phenotype of genetic diseases (7).
5. A single protein encoded by a single gene may have many different biological effects and functions, and these functions may differ based on the cell type in which the protein is expressed, the stage of development in which the protein is expressed, and the cellular milieu (e.g., concentrations of substrate or protein inhibitors) for a given cell type, at a particular moment in time. Hence, a specific aberration in a single gene may produce different diseases, depending on factors that are difficult to anticipate or analyze.
Sometimes, one gene may code for a protein that has multiple different roles, thus producing diseases of widely disparate clinical phenotypes. For example, nuclear lamina (lamin a/c) has several biological roles: controlling nuclear shape; influencing transcription; and organizing heterochromatin. Mutations in the LMNA gene cause more than 10 different clinical syndromes, including neuromuscular and cardiac disorders, premature aging disorders, and lipodystrophy. Likewise, the polyfunctional TP53 gene has been linked to 11 clinically distinguishable cancer related disorders (8).
A bull in a china shop will do more damage than a mouse in a china shop. For example, The APOE gene encodes apolipoprotein E, which is involved in the synthesis of lipoproteins. One common allele of the APOE locus, e4, increases the risk of two common diseases with no obvious biological relationship: Alzheimer disease and heart disease (9), (10). A rare locus of APOE is a associated with longevity (11).
6. The pathogenesis of a monogenic disease may be complex, requiring many events to occur in a particular sequence, over a period of time, culminating in a disease phenotype. Deviations from the usual steps in pathogenesis may delay or eliminate the occurrence of disease.
Many of the rare monogenic diseases express a characteristic clinical phenotype at birth (e.g., birth defects), or in early childhood. A minority of rare, monogenic diseases are not expressed until adulthood. What can we infer from this observation?
The many inherited cancer syndromes produce tumors in a younger age group than the same tumors that occur sporadically. Still, these inherited tumors tend to occur in early or mid-adulthood, not at or near birth. Cancer is a multi-step process. An inherited mutation that accounts for one step in the process may shorten the time for development of the cancer, but it cannot eliminate the remaining steps.
Huntington disease is a rare monogenic inherited disease that usually begins in adults between 35 and 45 years of age. It is caused by a CAG triplet repeat inside the Huntington gene. The mutant gene slowly poisons brain cells, particularly neurons in the caudate nucleus, putamen, and substantia nigra. The toxic effects of the mutant protein are slow to cause injury, hence the late onset of disease.
Cardiofaciocutaneous syndrome is a rare monogenic inherited disorder characterized by a set of distinctive congenital abnormalities involving the face, heart, and other organs. It is caused by mutations in any of several different genes, including BRAF. In a zebrafish model of cardiofaciocutaneous syndrome, fish embryos express the BRAF disease allele. Treatment of the affected embryos with inhibitors of the pathway affected by the BRAF mutation will restore normal development in these fish (12). The inhibitor needed to be administered in a window of time when the BRAF mutation exerted its teratogenic effect. In this case, the pathogenesis of disease could be interrupted by an additional event occurring at a crucial moment of time.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, monogenic diseases, complex diseases, common diseases, jules j berman
References:
[1] Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood 104:4010-4019, 2004.
[2] Soejima H, Higashimoto K. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. J Hum Genet 58:402-409, 2013.
[3] Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 18:8-14, 2010.
[4] Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70-74, 2003.
[5] Engle SJ, Womer DE, Davies PM, Boivin G, Sahota A, Simmonds HA, et al. HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome. Hum Mol Genet 5:1607-1610, 1996.
[6] Raeder H, Vesterhus M, El Ouaamari A, Paulo JA, McAllister FE, Liew CW, et al. Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PLoS One 8:e60229, 2013.
[7] Nebert DW, Zhang G, Vesell ES. From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metab Rev 40:187-224, 2008.
[8] Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 408:307-310, 2000.
[9] Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant . . . or not? Human Molecular Genetics 11:2417-2423, 2002.
[10] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 261:921-923, 1993.
[11] Beekman M, Blanch H, Perola M, Hervonen A, Bezrukov V, Sikora E, et al. Genome-wide linkage analysis for human longevity: genetics of healthy aging study. Aging Cell 12:184-193, 2013.
