Links to Rare Disease Posts

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.

For today, I've listed my posts from prior years, featuring the rare diseases.

Phenocopy Mimics of Rare Diseases: Lessons for the Common Diseases

Phenocopy Diseases: Their Relationship to Rare Diseases and Common Diseases

What Rare Diseases Teach Us About the Cellular Basis of Aging

Disease Complexity: Rare Diseases and Common Diseases

Case Reports of Rare Diseases Have General Value

When Rare Diseases and Common Diseases Converge to Same Clinical Picture

Rare Diseases and Common Diseases can Converge to the Same Clinical Conditions

Rare Disease Legislation in the U.S.

Definition of Rare Disease

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Improving Clinical Trials by Focusing on Rare Diseases

Rare Diseases of Unknown Origin

Rare Diseases are Sentinels for the Common Diseases

Biological Differences between Rare Cancers and Common Cancers

Rare Diseases are Biologically Different from Common Diseases

Rare Cancers are Biologically Different from Common Cancers

Rare Cancers

Clinical Trials and Rare Diseases

Rules for the Rare Diseases

The Rationale for Funding Rare Disease Research

New Book Explains the Importance of Rare Disease Research

- Jules Berman

key words: rare diseases, zebra diseases, orphan drugs, common diseases, pathology, principles of disease, pathogenesis, orphan diseases, complex diseases, genetics of disease, molecular biology of disease, epidemiology, sentinel, rare disease research, rare disease organizations, importance of rare diseases, funding for rare diseases, Jules J. Berman, Ph.D., M.D.

Rare Diseases and Common Diseases can Converge to the Same Clinical Conditions

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is a short excerpt from Chapter 10.

As applied to diseases, convergence occurs when different genes, cellular events, exposures, and pathogenetic mechanisms all lead to a similar clinical phenotype. Convergence is found in common diseases and in rare diseases. In the case of systemic responses to injury, convergence may have an evolutionary origin. For example, humans have evolved to respond in an orchestrated way to a variety of pathologic stimuli. Various antigens can stimulate an orchestrated acute allergic response that may be identical for a wide variety of antigens (hives, bronchial constriction, puffy eyes). Likewise, humans have evolved to a systemic response to local infection that is specific for our species [7]. Convergence is observed in all the rare diseases that have genetic heterogeneity, either allelic heterogeneity or locus heterogeneity (see Section 9.3). In these cases, many underlying genetic causes yield the same clinical phenotype.

10.1.2 Rule—Regardless of the path taken, many pathologic processes will converge to the same pathologic condition.
Brief Rationale—There are a limited number of ways that the body can respond to malfunctions.

Think about all the things that can go wrong with your car. The engine can stop, the fuel system can be interrupted, the battery may die, the brakes may fail, any of the four tires can flatten, the headlights may not work, the electrical system may suffer a circuit shortage, and so on. It seems like a long list, but it is not. Maybe a dozen common problems account for the vast majority of car problems. Add these to a few dozen less likely problems, and you have a listing that would cover 99% of automobile repair issues. Every auto repairman knows that there are a limited number of systems in the car that can go bad. Repairs are relatively easy if the repairman can determine the system or part that is at fault. Whereas the number of different auto problems is limited, the number of events that can lead to these problems is virtually infinite. An auto repairman knows that for every engine breakdown, there might be thousands of possible causes. A non-functioning engine can be corrected by taking out the bad engine and putting in a new engine. If he is a very good repairman, he will determine whether a problem in a different system (e.g., the fuel injector) was indirectly responsible for the engine failure. Diagnostic tools should determine when a defect in one system is responsible for a defect in another system. Humans, like automobiles, are highly complex. Nonetheless, there are a limited number of problems that can occur in a complex organism. Heart attacks exemplify pathological convergence. Many different pathological processes can lead to the blockage of a coronary artery, such as: atherosclerotic plaque, hypertrophy of the arterial wall, spasms of the artery, acute infection of the artery, thrombus formation within the artery, arterial tear or dissection, developmental defects resulting in narrowing. Genes and environment contribute to these mechanisms. In the end, they can all produce one clinical phenotype; the all-too-common heart attack.

