When Rare Diseases and Common Diseases Converge to the Same Clinical Picture

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.

In yesterday's blog, we discussed by a rare disease and a common disease may both have the same clinical presentation, a phenomenon that I call disease convergence. The short explanation for disease convergence is that there are a limited number of ways that the body can respond to malfunctions.

Here is an excerpt from Chapter 10, in which disease convergence is discussed:

Hypertension is another excellent example of convergence toward a common phenotype. As discussed in Section 5.4, there are numerous genetic and environmental causes of hypertension. The causes of hypertension may include overactivity of the renin–angiotensin system, or channel defects at various sites of the renal tubule, or arterial wall pathology, or increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease converge onto one physiologic pathway: increased net salt balance leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure [8]. Regardless of the underlying mechanism leading to an individual’s hypertension, diuretics such as hydrochlorothiazide or furosemide, which reduce the reabsorption of sodium in the kidneys, will almost always lower blood pressure. We see a similar phenomenon with rare and common causes of diabetes. Extremely rare single gene diabetes, including HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, is controlled with sulfonylurea, the same drug used to treat common type 2 diabetes. The cause of monogenic diabetes is quite different from the cause of common type 2 diabetes, but their pathways converge; and all these diseases respond to the same treatment [9].

Some of the rare diseases exhibit convergence with one another. For example, 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 in the mechanism whereby the epidermis is anchored onto the underlying dermis. Blisters are formed in locations where the epidermis lifts off the dermis, usually at sites of friction. 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 lies between the epidermis and the dermis. Regardless of the underlying cause, all variants of epidermolysis bullosa converge to a blistering phenotype.

10.1.3 Rule—A large set of cellular defects accounts for a relatively small number of possible pathologic conditions. Brief Rationale—In any complex system, there are a limited number of functional parts, but each functional part can break down due to a vast number of possible defects.

We can see that nothing in the universe is ever as chaotic as we might expect from the complexity of the individual elements of the system. Despite the enormous number of atoms in the universe, there seem to be just a few dozen types of cosmological bodies (e.g., stars, planets, black holes). These bodies assemble into galaxies that seem to have a relatively narrow array of shapes and sizes. In the case of biological systems, complex processes settle for a limited number of outcome categories.

10.1.4 Rule—Regardless of the complexity of a system, the outcomes are typically repeatable and stable.
Brief Rationale—All existing biological systems, despite their complexity, converge toward stability. If a biological system were unstable, it would cease to exist.

The phenomenon of convergence may explain some of the genetic complexity that seems to characterize many, if not all, of the common diseases. When there are hundreds or thousands of gene variations that are associated with one disease, it is likely that all these different genes contribute to a limited range of available disease pathways. In diseases that have a complex genetic etiology, it makes sense to examine the pathways that converge to a final clinical phenotype, rather than to try to understand the individual contribution from each variant gene.

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: convergence, disease convergence, orphan diseases, orphan drugs, drug development, common diseases, complex diseases, rare disease models of common diseases, disease pathway, complex diseases, common diseases, disease phenotype, pathogenesis, disease pathway

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