[12] Anastasaki C, Estep AL, Marais R, Rauen KA, Patton EE. Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Hum Molec Genet 18:2543-2554, 2009.
Monogenic diseases, caused by an aberration in a single gene, account for the majority of rare diseases. Monogenic diseases are the simplest diseases occurring in any organism, and one would think that once we identify the protein coded by the mutant gene, we would fully understand the disease. Nothing could be further from the truth. Knowing the gene, and its protein, may bring us to the root of the disease, but it does not explain how the disease develops; it does not explain the pathogenesis of the disease.
In point of fact, we know very little about the pathogenesis of most of the rare, monogenic diseases. When we try to study the pathogenesis of rare diseases, we quickly learn that they are much more complex than we had imagined. The complexity derives from the general biological properties of genes and of the cellular processes that influence the expression of genes. Let us examine a partial list of factors that add to the complexity of monogenic diseases.
1. A single gene may produce a protein product whose function varies depending on the specific site and type of mutation in the gene. Hence, variations in a gene can produce different diseases.
For example, different mutations of the same gene, desmoplakin, cause the following diseases:
- Arrhythmogenic right ventricular dysplasia 8
- Dilated cardiomyopathy with woolly hair and keratoderma
- Lethal acantholytic epidermolysis bullosa
- Keratosis palmoplantaris striata II
- Skin fragility-woolly hair syndrome
There are hundreds of examples of single genes that can produce more than one disease. Appendix I from my book, Rare Diseases and Orphan Drugs, contains a list of approximately 170 genes, with each gene known to be the underlying cause of more than one listed genetic diseases.
The disease caused by a gene may change depending on whether the gene is expressed as a germline mutation or a somatic mutation. In the case of the MYCN gene, a germline mutation resulting in MYCN gene haploinsufficiency (i.e., for which one gene is non-functional while the gene on its matching chromosome expresses a normal gene product) may produce Feingold syndrome, a developmental disorder characterized by microcephaly, limb malformations, esophageal and duodenal atresias, and other developmental alterations. The same gene, occurring in somatic cells (i.e., as new mutations in tissue cells of adult organisms), as an amplified gene, is associated with neuroblastoma formation.
In some cases, the diseases produced by a specific genetic mutation will change depending on the mutation's parental lineage. Prader-Willi syndrome is a genetic disease characterized by growth disorders (e.g., low muscle tone, short stature, extreme obesity, and cognitive disabilities). Angelman syndrome is a genetic disease characterized by neurologic disturbances (e.g., seizures, sleep disturbances, hand-flapping), and a typifying happy demeanor. Both diseases can occur in either gender and both diseases are caused by the same microdeletion at 15q11-13. When the microdeletion occurs on the paternally-derived chromosome, the disease that results is Prader-Willi syndrome. When the microdeletion occurs on the maternally-derived chromosome, the disease that results is Angelman syndrome.
In some cases, variation in the sites of mutations in a gene do not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott-Aldrich syndrome, mutations that truncate the protein product of the WAS gene will produce severe disease, while mutations that produce changes in single amino acids, without changing the length of the protein, will tend to produce mild disease (1).
In some cases, the gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, H19 differentially methylated region is a site on chromosome 11p15.5 in which microdeletions occur in some cases of Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Opposite methylation patterns in the H19 differentially methylated region will cause Beckwith-Wiedemann syndrome when there is gain-of-methylation and Russell-Silver syndrome when there is loss-of-methylation (2). Beckwith-Wiedemann syndrome is characterized by tissue overgrowth and tumor formation (3). Russell-Silver syndrome is characterized by dwarfism.
2. A single gene may encode a regulatory protein that effects many other proteins, to produce a disease that affects many different tissues, through unrelated mechanisms. It may be difficult or impossible to determine all the different proteins and pathways that are altered by a defective regulatory gene.
In general, diseases due to genes encoding transcription factors are characterized by multiple anomalies of development and growth. Transcription factors are proteins that bind to specific DNA sequences to control the transcription of DNA to RNA. A mutation in a single transcription factor can produce a phenotypically complex syndrome. For example a mutation in the gene encoding transcription factor TBX5 causes Holt-Oram syndrome, consisting of hand malformations, heart defects and other malformations.