In chapter 10, we explore disease convergence, and explain why rare diseases and common diseases may sometimes converge to the same clinical phenotype. In many cases, treatments developed for a rare disease will be effective against a common disease that shares its convergent pathway (example, rare causes of hypertension and common causes of hypertension all responding to to the same treatment regimens).

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare disease, rare disease research, rare diseases, orphan diseases, orphan drugs, drug development, common diseases, complex diseases, rare disease models of common diseases

Rare Disease Legislation in the U.S.

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is a short excerpt from Chapter 14.

Many countries have passed legislation ensuring that the rare diseases receive research funding, that pharmaceutical companies are encouraged to produce medications for the rare diseases, and that individuals and families receive necessary medical and emotional support. In the U.S., some of the most important political milestones have been the following:

- Public Law 97-414, the Orphan Drug Act of 1983 defines rare diseases and provides sponsors of drugs intended to treat rare diseases with protection from competition (i.e., 7 years of market exclusivity), tax credits, and various other incentives.

- Public Law 101-629, the Safe Medical Devices Act of 1990 provides incentives and exemptions for devices, much as prior legislation covered drugs. The Act applies to devices to treat or diagnose diseases affecting fewer than 4000 individuals [3].

- Public Law 105-115, the FDA Modernization Act of 1997 grants an exemption for orphan drugs from drug approval application fees that would otherwise apply [3]. 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 107-280, the Rare Diseases Act of 2002 directed the National Institutes of Health (NIH) to establish an Office of Rare Diseases and, through this office, to support regional centers of excellence or clinical research into the rare diseases [4]. The Act also increased funding for the development of diagnostics and treatments for the rare diseases [5].

- Public Law 108-155, the Pediatric Research Equity Act of 2003 is a somewhat ambivalent law that requires applications for new drugs to test for safety and effectiveness in relevant pediatric populations, while providing full and partial waivers from the law when such testing is considered impractical.

- Public Law 110-233, the Genetic Information Nondiscrimination Act of 2008 makes it illegal to discriminate against employees or applicants for employment based on their personal genetic information (i.e., whether individuals or family members have a genetic disease or condition, or whether individuals are at risk of developing a disease or condition based on genetic testing).

- Public Law 111-80, the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 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 [3].

- Public Law 111-148, the Patient Protection and Affordable Care Act of 2010, known widely as ObamaCare requires insurance companies to cover all applicants regardless of pre-existing conditions. As generally interpreted, the Act will eliminate lifetime caps on benefits.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare disease legislation, rare disease laws, u.s. support for rare diseases, rare disease research, rare diseases, orphan diseases, orphan drugs, fda, drug development

Definition of Rare Disease

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Short excerpt from the Introduction chapter:

“The beginnings and endings of all human undertakings are untidy.”
—John Galsworthy

In the U.S., Public Law 107-280, the Rare Diseases Act of 2002 states: “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 one case for every 1570 persons. This is not too far from the definition recommended by the European Commission on Public Health; fewer than one in 2000 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” (see Section 14.2). Unfortunately, it is very difficult to know, with any certainty, the specific prevalence or incidence of any of the rare diseases (see Glossary items, Prevalence, Incidence). 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, in 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 7000 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 these, 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 3000 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 6000 rare types of cancer [5–8]. Regarding the rare infectious diseases, well over 1400 different infectious organisms have been reported in the literature [9]. A single infectious organism 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). When we add in the many rare nutritional, toxic, and degenerative diseases that occur in humans, the consensus estimate of the number of rare diseases seems woefully inadequate. Nonetheless, the low-ball “7000” number tells us that there are many rare diseases; way too many for any individual to fully comprehend.