3. A protein with a single function may exert a pleiotypic response in different types of cells and tissues, causing may different phenotypic changes in tissues, to produce a seemingly complex disease phenotype.
Consider the example of the rare disease, ligneous conjunctivitis. Ligneous conjunctivitis is caused by a deficiency of a single protein, plasminogen. Plasmin, the activated form of plasminogen, breaks down fibrin, a protein produced during coagulation and clot formation. In the absence of plasminogen, fibrin accumulates in various sites, and the accumulating fibrin dries out as a hard material. On the surface of the eyes, dried fibrin elicits inflammation, leading to a thick, hardened focus of conjunctivitis (i.e., ligneous conjunctivitis). Accumulating fibrin in the middle ear and the tracheo-bronchial mucosa (of the lungs), leads to inflammation at these sites. In the brain, an occlusive hydrocephalus may occur, due to fibrin deposits blocking the normal flow and clearance of cerebrospinal fluid in the brain ventricles. In retrospect, the pathogenesis of ligneous conjunctivitis is simple to understand. All of the pleiotrophic effects are the result of a deficiency of a single protein, with a single function, that happens to be expressed in several different organs to produce a variety of clinical conditions that are closely related to one another; but not obviously so. Ligneous conjunctivitis is an example of the simplest form of pleiotropism, wherein seemingly unrelated phenotypes result from an alteration in a single expressed protein, and a single functional pathway.
Another example of pleiotypia resulting from a gene with a single function is found in the WHIM syndrome. WHIM is an acronym for Warts, Hypogammaglobulinemia, Infections and Myelokathexis (congenital leukopenia and neutropenia). We now know that WHIM is a combined immunodeficiency disease caused by an alteration in the chemokine receptor gene CXCR4 (4). Warts result from a lowered immune repression of papillomaviruses. Likewise, the other phenotypic components of the disease arise from the aberrant chemokine. Though the altered CXCR4 gene produces a syndrome with a complex phenotype, it does so through the action of one protein with one function.
4. A protein with a single function may exert a single type of response, but that response may depend on the genetic and epigenetic conditions under which the protein is expressed. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration.
If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical, in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse. If the mouse homolog served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same, in man and mouse.
Lesch-Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphporibosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompany the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal (5). How can this be? A single gene cannot cause a disease, all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.
Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY. Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene (6).
Though there is often striking phenotypic homogeneity among humans with the same genetic defect, there are many exceptions. Modifier genes can influence the time of onset of disease, the severity of disease, and the clinical phenotype of genetic diseases (7).
5. A single protein encoded by a single gene may have many different biological effects and functions, and these functions may differ based on the cell type in which the protein is expressed, the stage of development in which the protein is expressed, and the cellular milieu (e.g., concentrations of substrate or protein inhibitors) for a given cell type, at a particular moment in time. Hence, a specific aberration in a single gene may produce different diseases, depending on factors that are difficult to anticipate or analyze.
Sometimes, one gene may code for a protein that has multiple different roles, thus producing diseases of widely disparate clinical phenotypes. For example, nuclear lamina (lamin a/c) has several biological roles: controlling nuclear shape; influencing transcription; and organizing heterochromatin. Mutations in the LMNA gene cause more than 10 different clinical syndromes, including neuromuscular and cardiac disorders, premature aging disorders, and lipodystrophy. Likewise, the polyfunctional TP53 gene has been linked to 11 clinically distinguishable cancer related disorders (8).
Rule - A single pleiotropic gene is likely to be associated with several phenotypically unrelated diseases.
Brief Rationale - Genes with pleiotropic pathological effects, and genes that alter a pathway that operates in many different types of cells, are likely to play a role in the pathogenesis of more than one disease, simply because they perturb many different cellular processes.
A bull in a china shop will do more damage than a mouse in a china shop. For example, The APOE gene encodes apolipoprotein E, which is involved in the synthesis of lipoproteins. One common allele of the APOE locus, e4, increases the risk of two common diseases with no obvious biological relationship: Alzheimer disease and heart disease (9), (10). A rare locus of APOE is a associated with longevity (11).