Later chapters explain that the rare diseases, as a group, share a common set of biological properties that distinguish them from the common diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare diseases, orphan drugs, orphan diseases, common diseases, definition of rare diseases, rare disease organizations, organizations for rare diseases, rare disease research

Rules for the Rare Diseases

It's not a numerical accident that rare diseases are rare. Biological processes account for the rarity of certain diseases, and for the commonality of common diseases. When writing Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, I wanted to establish a set of biological principles that would extend to all the rare diseases and that would help explain the fundamental differences between rare diseases and common diseases.

Biological principles are much like geometric axioms. Once you have your set of principles, you should be able to construct conclusions, rules, and predictions about the behavior of the biological system to which the principles apply. Accordingly, I sprinkle the text of the book with lots of "rules" that follow logically from the first principles of the rare diseases.

The term "rule", in this context, means observations that are generally true. Biology is more messy than geometry. In the book, when the rules are discussed, I might include counter-examples and constraints. The rules are primarily intended to encourage readers to think critically about the subject matter.

There are more than 125 biological "rules" of rare diseases listed through the book. Each rule is followed by a very brief rationale. The rationale for each rule is fully developed in the chapters. I thought it would be fun to construct a button that searches the book, and pulls out a rule randomly from the text, for display in a window. By repeatedly hitting the button, each time it refreshes itself, you can read all the rules contained in the book (if you'd like).

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

The Rationale for Funding Rare Disease Research

This week, my latest book entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Academic Press, an imprint of Elsevier.

The book builds a rationale for increased funding for the rare diseases, and begins with the assertion that it has been much easier to find effective targeted treatments for the rare diseases than for the common diseases. Furthermore, treatments that are effective against rare diseases almost always find a place in the treatment of one or more common diseases. These assertions are not based on wishful thinking, and they are not based on extrapolation from a few past triumphs wherein some treatment overlap has been found in rare and common diseases. These assertions are based on the general finding that rare diseases encapsulate the many biological pathways that drive, in the aggregate, our common diseases. This simple theme is described and justified throughout the book. A smart way to fund medical research is to increase funding for the rare diseases, with the ultimate goal of curing the common diseases.

TABLE OF CONTENTS

Part I. Understanding the Problem.

Chapter 1. What are the Rare Diseases, and Why do we Care?

Chapter 2. What are the Common Diseases?

Part II. Rare lessons for Common Diseases.

Chapter 3. Aging.

Chapter 4. Metabolic Diseases.

Chapter 5. Diseases of the Heart and Vessels.

Chapter 6. Infectious Diseases and Immune Disorders.

Chapter 7. Cancer.

Chapter 8. Gastrointestinal and Renal Disorders.

Part III. Fundamental Relationships Between Rare and Common Diseases.

Chapter 9. All Diseases are Complex

Chapter 10. Rare Diseases and Common Diseases: Understanding their fundamental differences.

Chapter 11. Rare Diseases and Common Diseases: Understanding Their Relationships.

Chapter 12. Future Directions.

Glossary.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

Jules J. Berman, Ph.D., M.D.

tags: biology of rare diseases, common diseases, genetic disease, orphan diseases, orphan drugs, rare disease organizations, rare disease research, rare diseases, rare disease funding, rare disease research, funding for rare diseases, importance of rare diseases, funding opportunities, books about rare diseases, books about orphan drugs, orphan drug development

New Book Explains the Importance of Rare Disease Research

This week, my latest book entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. This book builds the case that the best way to advance our understanding of the common diseases is to focus our attention on the rare diseases.

The following text is excerpted from the book's Preface.

In biology, there are no outliers; no circumstances that are rare enough to be ignored. Every disease, no matter how rare, operates under the same biological principles that pertain to common diseases. In 1657, William Harvey, the noted physiologist, wrote: "Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease.