6. The pathogenesis of a monogenic disease may be complex, requiring many events to occur in a particular sequence, over a period of time, culminating in a disease phenotype. Deviations from the usual steps in pathogenesis may delay or eliminate the occurrence of disease.
Many of the rare monogenic diseases express a characteristic clinical phenotype at birth (e.g., birth defects), or in early childhood. A minority of rare, monogenic diseases are not expressed until adulthood. What can we infer from this observation?
Rule - Monogenic rare diseases that express in late adolescence, or in adulthood, are likely to require additional events (i.e., somatic genetic mutations, toxic exposures, or the accumulation of molecular species or cellular alterations caused by the original genetic defect) that occur over time.
Brief Rationale - If this were not the case, every inherited genetic defect would be expected to express itself clinically at birth or in early childhood.
The many inherited cancer syndromes produce tumors in a younger age group than the same tumors that occur sporadically. Still, these inherited tumors tend to occur in early or mid-adulthood, not at or near birth. Cancer is a multi-step process. An inherited mutation that accounts for one step in the process may shorten the time for development of the cancer, but it cannot eliminate the remaining steps.
Huntington disease is a rare monogenic inherited disease that usually begins in adults between 35 and 45 years of age. It is caused by a CAG triplet repeat inside the Huntington gene. The mutant gene slowly poisons brain cells, particularly neurons in the caudate nucleus, putamen, and substantia nigra. The toxic effects of the mutant protein are slow to cause injury, hence the late onset of disease.
Cardiofaciocutaneous syndrome is a rare monogenic inherited disorder characterized by a set of distinctive congenital abnormalities involving the face, heart, and other organs. It is caused by mutations in any of several different genes, including BRAF. In a zebrafish model of cardiofaciocutaneous syndrome, fish embryos express the BRAF disease allele. Treatment of the affected embryos with inhibitors of the pathway affected by the BRAF mutation will restore normal development in these fish (12). The inhibitor needed to be administered in a window of time when the BRAF mutation exerted its teratogenic effect. In this case, the pathogenesis of disease could be interrupted by an additional event occurring at a crucial moment of time.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, monogenic diseases, complex diseases, common diseases, jules j berman
References:
[1] Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood 104:4010-4019, 2004.
[2] Soejima H, Higashimoto K. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. J Hum Genet 58:402-409, 2013.
[3] Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 18:8-14, 2010.
[4] Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70-74, 2003.
[5] Engle SJ, Womer DE, Davies PM, Boivin G, Sahota A, Simmonds HA, et al. HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome. Hum Mol Genet 5:1607-1610, 1996.
[6] Raeder H, Vesterhus M, El Ouaamari A, Paulo JA, McAllister FE, Liew CW, et al. Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PLoS One 8:e60229, 2013.
[7] Nebert DW, Zhang G, Vesell ES. From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metab Rev 40:187-224, 2008.
[8] Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 408:307-310, 2000.
[9] Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant . . . or not? Human Molecular Genetics 11:2417-2423, 2002.
[10] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 261:921-923, 1993.
[11] Beekman M, Blanch H, Perola M, Hervonen A, Bezrukov V, Sikora E, et al. Genome-wide linkage analysis for human longevity: genetics of healthy aging study. Aging Cell 12:184-193, 2013.
[12] Anastasaki C, Estep AL, Marais R, Rauen KA, Patton EE. Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Hum Molec Genet 18:2543-2554, 2009.
Saturday, February 20, 2016
Rare Spliceosome Diseases
In animals, DNA sequences are not transcribed directly into full-length RNA molecules, ready for translation into a final protein. There is a pre-translational process wherein transcribed sections of DNA, so-called introns, are spliced together, and a single gene can be assembled into alternative spliced products. Alternative splicing is one method whereby more than one protein form can be produced by a single gene (1). Cellular proteins that coordinate the splicing process are referred to, in aggregate, as the spliceosome. Errors in normal splicing can produce inherited disease, and it estimated that 15% of disease-causing mutations involve splicing (2), (3). Examples of spliceosome diseases are spinal muscular atrophy and some forms of retinitis pigmentosa (1). In both diseases, pathology is limited to a specific type of cell; retinal cells and their pigment layer in retinitis pigmentosa, and motor neuron cells in the spinal muscular atrophy. One might expect that mutations in spliceosomes would cause deficiencies in diverse cell types, with multi-organ and multi-system disease (e.g., syndromic disease). That this is not the case is somewhat of a mystery, and the catalyst for much speculation. Faustino and Cooper have categorized splicing diseases into different types, including: those that affect a single gene, those that affect multiple genes, those that cause aberrant splicing that result in unnatural mRNAs, and those that cause the inappropriate expression of natural mRNAs (1).