We shall see that the rare diseases are much simpler, genetically, than the common diseases. The rare disease can be conceived as controlled experiments of nature, in which everything is identical in the diseased and the normal organisms, except for one single factor that is the root cause of the ensuing disease. By studying the rare diseases, we can begin to piece together the more complex parts of common diseases.

The book has five large themes that emerge, in one form or another, in every chapter.

1. In the past two decades, there have been enormous advances in the diagnosis and treatment of the rare diseases. In the same period, progress in the common diseases has stagnated. Advances in the rare diseases have profoundly influenced the theory and the practice of modern medicine.

2. The molecular pathways that are operative in the rare diseases contribute to the pathogenesis of the common diseases. Hence, the rare diseases are not the exceptions to the general rules that apply to common diseases; the rare diseases are the exceptions upon which the general rules of common diseases are based.

3. Research into the genetics of common diseases indicates that these diseases are much more complex than we had anticipated. Many rare diseases have simple genetics, wherein a mutation in a single gene accounts for a clinical outcome. The same simple pathways found in the rare diseases serve as components of the common diseases. If the common diseases are the puzzles that modern medical researchers are mandated to solve, then the rare diseases are the pieces of the puzzles.

4. If we fail to study the rare diseases in a comprehensive way, we lose the opportunity to see the important biological relationships among diseases consigned to non-overlapping sub-disciplines of medicine.

5. Every scientific field must have a set of fundamental principles that describes, explains, or predicts its own operation. Rare diseases operate under a set of principles, and these principles can be inferred from well-documented pathologic, clinical, and epidemiologic observations.

Today, there is no recognized field of medicine devoted to the study of rare diseases; but there should be.

Content and Organization of the Book

There are three parts to the book. In Part I (Understanding the Problem), we discuss the differences between the rare and the common diseases, and why it is crucial to understand these differences. To stir your interest, here are just a few of the most striking differences: 1) Most of the rare diseases occur in early childhood, while most of the common diseases occur in adulthood; 2) The genetic determinants of most rare diseases have a simple Mendelian pattern, dependent on whether the disease trait occurs in the father, or mother, or both. Genetic influences in the common diseases seldom display Mendelian inheritance; 3) Rare diseases often occur as syndromes involving multiple organs through seemingly unrelated pathological processes. Common diseases usually involve a single organ or involve multiple organs involved by a common pathologic process.

The most common pathological conditions of humans are aging, metabolic diseases (including diabetes, hypertension, and obesity), diseases of the heart and vessels, infectious diseases, and cancer. Each of these disorders is characterized by pathologic processes that bear some relation to the processes that operate in rare diseases. In Part II (Rare lessons for Common Diseases), we discuss the rare diseases that have helped us understand of the common diseases. Emphasis is placed on the enormous value of rare disease research. We begin to ask and answer some of the fundamental questions raised in Part I. Specifically, how is it possible for two diseases to share the same pathologic mechanisms without sharing similar genetic alterations? Why are the common diseases often caused, in no small part, by environmental (i.e., non-genetic) influences, while the rare disease counterparts are driven by single genetic flaws? Why are the rare diseases often syndromic (i.e. involving multiple organs with multiple types of abnormalities and dysfunctions), while the so-called complex common diseases often manifest in a single pathological process? In Part II, we will discuss a variety of pathologic mechanisms that apply to classes of rare diseases. We will also see how these same mechanisms operate in the common diseases. We will explore the relationship between genotype and phenotype, and we will address one of the most important questions in modern disease biology: "How is it possible that complex and variable disease genotypes operating in unique individuals will converge to produce one disease with the same biological features from individual to individual?"

In Part III (Fundamental Relationships Between Rare and Common Diseases), we answer the as-yet unanswered questions from Part I, plus the new questions raised in Part II. The reasons why rare diseases are different from common diseases are explained. The convergence of pathologic mechanisms and clinical outcome observed in rare diseases and common diseases, as it relates to the prevention, diagnosis, and treatment of both types of diseases, is described in detail.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.