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, DNA splicing, common diseases, jules j berman
References:
[1] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.
[2] Pagani F, Baralle FE. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389-396, 2004.
[3] Fraser HB, Xie X. Common polymorphic transcript variation in human disease. Genome Res 2009 Apr;19(4):567-575, 2009.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, DNA splicing, common diseases, jules j berman
References:
[1] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.
[2] Pagani F, Baralle FE. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389-396, 2004.
[3] Fraser HB, Xie X. Common polymorphic transcript variation in human disease. Genome Res 2009 Apr;19(4):567-575, 2009.
Friday, February 19, 2016
Rare Diseases and the Quantitative Traits of Common Diseases
"Only theory can tell us what to measure and how to interpret it." - Albert Einstein
Though hypertension influences the development of a great many serious co-morbidities (e.g., renal failure, stroke, heart failure), those of us inclined to dwell on technicalities will insist that hypertension is not a disease; it is a physiologic measurement. Hypertension occurs when our blood pressure rises above a certain quantitative threshold, but there is no specific pathologic finding that characterizes hypertension; nor is there a specific clinical phenotype that tells us that an individual with hypertension is ill. It is best to think of hypertension as a quantitative trait that signals a complex problem.
What is the quantitative measure of hypertension? Definitions vary, but an often-used cut-off is a systolic blood pressure exceeding 140 mm Hg, or a diastolic pressure exceeding 90 mm Hg. It is estimated that 25% of adults and over one billion people worldwide are hypertensive (1), (2). Because high blood pressure is a quantitative trait, and not a disease, the majority of the occurrences of hypertension cannot have a monogenic cause. Theory, strengthened by empiric observations, informs us that quantitative traits have multi-factorial causes, and that inherited quantitative traits have non-Mendelian inheritance. The non-Mendelian origin of inherited quantitative traits has been recognized since the early studies of RA Fisher, in 1919 (3), (4), (5). Research scientists could have saved themselves a great deal of effort, over the past few decades, searching for a specific genetic cause for commonly occurring cases of hypertension, had they simply recognized that hypertension is a quantitative trait, not a disease.
We typically find that hypertension co-occurs with rare diseases such as fibromuscular dysplasia, hyperaldosteronism, and various channelopathies; and common diseases such as metabolic syndrome, stroke, and left ventricular hyperplasia. Fibromuscular dysplasia is a rare condition of arteries wherein pathological growth of the artery's muscular wall produces a functional narrowing of the artery at the dysplastic site. Fibromuscular dysplasia occurs most often in young-to-middle aged women, but cases have occurred at every age and in either gender. Its cause is unknown. When fibromuscular dysplasia occurs in a renal artery, the blood flow to the kidney distal to the point of narrowing is reduced, thus producing an orchestrated physiological response of the renin-angiotensin-aldosterone system that produces hypertension.
Here is how the renin-angiotensin-aldosterone system works. Specialized cells located at the root of the glomeruli (i.e., the juxtaglomerular cells) release renin into the general circulation when the blood pressure drops. Renin is involved in a pathway that produces a powerful vasoconstrictor (i.e., angiotensin II) in the lungs. This same vasoconstrictor stimulates the adrenal cortex to secrete aldosterone (part of the mineralcorticoid system), which causes the kidney to increase its absorption of sodium and water; thus increasing the volume of fluid in the body. Increased blood volume produces an increase in blood pressure. In summary, when fibromuscular dysplasia reduces the blood floow to the kidney, the kidney responds as if there were a system-wide drop in blood pressure, setting into motion a two connected pathways that increase blood pressure. Because the hypertensive response does not "turn off" the localized hypotensive effect of fibromuscular dysplasia, the renin-angiotensin-aldosterone response stays "on" permanently, contributing to ever-worsening hypertension.
Observations of hypertension resulting from fibromuscular dysplasia of the renal artery, would suggest that variants of any components of the renin, angiotensin, or aldosterone system could contribute to quantitative alterations in blood pressure. As it happens, most of the rare monogenic and Mendelian forms of hypertension are associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules, resulting in increased retention of sodium and to an increased volume of body fluid, and the enlistment of the mineralcorticoid system (6), (7), (8), (9), (1).
Rare causes of hypertension dovetail with medically proven methods for treating and preventing common hypertension. Standard therapies for treating hypertension include drugs that target the angiotensin pathway (i.e., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and diuretics. The mainstay of prevention is dietary salt reduction (10).
Genome wide association studies have yielded several dozen genes associated with commonly occurring hypertension (11), (2). These associated genes seem to account for a very small portion of the occurences of hypertension in the general population (11). The function of the majority of the associated genes is unknown at present.
There are numerous genetic and environmental causes of hypertension, targeting a wide variety of cellular pathways and anatomic sites. As examples, the different causes of hypertension may include: over-activity of the renin-angiotensin system; defects at various sites of the renal tubule, arterial wall pathology; and increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease produce hypertension through the same, final pathway: increased net salt balance, leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure (1). Because all causes of hypertension produce an increase in net salt balance, almost all individuals with hypertension will respond to treatment with diuretics such as hydrochlorothiazide or furosemide, that reduce the reabsorption of sodium in the kidneys. A common, final mechanism accounting for all causes of hypertension, is an example of disease convergence. Disease convergence is an extremely important concept, as it provides an opportunity to treat many different diseases with a single medication, if they converge to the same pathway.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, hypertension, jules j berman
References:
[1] Lifton RP, Gharavi AG, Geller DS. Molecular Mechanisms of Human Hypertension. Cell 104:545-556, 2001
[2] International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-109, 2011.
[3] Fisher, RA. The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb 52:399-433, 1918.
[4] Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nature Biotechnology 30:1095-1106, 2012.
[5] Visscher PM, McEvoy B, Yang J. From Galton to GWAS: quantitative genetics of human height. Genet Res 92:371-379, 2010.
[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.
[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.
[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.
[9] Warnock DG. Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci 322:302-307, 2001.
[10] Hideaki Nakagawa H, Katsuyuki Miura K. Salt reduction in a population for the prevention of hypertension.Environ Health Prev Med 9:123-129, 2004.
[11] Cowley AW Jr, Nadeau JH, Baccarelli A, Berecek K, Fornage M, Gibbons GH, et al. Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. Hypertension 59:899-905, 2012
Though hypertension influences the development of a great many serious co-morbidities (e.g., renal failure, stroke, heart failure), those of us inclined to dwell on technicalities will insist that hypertension is not a disease; it is a physiologic measurement. Hypertension occurs when our blood pressure rises above a certain quantitative threshold, but there is no specific pathologic finding that characterizes hypertension; nor is there a specific clinical phenotype that tells us that an individual with hypertension is ill. It is best to think of hypertension as a quantitative trait that signals a complex problem.
What is the quantitative measure of hypertension? Definitions vary, but an often-used cut-off is a systolic blood pressure exceeding 140 mm Hg, or a diastolic pressure exceeding 90 mm Hg. It is estimated that 25% of adults and over one billion people worldwide are hypertensive (1), (2). Because high blood pressure is a quantitative trait, and not a disease, the majority of the occurrences of hypertension cannot have a monogenic cause. Theory, strengthened by empiric observations, informs us that quantitative traits have multi-factorial causes, and that inherited quantitative traits have non-Mendelian inheritance. The non-Mendelian origin of inherited quantitative traits has been recognized since the early studies of RA Fisher, in 1919 (3), (4), (5). Research scientists could have saved themselves a great deal of effort, over the past few decades, searching for a specific genetic cause for commonly occurring cases of hypertension, had they simply recognized that hypertension is a quantitative trait, not a disease.
We typically find that hypertension co-occurs with rare diseases such as fibromuscular dysplasia, hyperaldosteronism, and various channelopathies; and common diseases such as metabolic syndrome, stroke, and left ventricular hyperplasia. Fibromuscular dysplasia is a rare condition of arteries wherein pathological growth of the artery's muscular wall produces a functional narrowing of the artery at the dysplastic site. Fibromuscular dysplasia occurs most often in young-to-middle aged women, but cases have occurred at every age and in either gender. Its cause is unknown. When fibromuscular dysplasia occurs in a renal artery, the blood flow to the kidney distal to the point of narrowing is reduced, thus producing an orchestrated physiological response of the renin-angiotensin-aldosterone system that produces hypertension.
Here is how the renin-angiotensin-aldosterone system works. Specialized cells located at the root of the glomeruli (i.e., the juxtaglomerular cells) release renin into the general circulation when the blood pressure drops. Renin is involved in a pathway that produces a powerful vasoconstrictor (i.e., angiotensin II) in the lungs. This same vasoconstrictor stimulates the adrenal cortex to secrete aldosterone (part of the mineralcorticoid system), which causes the kidney to increase its absorption of sodium and water; thus increasing the volume of fluid in the body. Increased blood volume produces an increase in blood pressure. In summary, when fibromuscular dysplasia reduces the blood floow to the kidney, the kidney responds as if there were a system-wide drop in blood pressure, setting into motion a two connected pathways that increase blood pressure. Because the hypertensive response does not "turn off" the localized hypotensive effect of fibromuscular dysplasia, the renin-angiotensin-aldosterone response stays "on" permanently, contributing to ever-worsening hypertension.
Observations of hypertension resulting from fibromuscular dysplasia of the renal artery, would suggest that variants of any components of the renin, angiotensin, or aldosterone system could contribute to quantitative alterations in blood pressure. As it happens, most of the rare monogenic and Mendelian forms of hypertension are associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules, resulting in increased retention of sodium and to an increased volume of body fluid, and the enlistment of the mineralcorticoid system (6), (7), (8), (9), (1).
Rare causes of hypertension dovetail with medically proven methods for treating and preventing common hypertension. Standard therapies for treating hypertension include drugs that target the angiotensin pathway (i.e., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and diuretics. The mainstay of prevention is dietary salt reduction (10).
Genome wide association studies have yielded several dozen genes associated with commonly occurring hypertension (11), (2). These associated genes seem to account for a very small portion of the occurences of hypertension in the general population (11). The function of the majority of the associated genes is unknown at present.
There are numerous genetic and environmental causes of hypertension, targeting a wide variety of cellular pathways and anatomic sites. As examples, the different causes of hypertension may include: over-activity of the renin-angiotensin system; defects at various sites of the renal tubule, arterial wall pathology; and increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease produce hypertension through the same, final pathway: increased net salt balance, leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure (1). Because all causes of hypertension produce an increase in net salt balance, almost all individuals with hypertension will respond to treatment with diuretics such as hydrochlorothiazide or furosemide, that reduce the reabsorption of sodium in the kidneys. A common, final mechanism accounting for all causes of hypertension, is an example of disease convergence. Disease convergence is an extremely important concept, as it provides an opportunity to treat many different diseases with a single medication, if they converge to the same pathway.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, hypertension, jules j berman
References:
[1] Lifton RP, Gharavi AG, Geller DS. Molecular Mechanisms of Human Hypertension. Cell 104:545-556, 2001
[2] International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-109, 2011.
[3] Fisher, RA. The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb 52:399-433, 1918.
[4] Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nature Biotechnology 30:1095-1106, 2012.
[5] Visscher PM, McEvoy B, Yang J. From Galton to GWAS: quantitative genetics of human height. Genet Res 92:371-379, 2010.
[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.
[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.
[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.
[9] Warnock DG. Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci 322:302-307, 2001.
[10] Hideaki Nakagawa H, Katsuyuki Miura K. Salt reduction in a population for the prevention of hypertension.Environ Health Prev Med 9:123-129, 2004.
[11] Cowley AW Jr, Nadeau JH, Baccarelli A, Berecek K, Fornage M, Gibbons GH, et al. Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. Hypertension 59:899-905, 2012
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